EP1503978A1 - Process for the manufacture of sertraline - Google Patents

Process for the manufacture of sertraline

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Publication number
EP1503978A1
EP1503978A1 EP02734991A EP02734991A EP1503978A1 EP 1503978 A1 EP1503978 A1 EP 1503978A1 EP 02734991 A EP02734991 A EP 02734991A EP 02734991 A EP02734991 A EP 02734991A EP 1503978 A1 EP1503978 A1 EP 1503978A1
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EP
European Patent Office
Prior art keywords
dichlorophenyl
mixture
process according
cis
sertraline
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EP02734991A
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German (de)
French (fr)
Inventor
Jiri Stohandl
Jaroslav Frantisek
Zdenek Zapadlo
Marta Stohandlova
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates to the process for sertraline manufacture by the reductive amination of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)- naphthalenone in pure separated geometric cis and trans isomers.
  • the conversion of trans to cis isomer and the preparation of polymorph of 1S-cis isomer follows.
  • Another method describes preparation of aminoxide by reaction of naphthalenone with N-methylhydroxylamine followed by hydrogenation of the reaction product on Raney nickel catalyst (US 6,034,274).
  • the catalytic hydrogenation provides a higher yield of cis isomer than reduction in homogeneous phase but requires a special hydrogenation apparatus.
  • the contamination of the product by heavy metals may occur.
  • the whole procedure is a two-step process with an unstable intermediate and with a rather complicated isolation of the final product.
  • N-methyl-N- 1 ,2,3,4-tetrahydro-1-naphthylformamides are hydrolyzed and then isolated as salts from the base by selective crystallization in the presence of acid.
  • the reaction is carried out in the temperature range of 150-220 °C.
  • the reaction of 1-naphthol with 1 ,2-dichlorobenzene catalyzed by aluminum chloride claimed in the mentioned patent application is not new.
  • Hydrolysis of the formamides is carried out at boiling point under reflux in the mixture of Ci - C 8 alcohols with water in alkaline media, e.g. in butanol with potassium hydroxide.
  • the catalysis by means of titanium tetrachloride is connected with safety hazard (a storming dissociation in water and aggressive dissociation products).
  • safety hazard a storming dissociation in water and aggressive dissociation products.
  • the reduction by hydrides increases isolation difficulties resulting in lower yields.
  • the asymmetric syntheses of sertraline intermediate are not advantageous being multi-steps with a relatively low final yield and with demand on expensive row materials.
  • racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)naphthalenone (I) is manufactured by the method analogous to prior art (see: Zhur. Org. Khimii 18(4), 870-878 (1982), CA 76 #140, 2865 (1972), Houben-Weyl, Vll/2b, 1710), US 5,019,655.
  • Salts of metals listed above are added to increase the yield and decrease the content of undesirable reaction products.
  • the reductive amination can be carried out alternatively by methylammonium formate in the same media as listed above instead of a mixture of methylammonium chloride or methylammonium sulfate with sodium formate.
  • the solvent and salts are extracted with water in one step procedure after the reaction has been completed.
  • the product is extracted into chloroform or ethyl acetate.
  • the organic layer is washed out with water, dried and evaporated in vacuo.
  • the evaporated residue is dissolved in ethanol.
  • a half portion of hydrochloric acid (by volume) (1 : 1 , i.e., 5.5M) is added to the solution.
  • the mixture is refluxed.
  • trans isomer hydrochloride (Mb) remains dissolved whereas cis-isomer hydrochloride (lla) crystallizes from the solution and is washed and dried on the air.
  • Ethyl acetate is added to the filtrate evaporated almost to dryness and then it crystallizes under a lowered temperature.
  • Yield of the both isomers, cis and trans is 96.5 % whereof the cis isomer fraction contains 98.1 % of cis and 1.8 % of trans isomer.
  • the fraction of trans isomer contains 92.5 % of trans and 7.2 % of cis isomer (HPLC), m.p. is the same as given in literature (J. Med. Chem.
  • the hydrolysis is carried out in the same step without isolation of the intermediates.
  • the isomers lla and lib are readily obtained.
  • the purity of lla and lib is 98 % and 92 %, respectively; whereof the amount to 99.6 % represents the other of the two geometric isomers.
  • the reductive amination of naphthalenone (I) can be carried out by a mixture of methylammonium formate and triethylammonium formate in N-methylformamide medium under catalysis of salts (M a X b ) listed above.
  • the reaction temperature can be reduced at about 20 to 30 °C under these conditions.
  • the yield of 1S.4S enantiomer can be increased by the conversion of lib to lla.
  • the reductive amination product containing 92 % of trans and 8 % of cis isomer can be converted to base by adding dried triethylamine to the suspension of hydrochloride in tetrahydrofuran. The precipitate of triethylamine hydrochloride is filtered, washed out with tetrahydrofuran and dried.
  • Sodium hydride in a form of 60 % oily suspension and a fine powder of tertiary potassium butylate prepared by dissolving potassium in tertiary butanol (with a major part of solvent evaporated) are added to filtrate.
  • Tertiary potassium butylate provided the highest yield from all the basic catalysts.
  • a flask with the solution fitted with air condenser equipped with by-pass for nitrogen inlet is heated quickly to 50 °C under nitrogen atmosphere and intensive stirring. The reaction does not require 4 to 48 hours for completion at optimum temperature as stated in US 5,082,970. To reach the equilibrium, it takes only 4 to 10 minutes; moreover, to dissolve the catalyst, a short heating to 50 is sufficient.
  • the low reaction order ( ⁇ 1) and low activation energy has the consequence that the portion of catalyst and reaction temperature influences the equilibrium only to a small extent.
  • tertiary potassium butylate is dissolved and the equilibrium is reached in another five- minutes interval.
  • the solution is cooled under nitrogen atmosphere and then 250 ml of water and 50 g of sodium chloride are added. Two layers are formed; the organic layer is evaporated in vacuo. Since tetrahydrofuran has been in contact with a strong alkali at elevated temperature, there is no danger of increasing level of organic peroxides during evaporation.
  • Desired 1S,4S enantiomer is separated by means of a known in the art procedure of crystallization with chiral D(-)mandelic acid. Treating the mandelate suspension in ethyl acetate with 10-% sodium hydroxide solution leads to complete dissolution. The layers are separated. The organic layer is dried and evaporated. Obtained colorless oil is stirred with 2-propanol and precipitated in a 1.25 molar excess of 3M 2-propanolic hydrochloric acid. A slow addition of the acid yields a very viscous gel. After two hours of stirring diisopropyl ether is added. Intensive stirring causes a rapid recrystallization.
  • Any polymorph can be converted to polymorph Fll in a following way: a dried sertraline hydrochloride is dissolved in threefold (w/v) of N,N- dimethylformamide p. a. at the temperature of 80 - 90 °C. The solution cools spontaneously to 70 °C. Acetone p. a. is slowly added to the mixture under intensive stirring. Precipitated crystals are gelatinous and dense and recrystallize after short stirring. Polymorph is filtered through sinter S3 or S4 and dried at 50 - 60 °C in vacuo.
  • the reaction mixture is cooled to 25 °C and poured on ice. 35 ml of hydrochloric acid and 900 ml of chloroform are added. The layers are separated in a separating funnel and the aqueous layer is washed with a small portion of chloroform repeatedly. The organic extracts are combined and washed twice with water and the organic layer is dried over anhydrous sodium sulfate. Chloroform is distilled out under atmospheric pressure. The excess of 1 ,2-dichlorobenzene is distilled out at 100 °C in vacuo. 1 ,2-dichlorobenzene is recuperated and can be used in another batch.
  • the ratio of 3,4-dichlorophenyl- and 2,3-dichlorophenylnaphthalenone isomers is determined by HPLC with UV detection. The analysis is carried out on column Zorbax SB C-18, 250 x 4.6 mm under following conditions: mobile phase: methanol-water 67 : 33, flow rate: 1 ml/min, column temperature: 40 °C, wavelength: 230 nm.
  • the naphthalenone isomer ratio is calculated from the ratio of peak areas. (Response factors are approximately the same for the both isomers at the applied wavelength).
  • Adrien et al. US 5,019,655) declared 98-99 % purity (GC) of naphthalenone (I) obtained under similar conditions.
  • 2,3-dichlorophenyl isomer is almost the same.
  • the colorless product is undergone the fractional crystallization from ethanol.
  • a half of crystalline product is dissolved in a sixfold portion (w/w) of 96-% boiling ethanol and then cooled slowly to crystallize.
  • the mixture is inoculated with a small portion of nuclei at temperature of 60 °C and is left stayed for 6 hours, filtered and washed with a small portion of ethanol.
  • the second part of crude material is introduced to the mother liquor and recrystallized identically, filtered and washed.
  • the both parts of product are combined and dried. The same procedure is carried out twice so that the content of the 2,3-dichlorophenyl isomer has dropped under a critical limit.
  • the yield is 86 %, m.p. 102-104 °C. All the mother liquors are combined and evaporated to a quarter of the initial volume. The crystalline material is isolated the next day, filtered and added to another crude charge (the purity of that is similar).
  • the mixture is heated to 145 °C and the temperature is kept in the range of 145 -155 °C for 10 hours.
  • the reaction can be interrupted by cooling under 100 °C any time and started again by reheating.
  • the mixture is cooled down after finishing the reaction.
  • the reaction mixture is protected under nitrogen atmosphere until the temperature has dropped below 100 °C.
  • the solvent and salts are washed out with approximately 700 ml of water in one step.
  • the product is extracted with 700 ml of chloroform and/or ethyl acetate.
  • the layers are separated.
  • the organic layer is dried over sodium sulfate and evaporated to dryness.
  • the evaporated residue is dissolved in 480 ml of ethanol and 240 ml (i.e.
  • the yield is 57 g of cis isomer and 62.5 g of trans isomer as hydroch rides (i.e. 96.5 %).
  • Cis isomer fraction contains 98.1 % of cis and 1.8 % of trans isomer.
  • Trans isomer fraction contains 92.5 % of trans and 7.2 % of cis isomer (HPLC), m.p. are the same as in the literature (J. Med. Chem. 1984, 27, 1508-1515).
  • 60 g of mixed product of (lla) and (lib) (the content of 92 % of trans isomer and 8 % of cis isomer) from the reductive amination is converted to base as follows: 30 ml triethylamine (dried over molecular sieve A3) is added to the suspension of hydrochlorides in 500 ml of tetrahydrofuran and is stirred for 0.5 - 1 hour. The suspension is filtered and washed twice with a small portion of tetrahydrofuran. 3.8 g of sodium hydride (in a form of 60 % of solid in mineral oil suspension) and 18 g of fine powdered potassium tert- butylate is added to the filtrate.
  • Potassium tert-butylate is prepared by dissolving potassium in tert-butanol and evaporating the solvent (it still contains approximately 25-30 % of tert-butanol).
  • the reaction flask is connected to reflux with by-pass for nitrogen inlet and heated quickly to 50 °C under intensive stirring under nitrogen atmosphere.
  • Within five minutes potassium tert-butylate is dissolved almost completely and the equilibrium is reached in the next five minutes.
  • the solution is cooled freely under nitrogen atmosphere. 250 ml of water and 50 ml of saturated aqueous sodium chloride solution is added. The layers are separated and the organic layer is evaporated to dryness.
  • Example 7 The cis isomer (60 %, i.e., 36 g) is recrystallized as given in Example 4 and the product is combined with cis isomer obtained from the synthesis.
  • the mother liquor with 40 % of trans isomer has the same concentration as the original one. They are combined and reused in another charge.
  • the crystalline mandelate is filtered off, washed with a small portion of diethyl ether and dried on the air (the yield is 16 g, m. p. 187-189 °C).
  • Mandelate is converted to base by similar work up as racemic hydrochloride (lla). Only 200 ml of 2.5M sodium hydroxide and 500 ml of ethyl acetate are used. The organic layer is dried and evaporated. The product is dissolved in 2-propanol and precipitated with gaseous hydrogen chloride. The excess of hydrogen chloride is stripped by nitrogen. The resulting pH is to be 2 (universal indicator paper). The isolated compact gel has been stirred for 2 hours.

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Abstract

Process for the preparation of sertraline by reductive amination of racemic 4-(3, 4-dichlorophenyl)-3, 4-dihydro-1-(2H)-naphthalenone, carried out as one- reaction-vessel process without isolation of intermediates, in the form of pure separated cis and trans isomers, the way of conversion of trans isomer to cis isomer and preparation of FII polymorph of 1S-cis isomer from any other polymorph.

Description

PROCESS FOR THE MANUFACTURE OF SERTRA INE
Field of the Invention
The invention relates to the process for sertraline manufacture by the reductive amination of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)- naphthalenone in pure separated geometric cis and trans isomers. The conversion of trans to cis isomer and the preparation of polymorph of 1S-cis isomer follows.
State of the Art
Several processes for the preparation of 4-(3,4-dichlorophenyl)-1 , 2,3,4- tetrahydro-N-methyl-1-naphthaleneamine hydrochloride, the generic name of sertraline, possessing an antidepressant activity (5-HT serotonin reuptake inhibitor), e.g. the 1-naphthalenone condensation with methylamine in the presence of titanium tetrachloride (J. Med. Chem. 1984, 27, 1508-1515 or US 4,855,500) are known. The resulting ketimine was reduced by sodium borohydride. Another method comprises a molecular sieve as the condensation agent with reduction carried out by the catalytic hydrogenation on palladium catalyst (US 4,855,500).
Another method describes preparation of aminoxide by reaction of naphthalenone with N-methylhydroxylamine followed by hydrogenation of the reaction product on Raney nickel catalyst (US 6,034,274). The catalytic hydrogenation provides a higher yield of cis isomer than reduction in homogeneous phase but requires a special hydrogenation apparatus. Moreover the contamination of the product by heavy metals may occur. In addition the whole procedure is a two-step process with an unstable intermediate and with a rather complicated isolation of the final product.
The process cited in the literature (Cervinka et al., Coll. Czech Chem. Commun., 38 156 (1973)) is adapted for preparation of racemic 4-(3,4- dichlorophenyl)-N-methyl-1 ,2,3,4-tetrahydro-1-naphthylamine from 3,4- dichlorophenyl-1-tetralone in patent application EP 0947499. The starting 4-(3,4-dichlorophenyl)-3,4-dihydro-1 -(2H)-naphthalenone contains nearly 20 % of 4-(2,3-dichlorophenyl) isomer in this case, which causes problems in next synthetic steps and moreover decreases the total yield of racemic sertraline almost to 22 %, which is unacceptably low result. Process according to EP 0947499 uses the reaction of the mixture of 4-(3,4dichlorophenyl)-tetralone and 4-(2,3-dichlorophenyl)-tetralone with N-methylformamide in the presence of formic acid. Obtained N-methyl-N- 1 ,2,3,4-tetrahydro-1-naphthylformamides are hydrolyzed and then isolated as salts from the base by selective crystallization in the presence of acid. The reaction is carried out in the temperature range of 150-220 °C. The reaction of 1-naphthol with 1 ,2-dichlorobenzene catalyzed by aluminum chloride claimed in the mentioned patent application is not new. Hydrolysis of the formamides is carried out at boiling point under reflux in the mixture of Ci - C8 alcohols with water in alkaline media, e.g. in butanol with potassium hydroxide.
The catalysis by means of titanium tetrachloride is connected with safety hazard (a storming dissociation in water and aggressive dissociation products). The reduction by hydrides increases isolation difficulties resulting in lower yields. The asymmetric syntheses of sertraline intermediate are not advantageous being multi-steps with a relatively low final yield and with demand on expensive row materials.
Detailed Description of the Invention The process for the preparation of 4-(3,4-dichlorophenyl)-1 , 2,3,4- tetrahydro-N-methyl-1-naphthaleneamine (lla, lib) depicted in this invention is rather simple. There is neither hydrogenation by metal catalysts applied nor higher pressure or dehydration agents. The preparation of sertraline administrates a very high yield without impurities necessary to remove and/or dark colored tar residues. The reaction is performed without isolation of intermediates.
Precursor for the process for sertraline preparation according to this invention racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)naphthalenone (I) is manufactured by the method analogous to prior art (see: Zhur. Org. Khimii 18(4), 870-878 (1982), CA 76 #140, 2865 (1972), Houben-Weyl, Vll/2b, 1710), US 5,019,655.
1 ,2-dichlorobenzene reacts with 1-naphthol under catalysis of anhydrous aluminum chloride to produce racemic 4-(3,4-dichlorophenyl)-3,4-dihydro- 1-(2H)naphthalenone (I). The preparation was optimized to give the highest yield compared with literature data.
The process was carried out at low temperature so that the level of the interfering isomer formation was minimized because of the next reaction step. A crude beige crystalline product was obtained yielding 85 % (referred to 1-naphthol), m.p. 99-101 °C. Precursor (I) must be freed from impurities, especially the isomeric one prior to the reductive amination.
According to the invention wherein the reductive amination of 4-(3,4- dichlorophenyl)-3,4-dihydro-1-(2H)naphthalenone (I) is carried out in the presence of methylamine salts and alkali formate whereof the effective methylammonium formate is formed in situ, in medium of N-methylformamide and/or 1 ,2-dichlorobenzene. Salts of a common formula of MaXb are added. They dissolve partly in the reaction medium and thus increase the ionic strength. Diameter of the cation M+ must be relatively small e.g. lithium, beryllium, magnesium or aluminum cations. The anion X" can be halide, sulfate etc.
Salts of metals listed above are added to increase the yield and decrease the content of undesirable reaction products. The reductive amination can be carried out alternatively by methylammonium formate in the same media as listed above instead of a mixture of methylammonium chloride or methylammonium sulfate with sodium formate. The solvent and salts are extracted with water in one step procedure after the reaction has been completed. The product is extracted into chloroform or ethyl acetate. The organic layer is washed out with water, dried and evaporated in vacuo. The evaporated residue is dissolved in ethanol. A half portion of hydrochloric acid (by volume) (1 : 1 , i.e., 5.5M) is added to the solution. The mixture is refluxed. After the reaction has been completed, trans isomer hydrochloride (Mb) remains dissolved whereas cis-isomer hydrochloride (lla) crystallizes from the solution and is washed and dried on the air. Ethyl acetate is added to the filtrate evaporated almost to dryness and then it crystallizes under a lowered temperature. Yield of the both isomers, cis and trans, is 96.5 % whereof the cis isomer fraction contains 98.1 % of cis and 1.8 % of trans isomer. The fraction of trans isomer contains 92.5 % of trans and 7.2 % of cis isomer (HPLC), m.p. is the same as given in literature (J. Med. Chem. 1984, 27, 1508-1515). The hydrolysis is carried out in the same step without isolation of the intermediates. The isomers lla and lib are readily obtained. The purity of lla and lib is 98 % and 92 %, respectively; whereof the amount to 99.6 % represents the other of the two geometric isomers. The reductive amination of naphthalenone (I) can be carried out by a mixture of methylammonium formate and triethylammonium formate in N-methylformamide medium under catalysis of salts (MaXb) listed above. The reaction temperature can be reduced at about 20 to 30 °C under these conditions.
lla - cis (1S, 4S + 1 R, 4R) lib - trans (1S. 4R + 1 R. 4S) The yield of 1S.4S enantiomer can be increased by the conversion of lib to lla. The reductive amination product containing 92 % of trans and 8 % of cis isomer can be converted to base by adding dried triethylamine to the suspension of hydrochloride in tetrahydrofuran. The precipitate of triethylamine hydrochloride is filtered, washed out with tetrahydrofuran and dried. Sodium hydride in a form of 60 % oily suspension and a fine powder of tertiary potassium butylate prepared by dissolving potassium in tertiary butanol (with a major part of solvent evaporated) are added to filtrate. Tertiary potassium butylate provided the highest yield from all the basic catalysts. A flask with the solution fitted with air condenser equipped with by-pass for nitrogen inlet is heated quickly to 50 °C under nitrogen atmosphere and intensive stirring. The reaction does not require 4 to 48 hours for completion at optimum temperature as stated in US 5,082,970. To reach the equilibrium, it takes only 4 to 10 minutes; moreover, to dissolve the catalyst, a short heating to 50 is sufficient. The low reaction order (<1) and low activation energy has the consequence that the portion of catalyst and reaction temperature influences the equilibrium only to a small extent. Within five minutes tertiary potassium butylate is dissolved and the equilibrium is reached in another five- minutes interval. The solution is cooled under nitrogen atmosphere and then 250 ml of water and 50 g of sodium chloride are added. Two layers are formed; the organic layer is evaporated in vacuo. Since tetrahydrofuran has been in contact with a strong alkali at elevated temperature, there is no danger of increasing level of organic peroxides during evaporation. If it is not feasible to evaporate tetrahydrofuran immediately after the extraction, it is recommended to use 750 ml of water instead of 250 ml, and addition of 250 ml of chloroform. The layers are separated. The chloroform layer is washed out with water, dried over sodium sulfate and evaporated to dryness. Then, it is processed as the product of the reductive amination. The obtained light oil is dissolved in ethanol. 5.5M hydrochloric acid is added. The isolated cis isomer (60 %) is recrystallized and combined with the product resulting from the synthesis. Mother liquor with 40 % of trans derivative has the same concentration as the original one and therefore it can be combined in another charge resulting in full use of cis and trans isomers.
Desired 1S,4S enantiomer is separated by means of a known in the art procedure of crystallization with chiral D(-)mandelic acid. Treating the mandelate suspension in ethyl acetate with 10-% sodium hydroxide solution leads to complete dissolution. The layers are separated. The organic layer is dried and evaporated. Obtained colorless oil is stirred with 2-propanol and precipitated in a 1.25 molar excess of 3M 2-propanolic hydrochloric acid. A slow addition of the acid yields a very viscous gel. After two hours of stirring diisopropyl ether is added. Intensive stirring causes a rapid recrystallization. Any polymorph can be converted to polymorph Fll in a following way: a dried sertraline hydrochloride is dissolved in threefold (w/v) of N,N- dimethylformamide p. a. at the temperature of 80 - 90 °C. The solution cools spontaneously to 70 °C. Acetone p. a. is slowly added to the mixture under intensive stirring. Precipitated crystals are gelatinous and dense and recrystallize after short stirring. Polymorph is filtered through sinter S3 or S4 and dried at 50 - 60 °C in vacuo.
The process for sertraline manufacture according to the invention is easy and cheap even though the loss of undesirable enantiomer is approximately 50 %. Material costs are still more favorable than those by the enantioselective syntheses (asymmetrical) listed in patents.
Examples
Process for manufacture of cis- and trans-4-(3,4-dichlorophenyl)-1 , 2,3,4- tetrahydro-N-methyl-1-naphthaleneamine hydrochloride and sertraline hydrochloride from racemic naphthalenone according to the invention can be described in the following examples without limiting the scope of the invention. Example 1
Preparation of racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)- naphthalenone 1450 ml of 1 ,2-dichlorobenzene and 192 g of 1-naphthol (cca 1.33 mole) are introduced into a three-necked flask equipped with thermometer, stirrer, air condenser, and calcium chloride tube. 420 g of anhydrous aluminum chloride is slowly added (in 10 minutes) to the solution under constant stirring. Temperature is increased to 45 - 48 °C within short time, suspension is being solidified and stirring becomes difficult. After additional 15 minutes the catalytic complex suspension is liquefied and stirring becomes easy. Temperature has been kept at 60 °C under constant stirring for 6 hours.
The reaction mixture is cooled to 25 °C and poured on ice. 35 ml of hydrochloric acid and 900 ml of chloroform are added. The layers are separated in a separating funnel and the aqueous layer is washed with a small portion of chloroform repeatedly. The organic extracts are combined and washed twice with water and the organic layer is dried over anhydrous sodium sulfate. Chloroform is distilled out under atmospheric pressure. The excess of 1 ,2-dichlorobenzene is distilled out at 100 °C in vacuo. 1 ,2-dichlorobenzene is recuperated and can be used in another batch. After 1 ,2-dichlorobenzene has been removed to the constant weight, the oily residue (approximately 405 g) is cooled and 96-% ethanol (a portion that represents threefold of volume compared to the weight of product) is added and stirred (or better expose to ultrasonics) until it has crystallized completely. A crude crystalline product is filtered after 8 hours of standing, washed twice with a small portion of cool ethanol and dried on the air (or at 60 °C). 330 g of crude beige crystalline product is obtained yielding 85 % (referred to 1-naphthol), m.p. 99-101 °C. Example 2
The ratio of 3,4-dichlorophenyl- and 2,3-dichlorophenylnaphthalenone isomers is determined by HPLC with UV detection. The analysis is carried out on column Zorbax SB C-18, 250 x 4.6 mm under following conditions: mobile phase: methanol-water 67 : 33, flow rate: 1 ml/min, column temperature: 40 °C, wavelength: 230 nm. The naphthalenone isomer ratio is calculated from the ratio of peak areas. (Response factors are approximately the same for the both isomers at the applied wavelength). Adrien et al. (US 5,019,655) declared 98-99 % purity (GC) of naphthalenone (I) obtained under similar conditions. This result cannot be considered as the correct one. We have found that the ratio of isomers originated from the synthesis changes only slightly in a broad range of temperature (40 - 95 °C) and a broad ratio of reactants, and the resulting purity can hardly exceed 95 % after their complete resolution.
Example 3
Purification of Crude Crystalline Product of 4-(3,4-dichlorophenyl) 3,4- dihydro-1-(2H)-naphthalenone (I)
Purification of crude crystalline product (I) for the reductive amination is carried out as follows: the dried crude crystalline product is dissolved in a sixfold volume of acetone at the temperature close to b.p. of acetone and 8
% of activated charcoal is added (e.g. Norit). The mixture is left staying with occasional stirring for ten minutes and still hot is filtered. A filtrate is yellowish after refining. Acetone is evaporated to dryness. The colorless crystals are obtained, b.p. 100-102 °C, the yield is 94.5 %. The product is free from non-polar impurities, however, the content of the
2,3-dichlorophenyl isomer is almost the same. The colorless product is undergone the fractional crystallization from ethanol. A half of crystalline product is dissolved in a sixfold portion (w/w) of 96-% boiling ethanol and then cooled slowly to crystallize. The mixture is inoculated with a small portion of nuclei at temperature of 60 °C and is left stayed for 6 hours, filtered and washed with a small portion of ethanol. The second part of crude material is introduced to the mother liquor and recrystallized identically, filtered and washed. The both parts of product are combined and dried. The same procedure is carried out twice so that the content of the 2,3-dichlorophenyl isomer has dropped under a critical limit. After three recrystallization runs, the yield is 86 %, m.p. 102-104 °C. All the mother liquors are combined and evaporated to a quarter of the initial volume. The crystalline material is isolated the next day, filtered and added to another crude charge (the purity of that is similar).
Example 4
Reductive Amination of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)- naphthalenone (I)
105 g of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (I) with the content of 2,3-dichlorophenylderivative less than 0.16 % (purified by recrystallization) is dissolved in 230 ml of N-methylformamide in a one-liter two-necked flask equipped with air condenser, by-pass for nitrogen inlet, and thermometer. 4.5 g of lithium chloride, 49.5 g of anhydrous potassium formate, and 49.5 g of methylammonium hydrochloride is added to the solution. The mixture is heated to 145 °C and the temperature is kept in the range of 145 -155 °C for 10 hours. The reaction can be interrupted by cooling under 100 °C any time and started again by reheating. The mixture is cooled down after finishing the reaction. The reaction mixture is protected under nitrogen atmosphere until the temperature has dropped below 100 °C. The solvent and salts are washed out with approximately 700 ml of water in one step. The product is extracted with 700 ml of chloroform and/or ethyl acetate. The layers are separated. The organic layer is dried over sodium sulfate and evaporated to dryness. The evaporated residue is dissolved in 480 ml of ethanol and 240 ml (i.e. a half portion) of hydrochloric acid (1 : 1 , i.e. 5.5M) is added. The mixture is refluxed under constant stirring for 12 hours. Hydrochloride of trans isomer (lib) remains in the solution after the hydrolysis has been completed. Hydrochloride of cis isomer (lla) crystallizes. The crystals are filtered off, washed twice with acetone and dried on the air. A filtrate is evaporated almost to dryness, 450 ml of ethyl acetate is added and is crystallized at 5 - 10 °C. The isolated trans isomer (crystallizing for 4 hours) is filtered off and washed twice with ethyl acetate. The yield is 57 g of cis isomer and 62.5 g of trans isomer as hydroch rides (i.e. 96.5 %). Cis isomer fraction contains 98.1 % of cis and 1.8 % of trans isomer. Trans isomer fraction contains 92.5 % of trans and 7.2 % of cis isomer (HPLC), m.p. are the same as in the literature (J. Med. Chem. 1984, 27, 1508-1515).
Example 5
An Alternative Way of the Reductive Amination of Naphthalenone (I)
105 g of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone (I), 58.5 g of methylammonium formate, 6 g of magnesium sulfate, 28 g of triethylammonium formate, and 200 ml of N-methylformamide is introduced into a two-necked flask equipped with thermometer, air condenser and nitrogen by-pass for working under inert atmosphere. The mixture is heated to 125 °C and then the temperature is increased slowly to 145 °C within two hours. The temperature is kept for 14 hours. The reaction mixture is protected under nitrogen atmosphere until the temperature drops below 100 °C. The evaporated residue is dissolved in 400 ml of 2-propanol and 150 ml of hydrochloric acid (1 : 1 , i.e., 5.5M) is added. The mixture is refluxed for 6 hours. Further work up is as described in Example 4.
Example 6
Conversion of Geometric Isomers (lib) to (lla)
60 g of mixed product of (lla) and (lib) (the content of 92 % of trans isomer and 8 % of cis isomer) from the reductive amination is converted to base as follows: 30 ml triethylamine (dried over molecular sieve A3) is added to the suspension of hydrochlorides in 500 ml of tetrahydrofuran and is stirred for 0.5 - 1 hour. The suspension is filtered and washed twice with a small portion of tetrahydrofuran. 3.8 g of sodium hydride (in a form of 60 % of solid in mineral oil suspension) and 18 g of fine powdered potassium tert- butylate is added to the filtrate. Potassium tert-butylate is prepared by dissolving potassium in tert-butanol and evaporating the solvent (it still contains approximately 25-30 % of tert-butanol). The reaction flask is connected to reflux with by-pass for nitrogen inlet and heated quickly to 50 °C under intensive stirring under nitrogen atmosphere. Within five minutes potassium tert-butylate is dissolved almost completely and the equilibrium is reached in the next five minutes. The solution is cooled freely under nitrogen atmosphere. 250 ml of water and 50 ml of saturated aqueous sodium chloride solution is added. The layers are separated and the organic layer is evaporated to dryness. Since tetrahydrofuran has been in contact with a strong alkali at elevated temperature there is no danger of increasing level of organic peroxides and explosion while evaporating. If it is not feasible to evaporate tetrahydrofuran immediately after the extraction, it should be better to take 750 ml of water instead of 250 ml and to add 250 ml of chloroform. The layers are separated and the chloroform layer is washed twice with water, dried over sodium sulfate and evaporated to dryness. 50 g of so obtained light oily material is dissolved in 200 ml of ethanol and 200 ml of 5.5M hydrochloric acid is added. The crystalline material of cis isomer is separated immediately. It is stirred for additional two hours. The cis isomer (60 %, i.e., 36 g) is recrystallized as given in Example 4 and the product is combined with cis isomer obtained from the synthesis. The mother liquor with 40 % of trans isomer has the same concentration as the original one. They are combined and reused in another charge. Example 7
Preparation of 1S-cis-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl-1- naphthaleneamine-mandelate and Hydrochloride
26.8 g of cis racemic substance hydrochloride (lla) worked up as in Example 3 is converted to base by dissolving in a mixture of 100 ml of sodium hydroxide (5M) and 220 ml of ethyl acetate. The layers are separated, the organic layer is dried over sodium sulfate and evaporated to dryness. 23.8 g of so obtained oily base is dissolved in 200 ml of ethanol, (redistilled at 100 torr) and 12 g of D(-)mandelic acid is added. The mixture is heated to 60 °C until all the components are dissolved. The solution is cooled to 10-15 °C and crystallized overnight. The crystalline mandelate is filtered off, washed with a small portion of diethyl ether and dried on the air (the yield is 16 g, m. p. 187-189 °C). Mandelate is converted to base by similar work up as racemic hydrochloride (lla). Only 200 ml of 2.5M sodium hydroxide and 500 ml of ethyl acetate are used. The organic layer is dried and evaporated. The product is dissolved in 2-propanol and precipitated with gaseous hydrogen chloride. The excess of hydrogen chloride is stripped by nitrogen. The resulting pH is to be 2 (universal indicator paper). The isolated compact gel has been stirred for 2 hours. An equal volume of diisopropyl ether is added so that the recrystallization has been forced. The product is filtered through sinter S3, washed with diisopropyl ether and dried to the constant weight at 60 °C in vacua (it takes approximately 4 hours). The content of residual solvents is determined by GC.
Example 8
I. Preparation of Polymorph
The base of 1S-cis-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl- naphthaleneamine (48 grams) prepared from sertralin D(-)mandelate is dissolved in 400 ml of 2-propanol, and precipitated with 1.25 molar excess of 3M 2-propanolic hydrochloric acid under stirring. A slow addition of acid has yielded a very viscous and thick gel. It is stirred for two hours, then an equal volume of diisopropyl ether (400 ml) is added. An intensive stirring for another two hours has caused a rapid crystallization. The crystalline product is sucked through sinter S3, washed with diisopropyl ether and dried on the air. RTG d iff ractog rams and DSC curves are identical with literary data of polymorph Fll.
II. Alternative way from hydrochloride The dried product is dissolved in threefold portion (w/v) of N,N-dimethylformamide p. a. and heated to 80-90 °C. After complete dissolution occurs, the solution is cooled spontaneously to 70 °C. Fourfold volume of acetone p. a. is added slowly under intensive stirring. Then crystallization of the product begins. At first the precipitated crystalline product is thick and gelatinous, a long run stirring (2-4 hours) results in recrystallization. The product is filtered through sinter S3 and dried at 50-60 °C for 5 hours in vacuo. RTG diffractograms and DSC curves are identical with literary data of polymorph Fll.
Industrial Applicability
The process described can be utilized in industry for the manufacture of sertraline, an active antidepressant agent (5-HTserotonin re-uptake inhibitor).

Claims

C LA I M S
1. A process of sertraline preparation characterized in that the reductive amination of racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)- naphthalenone(l) is carried out by the mixture of methylamine salt and alkaline formate in the presence of at least one inorganic salt of lithium or beryllium or magnesium or aluminium in media of N-methylformamide or 1 ,2-dichlorobenzene or a mixture of N-methylformamide with 1 ,2-dichlorobenzene under inert atmosphere and the obtained product hydrolyses to cis and trans isomers of
4-(3,4-dichlorophenyl)-1 ,2,3,4 -tetrahydro-N-methyl-1 -aphthaleneamine hydrochloride which are isolated separately with a minimum content of opposite geometric isomer.
2. The process according to claim 1 characterized in that the salt of methylamine is methylammonium halide or methylammonium sulfate or methylammonium formate or a mixture of at least two said compounds.
3. The process according to claim 1 , characterized in that the mixture of methylammonium formate with N-triehylammonium formate is used for reductive amination of racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1- (2H)-naphthalenone.
4. The process according to claims 1 to 3, characterized in that the mixture of Ci - C alcohols with aqueous solution of hydrochloric acid in a ratio of organic phase to water 1 : 4 to 4 : 1 is used as aqueous-alcoholic hydrolytic medium for the reductive amination whereas the molar concentration of HCI in water is in the range from 1.0M to 6.0M.
5. The process according to claims 1 to 4, characterized in that all the reaction steps, the reductive amination of racemic 4-(3,4- dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone, the hydrolysis of formamides rising from the reaction, the preparation and isolation of hydrochlorides of the both geometric isomers are carried out as one- reaction-vessel process without intermediate isolation.
6. The process according to claims 1 to 5 characterized in that the trans isomer conversion to cis isomer from its base by catalysis of alkaline metal alcoholate at 50 °C - 55 °C.
7. The process according to claims 1 to 5 characterized in that the polymorph of 1S-cis enantiomer of sertraline from isopropanolic solution of the base by precipitation with isopropanolic solution of hydrochloric acid under addition of diisopropylether is prepared.
8. The process according to claims 1 to 7 characterized in that by precipitation of sertraline from its solution in Cι - C2 N,N-dialkylamide of Ci - C4 aliphatic acid by C3 - C8 aliphatic ketone the polymorph 1S-cis enantiomer of sertraline from any other polymorph is prepared.
EP02734991A 2002-05-10 2002-05-10 Process for the manufacture of sertraline Withdrawn EP1503978A1 (en)

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GB0507090D0 (en) 2005-04-07 2005-05-11 Sandoz Ag Process for preparing polymorphic form ll of sertraline hydrochloride
EP1885683A2 (en) 2005-06-03 2008-02-13 Hetero Drugs Limited A highly stereoselective synthesis of sertraline
WO2007119247A2 (en) * 2006-04-17 2007-10-25 Unichem Laboratories Limited Improved manufacturing procedure for the preparation of polymorphic form ii of cis-(1s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthleneamine hydrochloride (sertraline hydrochloride)
CN104876812B (en) * 2015-05-20 2020-12-08 浙江华海药业股份有限公司 Process for preparing sertraline hydrochloride intermediates and impurities

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US4855500A (en) * 1988-05-04 1989-08-08 Pfizer Inc. Process for preparing a ketimine
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HU226423B1 (en) * 1998-05-05 2008-12-29 Egis Gyogyszergyar Nyrt Process for producing a 1(2h)-naphtalene-1-ylidene derivative
YU32700A (en) * 1999-06-09 2002-03-18 Pfizer Products Inc. Process for preparing sertraline from chiral tetralone

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