PROCESS FOR PREPARING SERTRALINE

Abstract: The invention provides the substantially geometrically pure cis-stereoisomeric form of a compound of formula (I) and the substantially geometrically and optically pure cis-stereoisomeric form of a compound of formula (II) wherein R<1> is H or C1-C4 alkyl, together with processes for their preparation. The compounds are intermediates for the preparation of the antidepressant agent known as sertraline.

Description: PROCESS FOR PREPARING SEΠRAIJHE This invention relates to novel cis-N-a anoyl-N-methyl- 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahyάtc-l-naph-Oιylarαine analogues, which are key intermediates in a new process for preparing sertraline, together with intermediates thereto and processes for the preparation thereof. A specific embodiment of the invention relates to the (lS,4S)-stereoisomeric form of such cis-N-a_Ucanoyl-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tet_rahydro-l-napht_hylamines, intermediates thereto and processes for the preparation thereof. These novel cis-l,4-disubstituted tetrahydrorøphthyl-imines and processes thereto are particαLarly advantageous in the synthesis of the antidepressant agent knctwn as sertraline, or cis-(lS,4S)- N-methyl-4-(3,4-dichloropheιτyl)-1,2,3,4-tetrahydro-l- naphthylaπ ne, which is disclosed in US 4,536,518 and in the Journal of Medicinal Chemistry, 1984, 27, 1508. Ihe novel compounds of the present invention have been made available by the unexpected discovery that the required cis-isαmer may be generated stereoselectively, in high yield, by catalytic hydrogenation of the appropriate N-alkanoyl-N-methyl- 4-(3,4-dichlorophenyl)-1,2-dihydro-l-naphtiylamine precursor, allowing ready removal of the unwanted trans-isomer. More importantly, when the precursor itself is optically pure .and the l-(N-al_*canoyl)me_hylamino substituent possesses the S-configuration, catalytic hydrogenation thereof affords the cis-(lS,4S)-en∑mtiσϊner in high yield and with high ster<aoselectivity, thus obviating the need for a final stage optical resolution to separate sertraline from the unwanted cis-(IR,4R)-^n_mtiome_r. Thus the present invention provides:- a) the substantially geometrically pure cis-stereoisomeric form, consisting of a racemic mixture of the cis-(lS,4S) and the cis-(lR,4R) enantiomers, of a cxarpound of formula: wherein R is H or .-C alkyl and * denotes an unresolved asyι ** π * πetric centre; b) the substantially gecmetriceilly and optically pure cis-stereoisomeric form, consisting of the cis-(lS,4S) enantiomer, of a (xarpound of formula: wherein R ,ι i ,s H or C^ -C. alkyl and S represents the absolute configuration of a resolved asymmetric centre; c) processes for preparing the substantially geometrically pure cis-stereisσmeric form of a coirpound of formula (I) or the substantially geometrically and optically pure cis-stereoisomeric form of a compound of formula (II) by subjecting, respectively, a coπpound of foππula: wherein R and S are as previously defined for formulae (I) and (II) , in a suitable solvent, to hydrogenation in the presence of platinum or palladium as catalyst; d) novel intermediates of formulae (III) and (IV) . Alkyl groups containing three or four carbon atoms may be straight or branched chain. The term "substantially geometrically pure" means that the compounds of the formula (I) contain less than 4%, and preferably less than 2%, of the undesired diastereoisomeric pair of trans- (1S,4R) and (lR,4S)-enantiαmers. The term "substantially geometrically and optically pure" -means that the ∞mpound of formula (II) contains less than 4%, and preferably less than 2%, of the undesired trai"is-(lS,4R)-«3nantiαmer. In the above definitions of the ∞πpciunds of formulae (I) , (II) , (III) and (IV) , preferably R 1 is H or methyl. The c tpounds provided by the present invention may be prepared as follows:- 1. A cxsrnpound of formula (I) is prepared by hydrogenation of a cαipound of formula (HI) , in the presence of platinum oxide, in a suitable solvent, e.g. tetrahydrofuran, ethyl acetate or ethanol. Typically the reaction is conducted under pressure at about 50 p.s.i. (3.45 bar) of hydrogen and at a tertperature of from 20 to 25°C for 1 to 2 hours. The product of formula (I) may then be isolated and purified by conventional techniques, e.g. by removal of the catalyst by filtration, evaporation under vacuum of the filtrate, then crystallisation of the crude residue to remove minor amounts of the unwanted trans- is ner. Alternatively, the separation of cis- and "t-rans-isαners can be effected after removal of the N-alkanoyl group to .furnish a ∞πpound of formula (IX) , wherein * is cis previously defined, in the next stage of the synthetic sequence depicted in Scheme 1. iScheme 1 optical resolution The N-alkanoyl group of a cαπpound of formula (I) , the major isσmer of the aforementioned crude residue, is removed by hydrolysis using an aqueous inorganic base such as an alkali metal hydroxide salt, preferably potassium hydroxide, as a 10 molar solution in water. Typically the hydrolysis is carried out in ethylene glycol at the reflux terrperature of the reaction medium for from 2 hours to 4 days. For a cxarpound of formula (I) wherein R is H, the N-alkanoyl group is preferably removed by acidic hydrolysis using a mineral acid, e.g. hydrochloric acid, in a suitable solvent such as 2-propanol, 1,4-dioxan or ethyl acetate, at the reflux terrperature of the reaction medium for from 2 to 8 hours. The product (IX) is then isolated and purified by conventional procedures, e.g. extractive work-up, optional column c3 * ιrα * natøgraphy to remove minor cimounts of the unwanted trans-iso er, and conversion to the hydrochloride salt. This salt may then be processed via the resolution procedure described in US 4,536,518 to provide the cis-(lS,4S)-enantiomer (sertraline) . A cxmpound of formula (III) required for the preparation of a ccπpound of formula (I) may be obtained by the route depicted in Scheme 1, wherein R , * and S are as previously defined, using conventional procedures. Thus, typically, a compound of formula (VTA) wherein R is C.-C. alkyl can be prepared by acylating a compound of formula (VA) with either an acyl halide of formula ( .-C alkyl)CO(Cl or Br) or with an acid anhydride of formula [(C -C alkyl)CO] 0. When .an acyl halide is employed the reaction may be carried out at from 0 to 25°C, preferably at frcm 5 to 10°C, in a suitable organic solvent, e.g. dicihlorσmethane, .and in the presence of an acid acceptor, e.g. triethylamine. When an acid anhydride is used the reaction may be conducted at up to the reflux terrperature of the reaction medium, preferably at 100°C, in a suitably compatible solvent, e.g. a carboxylic acid of formula (C -C. alkyl)CO-H. To obtain a coirpound of formula (VIA) wherein R is H, cσπpound (VA) is formylated using acetic-formic anhydride which may be generated by the addition of 98% formic acid to stirred acetic anhydride, typically between 0 and 10°C. The freshly prepared mixed anhydride is then reacted with cαrrpound (VA) in an appropriate solvent, e.g. 98% formic acid, at from 5 to 25°C. Conversion of a ∞mpound of formula (VTA) to a ketone of formula (VIIA) , via a benzylic oxidation reaction, can be effected with a variety of oxidising agents such as an inorganic permanganate salt, ammonium cerium(IV) nitrate, cobalt(III) acetate or 2,3-dichlorc>-5,6-dicyano-l,4-benzoquinone, in a suitable solvent. Preferably the reaction is carried out using 3-5 molecular equivalents of potassium permanganate in aqueous acetone in the presence of a buffering reagent such as an alkali, or alkaline earth, metal salt, e.g. magnesium sulphate. The oxidant may be added in portions in a controlled manner, in order to moderate the potentially vigorous reaction, to a solution of the substrate (VTA) at from 5 to 30°C. Subsequent to this addition, wanning of the reaction mixture at frαn 30 to 50°C may be required in order to complete the oxidation. A cxa-tpc-und of formula (VIIIA) can be prepared stereoselectively from a cαπpound of formula (VIIA) using a 3,4-dichlorophenylmagnesium halide, preferably the iodide, under standard Grignard reaction conditions. Thus, typically, a solution of the ketonic substrate (VIIA) in a suitably cα_τpatible solvent, e.g. dry toluene or dry tetrahydrofuran, is added to a freshly prepared solution of the Grignard reagent in an appropriate solvent such as dry diethyl ether, at a t"emperature of from 5 to 25°C, under anhydrous conditions. The reaction is allowed to proceed at from 20-25°C for from 4 to 24 hours and the mixture may be heated under reflux for up to 1 hour, if necessary, to promote a better conversion of (VIIA) to (VIIIA) . Minor amounts of the trans-alcohol may be removed, if required, by column c±rαjiatography and/or crystallisation. Ttansformation of a tertiary alcohol of formula (V IIA) to an alkene of formula (HI) can be carried out under a variety of conditions such as heating alone, with phosphorus oxychloride in pyridine, with sodium acetate in acetic anhydride, or with 4-dimet±ιyla_τιincpyridir-e in acetic anhydride. Preferably, however, the dehydration is effected by using a Lewis acid in a suitable solvent, e.g. boron trifluoride in glacial acetic acid, at about ambient temperature. 2. A ccπpcund of formula (II) may be prepared from a cσπpound of formula (IV) in a manner analogous to that described above for the preparation of coirpound (I) from cσπpound (III) . In this case hcwever the major product frcm the catalytic hydrogenation is the single c;_s-(lS,4S)-enantianer (II). Again, the separation of the cis- and t-.ans-iscmers is most conveniently accσrrplished after removal of the N-alkanoyl group, which -.uirnishes sertraline directly (see Scheme 2) , although crystallisation of the crude hydrogenation product suffices to remove minor amounts of the unwanted trans-(IS,4R)-enantiσmer. The N-alkanoyl group of compound (II) , the major component of the aforementioned hydrogenation reaction, may be removed by the hydrolysis methods described hereinbefore for the conversion of (I) to (IX) - see Scheme 1. Sche e 2 A cαrrpound of formula (IV) required for the preparation of a coπpound of formula (II) may be obtained from cαrrpound (VB) by the route depicted in Scheme 2, wherein R , * and S are as previously defined, using the procedures described for the preparation of a cαπpound of formula (III) from compound (VA) - see Scheme 1. In this case however prior resolution of the amine (VA) is effected to provide the optically pure S-enantiσmer (VB) . The resolution is carried out in a conventional manner by fractional crystallisation of a salt of the amine (VA) , formed with an optically pure acid such as a sulphonic or carboxylic acid, preferably (2S,3S) (-) tartaric acid or N-acetyl-(S)- phenylalanine, from an appropriate solvent e.g. water or ethanol. The free amine (VB) is then liberated by treatment of the resolved amine salt with a base, typically an aqueous solution of sodium or potassium hydroxide. The amine (VB) may also be obtained by assyirr etric reduction of the i ine precursor, which is directly accessible from α-tetralone and irethylamine, by methods well known to persons skilled in the art. The invention will now be more particularly illustrated by the following experimental Examples. The purity of the compounds was monitored by thin layer c±ircsmatography (TIC) using Merck Kieselgel 60 F_ 54 plates. Routine " Ti-nuclear magnetic resonance (πmr) spectra were recorded using a Nicolet QE-300 spectrometer 13 and C πmr spectra were recorded using a Bruker 250 -spectrometer; they were in all cases consistent with the proposed structures. Nuclear Overhauser effect (nOe) experiments were conducted using a Bruker 250 spectrometer. EXr^EPLE 1 N- (1,2,3.4-φetrahvdro-i-naphthyl)-N-iriethylac-etemide A stirred solution of N-metftyl-l,2,3,4-tetxahydro-l- rapfothylamine hydrochloride (70.2g) in water (40Crml) was basified to pH about 11, by addition of ION aqueous sodium hydroxide solution (40ml) , and extracted with dichlorα-rethane (250ml, then 100ml) . The combined, stirred organic extracts were treated with triethyla ine (40.5g), cooled to 5°C, and acetyl chloride (31.4g) was then added dropwise over 40 minutes, keeping the reaction terrperature below 10°C. After being stirred for a further 20 minutes the solution was washed with water (100ml) , IN aqueous sodium hydroxide solution (100ml) and water (100ml) . Evaporation under vacuum of the dichlorα-rethane solution gave the title cαπpσund as a pale brown mobile oil (72.8g, 100%) ; Rf 0.69 (silica; chloroform, irethanol; 95:5) . GLC assay on a 2.1m x 4mm 3% OV-17 column, terrperature programmed from 100°C to 250°C at 10°C/minute, showed the product to be 99.9% pure (retention time 13.8 minutes) . • *Η-niπr (300MHz. CDCL..: δ = 1.64-1.92 ( , 2H) , 1.95-2.14 (m, 2H) , 2.13 and 2.19 (2 acetyl OL, rotamer singlets, 3H) , 2.67 and 2.72 (2 NMe rotamer singlets, 3H) , 2.76-2.90 (m, 2H), 4.97-5.07 and 5.91-6.00 (2 rotamer multiplets, 1H) , 6.98-7.24 (m, 4H) p.p.m. EXAMPLE 2 N- ( 1.2.3,4--Tetr«ahydro-4-keto-l-naphthyl)-N-methylaceta_τιide A stirred solution of N-(l,2,3,4-te-crahydro-l-naphthyl)- N-irethylacetamide (93.4g) in acetone (1050ml) was treated with magnesium sulphate heptahydrate (139.4g) and water (350ml) and the mixture was chilled to 5°C. Solid potassium permanganate (232.3g) was added portionwise over 2 hours with cooling to keep the reaction terrperature below 35°C. The mixture was warmed, held at 45° to 50°C for 40 minutes, filtered and the solids washed with acetone (5 x 100ml) . The combined filtrate and washes were evaporated under vacuum to remove acetone, and the resulting aqueous solution was extracted with dicliLorσmethane (3 x 150ml) . The organic extracts were evaporated under vacuum to give an oil (76g) which was stirred with diethyl ether (200ml) ; a solid separated and was collected by filtration (69g) . This solid was reslurried with fresh diethyl ether (lOOml) , collected and dried to give the title compound as white crystals (61.7g, 61.8%), .p. 101-103°C; Rf 0.54 (silica; chloroform, methanol; 95:5). Found: C,71.97; H,6.96; N,6.51.C 13 H ^ requires C,71.85; H,6.96; N 6.44%. GLC assay on a 2.1m x 4mm 3% OV-17 column, terrperature programmed from 100° to 220°C at 10°C/minute, showed the product to be 99.2% pure (retention time 22.0 minutes) . rl-τmr (300MHz. CDCL.): δ = 2.17-2.33 ( , 2H), 2.29 and 2.31 (2 acetyl CH_ rotamer singlets, 3H), 2.70-2.94 (m, 2H) , 2.77 and 2.83 (2 NMe rotamer singlets, 3H) , 5.18-5.26 and 6.19-6.28 (2 rotamer multiplets, 1H) , 7.10-7.24 (2 aromatic rotamer doublets, IH) , 7.36-7.51 (m, IH) 7.53-7.66 (m, 1H) , 8.07-8.14 (d, IH) p.p.m. EXAMPLE 3 (1R*. 4S*)-N-[ ~ 4-(3.4-Dichlorophenyl)-1,2.3,4-tetrahvdro -4-hvdroxy-l-naphthyll-N-_re1_hylac^temide Magnesium turnings (2.04g) and a crystal of iodine were stirred in dry diethyl ether (24ml) cis a solution of l,2-dichloro-4-iodobenzene (23.17g) in dry diethyl ether (60ml) was added over 15 minutes. The mixture was stirred for 15 minutes and refluxed for a further 15 minutes to complete formation of the Grignard reagent. The mixture was cooled to room terrperature and a solution of N-(1,2,3,4-tetrahydro-4-keto-l-naphthyl)- N-methylacetainide (12.3g) in dry tetrahydrofuran (I34ml) was added over 5 minutes. The mixture was stirred for 4 hours at room terrperature, heated under reflux for 30 minutes, cooled and treated with 4N aqueous sulphuric acid (30ml) . The lower .aqueous phase was separated and discarded, dic±ilorαmethane was added, and the solution was washed with water (2x25ml) . The organic layer was evaporated under vacuum to give a mixture of racemic cis-(lR*, 4S*)- and trans-(1R*, 4R*)-isσmers (ratio 87:13 respectively by nmr spectroscopy techniques) cis a light brown gum (24.5g) which was stirred with diethyl ether (150ml) for 1 hour, then filtered, to give the title compound as cream crystals (10.2g, 49.5%) , m.p. 146-148°C; Rf 0.41 (silica; chloroform, methanol; 95:5). Found: C,62.96; H,5.24; N,4.00 C ιg H ιg Cl 2 0 2 requires C,62.65; H,5.26; N 3.85%. GLC assay on a 2.1m x 4mm 3% OV-17 column, terrperature programmed from 100° to 275°C at 10°C/minute, showed the product to be 96% pure (retention time 41.5 minutes) ronteining 3% recovered ketone. • bϊ-n r f300MHz, CDC1 ) : 5 = 1.48-1.65 (m, IH) , 1.73-1.95 (m, IH) , 2.18-2.41 (m, 2H) , 2.21 and 2.29 (2 acetyl CH rotemer singlets, 3H) , 2.66 and 2.73 (2 NMe rotamer singlets, 3H) , 5.06-5.15 and 5.95-6.03 (2 rotamer multiplets, IH) , 6.90-7.47 (m, 7H) p.p.m. EXAMPLE 4 N-( ~ 4-(3,4-Dichlorophenyl)-1.2-d-ivdro-l-naphthyl1 -N-mei^ylacetamide A solution of (IP*, 4S*)-N-[4-(3,4-dichlorophenyl)- l,2,3,4-tetrahydro-4-hydroxy-l-røphtΛyl]-N-ιre^ (5g) in glacial acetic acid (50ml) was treated with boron trifluoride etherate (2ml) and stirred for 2.5 hours at ambient terrperature. The solution was poured into water (100ml) , extracted with dicωorαmethane (2x50ml) and the combined extracts washed with saturated aqueous sodium bicarbonate solution (200ml) . The dichloromethane solution was then evaporated under vacuum and the residual foam (4.8g) was drroiratepgraphed on silica (200g) eluting with hexane-chloroform (1:2), chloroform and then chloroform-methanol (9:1) . Evaporation under vacuum of the requisite fractions gave the product as an oil (3.6g, 75.7%); Rf 0.22 (silica; chloroform) and 0.58 (silica; chloroform, methanol; 95:5) . GLC assay on a 2.1m x 4n_., 3% OV-17 cxxLumn, run isothermally at 250°C, showed the product to be 98% pure. Tfr-πmr (300MHz. CDC1 ) : δ = 2.24 and 2.25 (2 acetyl OL rotamer singlets, 3H) , 2.50-2.75 (m, 2H) , 2.91 and 2.93 (2 NMe rotamer singlets, 3H) , 5.19-5.30 and 6.02-6.08 (2 rotamer multiplets, H) , 6.09-6.19 (m, IE) , 6.97-7.52 (m, 7H) p.p. . EXAMPLE 5 cis-fIP*,4R*)-N-f4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahvdro-l- naphthyll-N-met±ιylac * etaπιide A solution of N-[4-(3,4-dic^orophenyl)-l,2-dihydro-l- naphthyl]-N-metoylacetamide (0.5g) in tetrahydrofuran (12.5ml) was hydrogenated over platinum oxide (O.lg) at room terrperature and 50 p.s.i. (3.45 bar) for 1.25 hours. The catalyst was removed by filtration, and the filtrate was evaporated under "- cuum to give the -crude product as an oil (0.50g, 99.4%); Rf 0.19 (silica; chloroform) . A ht-πmr assay (300MHz, CDC1 ) of this material showed it to be a 70:30 mixture of the cis-iscmer (<5 = 4.17-4.28 ppm, m, for the H proton) .and the trans-isσmer (<S * ■= 4.00-4.12ppm, m, for the H. proton) , respectively. The separation of cis- and trans-isomers is more eff ctively carried out after removal of the acetyl group. However, crystallisation of a sample of the crude product frcm diethyl ether provided a reference sample of the title cxmpound as white crystals, m.p. 93-95°C, Rf 0.60 (silica; chloroform, methanol; 95:5). Found: C,65.99; H,5.45; N,4.54. C ιg H 19 Cl 2 NO requires C,65.52; H,5.50: N,4.02%. EXAMPLE 6 cis-(IP*,4R*)-N-Methyl-4-(3,4-dichlorophenyl)- 1.2.3,4-tetrahvdro—1-napht±ιylamine hydrochloride A solution of cis-(lR*,4R*)-N-[4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-naphthy1]-N-methylaceta ide (2.Og cis/trans milxture) in ethylene glycol (40ml) was tr«=ated with ION aqueous potassium hydroxide solution (20ml) and then heated under reflux for 81 hours. The cooled mixture was diluted with water (25ml) , acidified to pH 1 with concentrated hydrochloric acid (21ml) and extracted with dichloromethane (2x50ml) . The extracts were evaporated under vacuum to give a yellow gum (1.83g) which was tircaTBtographed on silica (73g) , eluting with chloroform and then a chloroform/methanol mixture. Chloroform eluted recovered starting material (1.46g, 73% recovery) , while the dhlorof^orm/methanol mixture eluted first the product as its free base (0.080g, 4.5%) and then mixed cis- and trans-fractions. The cis-amine base (0.080g) in 2-propanol (0.6ml) was treated with a 2-propanolic solution of hydrogen chloride (0.3ml of 24% w/v solution) and granulated for 2 hours. Filtration gave the product (0.078g; 3.8% step yield) as white crystals, m.p. 275-277°C; Rf 0.13 (silica; chloroform, methanol; 95:5). Found: C,59.89; H,5.42; N,4.16. C 17 H 17 C1 2 N;HC1 requires C,59.58; H,5.29; N,4.09%. EXAMPLE 7 (S) (+) -N-Methyl-1 ,2 ,3 , 4-tetxahvdro-l-naphτj ylamine (a) A cold solution of N-ιrιethyl-l,2,3,4-tetrahydro-l- naphthylamine (3.87g) in ethanol (77.5ml) was added to a hot solution of N-acetyl-(S)-phenylalanine (5.0g) in ethanol (75ml) . The clear solution was chilled to induce crystallisation and refrigerated at 4°C overnitght. Filtration, washing with ethanol (2x5ml) and drying gave the crude N-ac^tyl-(S)-phenylalanine salt of the (S) -amine (3.61g, 40.7%) as white crystals, m.p. 190-193 °C. Recrystallisation of 2.7g of this material from ethanol (60ml) gave the N-acetyl-(S)-phenylalanine salt of the title coπpound (2.04g, 61.7% overall yield based on available enantiσmer) as white crystals, m.p. 191-193°C, [α] + 34.1° (c=0.49, water) . Found: C,71.74; H,7.56; N,7.61. requires C,71.71; H,7.66; N,7.60%. A sairple of this salt (0.7g) was stirred in a mixture of water (5ml) and dichloromethane (5ml) , then 5N aqueous sodium hydroxide solution was added dropwise to adjust the pH of the aqueous phase to 11. The phases were separated and the aqueous phase was washed with dichlorαmethane. Evaporation under vacuum of the cxxmbined organic layers gave the title compound as a colourless oil (0.30g, 97.9% from salt), [α] n + 10.1° (c=5, EtOH); Rf 0.37 (silica; ethyl acetate, methanol, 15. N aqueous NH_; 80:20:1). (b) A solution of (2S,3S) (-) tartaric acid (160.3g in water (500ml) was treated with N-methyl-l,2,3,4-tetrahydro—l- r-aj-htbylamine (172.2g) , the teriperature being allowed to rise to 35°C. The resulting clear solution was chilled to induce crystallisation and granulated for several hours at 5°C. Filtration, washing with water (3x50ml) and drying gave the crude (-) tartaric acid salt of the (S)-amine (198.2g) as a white solid, m.p. 99-l06°C. Fractional recrystallisation from water gave the (-)tartaric acid salt of the title (xπpound (59.3g, 33.7% overall based on available enantiomer) as white crystals, m.p. 107-109°C, [α] - 12.4° (c=4.96, water). Found: C,54.82; H,7.09; N,4.21. C Jϊ N0 6 ;BLO requires C,54.70; H,7.04; N,4.25%. The salt (53.6g) was dissolved in water (150ml) by wanning to 40°C. The solution was basified to pH 11 by dropwise addition of 5N aqueous sodium hydroxide solution, and the mixture was extracted with dichloromethane (2x150ml) . Evaporation under vacuum of the combined organic extracts gave the title coπpσund as a colourless oil (26.Og, 96.4% from salt), [α]_ + 10.4° (σ=5, EtOH). A sample of this oil (0.16g) was acylated with (+)-α-metho>cy-^-(teifluoroιrethyl)- phenylacetyl chloride (0.5g) in carbon tetrachloride (2.5ml) containing pyridine (0.75ml) . Isolation of the amide and il-πmr assay losing the method of Mosher (J. Qrg. Chem., 1969, 34. 2543) showed the title cσrrpound to be a 95:5 mixture of the (S)- and (R)-enantiσmers, respectively. EXAMPLE 8 (S) (-)-N-(1,2,3,4- etrahydro-l-naphthyl)-N-methylformamide Acetic anhydride (73.5g) was chilled and stirred as 98% formic acid (44.2g) was added over 30 minutes keeping the temperature below 10°C. The resulting solution of acetic-formic anhydride was stirred for a further 15 minutes at 5°C and added over 5 minutes to a stirred, chilled solution of (S) (+)-N-methyl- 1,2,3,4-tetrahydro-l-naphthyla_nine (26g) in 98% formic acid (26ml) . The reaction solution was stirred at ambient temperature for 1 hour, poured into an ice-water -mixture (200g) and basified with ION aqueous sodium hydroxide solution (about 250ml) to pH 10; the mixture was then extracted with dichloroiriethane (3x200ml) . The combined extracts were back- s washed with IN aqueous hydrochloric acid (100ml) , then water (100ml) , and evaporated under vacuum to give the title cσπpound (28.69g, 94%) as a solid, m.p. 52-54°C; Rf 0.80 (silica; chloroform, methanol; 95:5). A chiral HPLC assay on an acetylated β-cyclodextrin column showed this material to be a 94:6 mixture of the (S)- and (R)-enantiσmers, respectively. A sample of the product (1.5g) was crystallised from a mixture of ethyl acetate (2ml) and hexane (15ml) to give a purified sample of the title cxmpound (0.79g, 52.7% recovery) as white crystals, m.p. 55-56°C, [α] -19.9° (c=5, EtOH) , containing no detectable (R)-enantiσmer on chiral HPLC assay. Found: C,76.29; H,7.87; N,7.47. C^H^NO requires C,76.16; H,7.98; N,7.40%. EXAMPLE 9 (S) (-)-N-(1,2,3,4- etrahvdro-4-keto-l-naphthyl)-N-methylformamide To a chilled solution of (S) (-)-N-(1,2,3,4-tetrahydro-l- naphthyl)-N-methylformamide (26g) in acetone (585ml) was added magnesium sulphate heptahydrate (78g) , water (195ml) and then, portionwise over 1 hour, potassium permanganate (104g) . The mixture was stirred for 6 hours with water-bath cooling to k«aep the reaction terrperature below 30°C, then filtered and the cake washed with acetone (2x150ml) . The filtrate and washes were cxtmbined, treated with 10% aqueous sodium metabisulphite solution (240ml) and extracted with dichlorσmethane (600ml and then 300ml) . The conbined extracts were evaporated under vacuum to an oil (21.Ig) which was ctircαiHtographed on silica (805g) , eluting with a dichloromethine/methanol mixture (98:2) to give the product as an oil (12.36g, 44.3%); Rf 0.18 (silica; ethyl acetate) and 0.58 (silica; chloroform, methanol; 95:5). A sample of the product (1.16g) was triturated with diethyl ether (20ml) to induce crystallisation, giving a purified sample of the title cσπpound (0.75g), m.p. 90-92°C, [α] D -52.7° (c=0.5, EtOH). Found: C,70.42; H,6.46; N,6.89. C 12 H 13 NO requires C,70.92; H,6.45; N,6.64%. EXAMPLE 10 (IS.4R) (+)-N-r4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-4- hydroxy-1-naphthyl]-N-methylfO-rmamide Magnesium txrrnings (0.89g) and a crystal of iodine were stirred in dry diethyl ether (25ml) as a solution of l,2-dichloro-4-iodobenzene (10.08g) in diethyl ether (25ml) was added over 10 minutes. After the exotherm subsided, the mixture was heated under reflux for a further 15 minutes to complete consumption of the magnesium metal. The mixture was then chilled to 5°C and a solution of (S) (-)-N-(1,2,3,4-tetrahydro-4-keto-l- naphthyl)-N-methylformamide (5g) in dry toluene (100ml) was added over 10 iniπutes. After being stirred for 22 hours the resulting mixture was poured into 10% aqueous ammonium chloride solution (200ml) . The phases were separated, the aqueous layer was washed with toluene (25ml) and the combined organic layers were evaporated under vacuum to give a mixture of cis-(lS,4R)- and txans-(lS,4S)-enantiαmers (ratio 87:13 respectively by πmr spectroscαpy techniques) as a dark oil (11.7g) , which was __roπatographed on silica (500g) . Elution with hexane-ethyl acetate mixtures (1:2 to 1:4) gave the title ∞rrpαund cis a foam (3.52g, 40.8%); Rf 0.37 (silica; ethyl acetate) and 0.50 (silica; chloroform, methanol; 95:5) which was sufficiently pure for use in the next step. A small reference sample of purified product was obtained by slew crystallisation from a diethyl ether-hexane mixture (6:4) . The title cαrrpound was obtained cis off-white crystals, m.p. 124-126°C, [β] D + 21.9° (σ=0.5, EtOH) . Found: C,61.54; H,4.73; N,3.92. requires C,61.72; H,4.89; N,4.00%. EXAMPLE 11 (S^ (-)-N-1 ~ 4-(3.4-Dichlorophenyl)-1.2-dihvdro- 1-naphthy11-N-methylformamide A solution of (lS,4R)(+)-N-[4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydro-4-hydro^-l-naphthyl]-N-ιrethylfo_πrømide (2g) in glacial acetic acid (20ml) was treated with boron trifluoride etherate (0.8ml) and stirred for 1 hour at ambient terrperature. The solution was poured into water (40ml) , extracted with chloroform (2x20ml) and the combined chloroform extracts were backwashed with saturated aqueous sodium bicarbonate solution (3x20ml) . The chloroform solution was evaporated under vacuum and the residual glassy solid (2.03g) was cihrσmatographed on silica (lOOg) eluting with hexane-ethyl acetate mixtures (1:1 to 1:4) . Evaporation under vacuum of the requisite fractions gave the product as a glass (0.90g, 47.4%), Rf 0.24 (silica; chloroform); [α] D -50° (σ=0.5, EtOH). Found: C, 64.93; H,4.80; N,3.83. C 18 H 15 C1 2 N0 requires C,65.08; H,4.55; N,4.22%. i-Tmr (300MHz. CDCL.): δ = 2.57-2.84 (m, 2H) , 2.89 and 2.94 (2 NMe rotamer singlets, 3H) , 4.90-4.99.and 5.82-5.91 (2 rotamer multiplets, IH) , 6.07-6.14 (m, IH) , 7.00-7.55 (m, 7H) , 8.19 and 8.30 (2 formyl CH rotamers, IH) p.p.m. EXAMPLE 12 cis-(IS,4S) (+)-N-T4-(3,4-Dichlorophenyl)-1,2,3,4- tefa^hyσro-l-naphthyll-N-methylformamide A solution of (S) (-)-N-[4-(3,4-dichlorophenyl)-l,2-dihydro-l- røphthyl]-N-methylformamide (0.64g) in tetrahydrofuran (10ml) was hydrogenated over platinum oxide (0.13g) at room terrperature and 50 p.s.i. (3.45 bar) for 1.5 hours. The catalyst was removed ky filtration and the filtrate was evaporated under vacuum to give the crude product as a gum (0.62g, 96.9%). A " Η-nmr assay (300 MHz, CDCl ) of this material showed it to be an 88:12 mixture of the required (IS, 4S) cis-isomer (δ — 4.19-4.27 ppm, m, for the H proton) and the (IS, 4R) trans-isαmer (-5 = 4.05-4.14 ppm, m, for the H proton) , respectively. The separation of cis- and trans-isαmers is most efficiently effected after removal of the formyl group. However, crystallisation of a sample of the crude product from an ethyl acetate-hexane mixture (1:7) provided a reference sample of the title compound as white microcrystals, m.p. 86-87°C; Rf 0.65 (silica; chloroform, m≥thanol; 95:5); [ ] + 24.3° (c=0.57, EtOH) . Found: C,64.02; H,5.16; N.4.17. C^H^O^ O requires C,64.67; H,5.13; N,4.19%. • Η-πrrrr (300 MHz. CDC1 3 ) : 5 = 1.72-1.87 (m, IH), 1.89-2.15 (m, 2H), 2.26-2.40 (m, H) , 2.75 and 2.79 (2 NMe rotamer singlets, 3H), 4.19-4.27 (m, IH) , 4.74-4.83 and 5.72-5.80 (2 rotamer multiplets, IH) , 6.79-7.40 (m, 7H) , 8.30 and 8.35 (2 formyl CH rσtamers, IH) p.p.m. EXAMPLE 13 cis-(IS,4S) (+)-N-Methyl-4-(3.4-dichlorophenyl)-1.2.3.4- tet_rahydro-l-naphthylamine hydrochloride (sertraline hydrochloride) A solution of cis-(lS,4S) (+)-N-[4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-naphthyl]-N-ιrethylf^ormamide (0.35g of 88:12 cis-trans mixture from Example 12) in 2-propanol (3.5ml) was treated with concentrated aqueous hydrochloric acid (1.05ml) and heated under reflux for 6 hours. The solution was refrigerated overnight and a first crop of product collected by filtration (0.126g) . The filtrate was concentrated to a third of its volume, diluted with hexane (1ml) , refrigerated overnight and filtered to give a second crop of product (0.134g) . The two crops were combined and slurried in 2-propanol (1ml) overnitght. Filtration gave the product (0.25g, 69.4%) as white crystals, m.p. 237°-240°C; [α] D + 40.6° (c=1.0, N/20 ltv≥thanolic HCl) . N.B. N-Methyl-l,2,3,4-tetrahydro-l-na^thylamine (cσrrpound VA) is obtainable according to Coll. Czech. Qiem. Cαmmun., 1973, 38, 1159.

Claims: CLAI S 1. A process for the preparation of the substantially gecEmetrically pure cis-stereoisomeric form of a compound of formula: wherein R is H or C.-C, alkyl and * denotes an unresolved asymmetric centre, which comprises catalytic hydrogenation of a cσπpαund of formula: wherein R is as defined for formula (I) . -27- 2. A process for the preparation of the sustantially geometrically and optically pure cis-stereoisomeric form of a cαπpound of formula: wherein R ,1 i_•s H or C.-C alkyl and S represents the absolute configuration of a resolved asyπrmetric centre, which comprises catalytic hydrogenation of a cσrrpound of formula: wherein R and S are as defined for formula (II) . 3. A process as claimed in claims 1 and 2 wherein the hydrogenation catalyst is platinum or palladium. 4. A process as claimed in claim 3 wherein the hydrogenation catalyst is platinum. 5. The substantially geometrically pure cis-stereoi_3omeric form of a cαrrpound of formula: wherein R is H or C . -C alkyl and * denotes an unresolved a≤ymπetric centre. 6. The substantially geometrically and optically pure cis-≤tereoisσmeric form of a cα.rpound of formula: wherein R is H or C,-C. alkyl and S represents the absolute configuration of a resolved asymmetric centre. 7. A cσπpound of formula (III) as defined in claim 1. 8. A compound of formula (IV) as defined in claim 2. 9. A compound cis claimed in any one of claims 5 to 8 or a process as claimed in any one of claims 1 to 4 wherein R is H or methyl.

Inventors: WILLIAMS MICHAEL TREVELYAN, WILLIAMS, MICHAEL, TREVELYAN
Applicants: PFIZER, PFIZER LTD, PFIZER INC., PFIZER LIMITED
Application year: 1992
Main classification: C07C233
IPC codes: C07C231, C07C233