^" This invention relates to novel xans-N-al anoyl-N-ιnethyl-4- (3,4-^iLc lorophenyl)-1,2,3,4-tetrahydrc>-l-røphthylamine analogues, which are intermediates in a new process for preparing sertraline, together with intermediates thereto and processes for the preparation thereof.

More specifically the invention relates to the (1R,4S)- stereoisomeric form of the said txans-l,4-disubstituted tetrahydroriaphthylamines which, upon N-deacylation, afford trans- (1R,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l - naphthylamine. ϊhe latter, v ^* hich is disclosed in US 4,556,676 and in the Journal of Medicinal Chemistry, 1984, 27, 1508, is isomeric with the antidepressant agent known as sertraline, or cis-(lS,4S)- N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l- -oaphi^ylamine, which in turn is disclosed in US 4,536,518 and in the Journal of Medicinal Chemistry, 1984, 27, 1508. The ^{■ *} ans-(lR,4S)-isc ^* mer may be converted to the cis-(lS,4S)-isαmer (sertraline) by the conventional procedures subsequently summarised.

The novel cσπpoiinds of the present invention have been made available by the unexpected discovery that the required trans- iscfmer may be generated stereoselectively, in high yield, by ionic hydrogenation of the appropriate (lR,4S)-N-alkanqyl-N-methyl-4- (3,4-dichlorophenyl)-4-hydroxy-l,2,3,4-tetrahydro-l-naphthyl amine precursor, allowing ready removal of the unwanted (lR,4R)-isomer. πirportantly, since the said precursor possesses the 1-(N- a3Jarκ3yl)methylamino substituent in the R-configuration, ionic

hydrogenation "thereof affords the trarιs-(lR,4S)-enantioιner in high yield and with high stereoselectivity, thus obviating the need for a subsequent optical resolution to remove the unwanted trans-(IS,4R)-enantiomer.

Thus the present invention provides:- a) the substantially geometrically and optically pure trans- stereoisomeric form, consisting of the trans-(1R,4S)-enantiomer, of a ∞mpound of formula:

wherein R is H or C,-C aUcyl, and R and S represent the absolute ∞rifigurations of the asymmetric centres; b) a process for preparing the substantially geometrically and optically pure trans-stereoisomeric form of a cx ipound of formula (I) by subjecting a ccartpound of formula:

wherein R , R and S are as previously defined for formula (I) , in a suitable solvent, to ionic hydrogenation conditions.

Alkyl groups containing three or four carbon atoms may be straight or branched chain.

The term "substantially geometrically and optically pure" means that the compounds of the formula (I) contain less than 4%, and preferably less than 2%, of the undesired cis-(IR,4R)- enanticmer.

In the above definitions of the cσrtpounds of formulae (I) and (II) , preferably R is H.

The compounds provided by the present invention may be prepared as follows.

A compound of formula (I) is obtained by ionic hydrogenation of a coirpound of formula (II) in a suitable solvent, such as dichloromethane, using a combination of either a protic acid, e.g. trifluoroacetic acid, or preferably a Lewis acid, e.g. boron

trifluoride, with a hydride donor, e.g. triethylsilane. Typically the reaction is conducted at from -40 to +25°C for up to to 40 hours, preferably about 20 hours. The product of formula (I) may then be isolated and purified by conventional techniques, e.g. by extractive work-up, followed by chrcaiatographic purification and/or crystallisation of the crude product, to remove any recovered starting material and minor amounts of the unwanted cis-(lR,4R)-isomεr. Alternatively, the separation of trans- and cis-iscamers can be effected after removal of the N-aUcanoyl group, to furnish a cxsmpound of formula (VI) , wherein R and S are as previously defined, in the next stage of the synthetic sequence depicted in the following Scheme.

Sche e

The N-alkanoyl group of a α-ππpound of formula (I) , the major isσmer of the aforementioned crude product, 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 temperature of the reaction medium for from 2 hours to 4 days. For a c-ompound 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 temperature of the reaction medium for from 2 to 8 hours. The product (VI) is then isolated and purified by conventional procedures, e.g. extractive work-up, optional column chrciπatography to remove minor amounts of the unwanted cis- (lR,4R)-isomεr, and conversion to the hydrochloride salt. The purified free a ine may then be transformed to the cis-(lS,4S)- enanticmer (sertraline) , as summarised on page 9 et seq.

A compound of formula (II) required for the preparation of a cαrr-pσund of formula (I) may be obtained by the route depicted in the Scheme, wherein R , R and S are as previously defined, using routine procedures.

Initially, resolution of the amine (IIIA) is effected to provide the optically pure R-enantiomer (IHB) . The resolution is carried out in a conventional manner by fractional crystallisation of a salt of the amine (IIIA) , formed with an optically pure acid such as a sulphonic or carbox lic acid, preferably (2R,3R) (+) tartaric acid, from an appropriate solvent, e.g. water. Ihe free

amine (IIIB) is then liberated by treatment of the resolved amine salt with a base, typically an aqueous solution of sodium or potassium hydroxide.

Ihe amine (IIIB) may also be obtained by asymmetric reduction of the imine precursor, vAiich is directly accessible from α-tetralone and metftylamine, by methods well known to persons skilled in the art.

A c-ompound of formula (IV) wherein R is C,-C. alkyl can be prepared by acylating a compound of the formula (IIIB) with either an acyl halide of formula (C-.-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 from 5 to 10°C, in a suitable organic solvent, e.g. dic""hlo ^* TO ^* methane, and in the presence of an acid acceptor, e.g. teiethylamine. ^" When an acid anhydride is used the reaction may be conducted at up to the reflux tetmperature of the reaction mediimi, preferably at 100°C, in a suitably compatible solvent, e.g. a carboxylic acid of formula (C,-C alkyl)CO_H. To obtain a compound of formula (IV) wherein R is H, cxjmpound (IIIB) is forπiylated 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 compound (IIIB) in an appropriate solvent, e.g. 98% formic acid, at from 5 to 25 C.

Conversion of a c rpoimd of formula (IV) to a ketone of formula (V) , via a benzylic oxidation reaction, can be effected with a variety of oxidising agents such as an inorganic

permanganate salt, airarnonium cerium(IV) nitrate, cobalt(III) acetate or 2,3-^chlorc>-5,6-ά-icyano-l,4-berιzoqιαinone, 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. Ihe oxidant may be added in portions in a controlled manner, in order to moderate the potentially vigorous reaction, to a solution of the substrate (IV) at from 5 to 30 C. Subsequent to this addition, wa ^* raιing of the reaction mixture at from 30 to 50°C may be required in order to complete the oxidation.

A cctπpound of formula (U) can be prepared stereoselectively from a ccjmpσund of formula (V) using a 3,4-dic--hloropheny.Lmagrιesium halide, preferably the iodide, under standard Grignard reaction conditions. Thus, typically, a solution of the ketonic substrate (V) in a suitably compatible 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 temperature of from 5 to 25 C, under anhydrous conditions. Die 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 prcanote a better conversion of (V) to (II) . Minor amounts of the (1R,4R)-alcohol may be removed by column chromatography and/or crystallisation.

Ihe trans-(1R,4S)-amine (VI) may be converted to sertraline e following process.

sertraline

The process involves controlled oxidation of the trans- eriantiamer (VI) to afford the imine (VII) which is subsequently reduced, for example by catalytic hydrogenation using 10% palladium on charcoal as catalyst as described in US 4,536,518, to provide a mixture (approximately 7:3 ratio) of sertraline and regenerated (VI) ; the latter can be separated from sertraline by conventional means and recycled to provide further batches of sertraline. Alternatively, nickel based catalysts may be ^• used in the hydrogenation step to afford a mixture (approximately 8:1 ratio) of sertraline and (VI) .

In an alternative process optimisation procedure illustrated below, the cis-(lR,4R)-enantiomer (VIII), which in cxsmmon with (VI) is an unwanted by-product of processes in ^* which sertraline is produced by resolution of a mixture of all four stereoisomers, may also be recycled to sertraline via the imine (VH) . Firstly, however, (VHI) is isomerised by base treatment to a mixture (approximately 2:1 ratio) of (VIII) and the trans-(1R,4S)- enantiomer (VI) ; the latter is then separated, and converted to imine (VII) as in the first recycle process disclosed above. Clearly, the remaining cis-(TR,4R)-erøntiσπver (VIII) can re-enter this base equilibration process as required.

Alternatively, in a related process, the unwanted cis- (1R,4R)-enantiomer (VIII) may be oxidised to the α-tetralone (IX) ^• which, in turn, can be isomerised to furnish the known, racemic 4-(3,4-cUchloropherτyl)-α-tetralone (X), disclosed in US 4,536,518 and the Journal of Medicinal Chemistry, 1984, 27, 1508. (X) is then t ^* ransformed to sertraline via racemic imine (XI) , preferably by catalytic hydrogenation of (XI) using a palladium or nickel catalyst as mentioned above, followed by separation of the cis-racemate and its subsequent resolution as described in US 4,536,518. This process is depicted overleaf.

The invention will now be more particularly illustrated by the following experimental Examples. Ihe purity of the cxπiipounds was monitored by thin layer chromatography (TLC) using Merck Kieselgel 60 F„. plates. Routine ^" Η-nuclear magnetic resonance

(nmr) spectra were recorded using a Nicolet QE-300 spectrometer

13 and C nmr 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.

FXMPLE 1 (R) -N-Methyl-1,2,3,4-tetrahydrc)-l-na!dιthylamine A solution of (2R,3R) (+) tartaric acid (160.3 g) in water (500 ml) was treated with N-metoyl-l,2,3,4-"tetrahydro-l-naphthyl- amine (172.2 g) . The resulting solution was cooled from 33°C to room temperature, seeded and stirred for 16 hours. The slurry was refrigerated for 4 hours, filtered and the solid was washed with water (3 x 50 ml) . live, crude salt (196.2 g) was fractionally recrystallised from water giving the purified (+) tartaric acid salt of the title ccarnpoiind (42 g, 25.3% based on available enantiomer) as white crystals, m.p. 107-109 C, [α] +12.3° (c=4.2, water). Found: C,54.85; H,7.06; N,4.22. ^C _Λ -~- ⁱ ₂ - - ⁾ ₍ -' -~- _> ° requires C,54.70; H,7.04; N,4.25%.

The salt (38.9 g) was dissolved in water (150 ml) , with warming to 40 C, and then basified by the addition of 5N aqueous sodium hydroxide solution (100 ml) . The cooled mixture was extracted with dicih o-rcimethane (2 x 150 ml) . Evaporation under vacuum of the extracts gave the title ccfmpound as a colourless oil (19.1 g, 97.2% from salt), [α] -10.3° (c=5, EtOH) . ^H-nrnr assay of the (+)-α-"tιetoo^-α-(trifluorcmrethyl)phenylace-tyl derivative using the method of Mosher (J. Org. Chem., 196934, 2543) showed the title cxsnpouiid to be a 95.5:4.5 mixture of the (R) and (S) enanticmers, respectively.

EXfiMFLE 2 (R) (+)-N-(1,2,3,4-Tetrahvdro-l-na hthyl)-N-methylformamide Acetic anhydride (54.1 g) was chilled to 0°C and stirred as 98% formic acid (33.1 g) was added over 30 -αύnutes, keeping the

temperature below 5°C. The solution was warmed to 50°C, held at this temperature for 15 minutes, and chilled to 5 C. Ihe resulting solution of acetic-formic anhydride was added over 5 minutes to a stirred, chilled solution of (R) (-)-N-methyl-l,2,3,4- tetrahydrcr-l-na ^* ρhthylamine (19.08 g) in 98% formic acid (19.08 ml) , keeping the tempeature below 10 C. The reaction solution was warmed to room teirperature, stirred for 1 hour, poured into an ice-water mixture (200 g) and stirred for 30 minutes. Ihe mixture was basified to pH 9 with ION aqueous sodium hydroxide solution (about 230 ml) and extracted with dichloromethane (3 x 200 ml) . The combined extracts were back-washed with IN aqueous hydrochloric acid (100 ml) , then water (100 ml) , and evaporated under vacuum to give the title cσπipound (21.63 g, 96.6%) as a solid, .p. 53-55°C; Rf 0.80 (silica; chloroform, methanol; 95:5).

A sample of the product (1.5 g) was crystallised from a mixture of ethyl acetate (1.5 ml) and hexane (15 ml) to give a purified sample of the title cxmpound (0.92 g, 61.3% recovery) as ^• white crystals, m.p. 55-56°C, [α] _D +l9.4° (c=0.5, EtOH) . A chiral HPLC assay on an acetylated β-cyclodextrin column showed this material to contain less than 1% of the (S)-enantiomer. Found: C,76.04; H,7.94; N,7.43. C ₁₂ H ₁₅ NO requires C,76.16; H,7.98; N,7.40%. j-rmr (300 MHz. CDC1 ₃ ) : δ = 1.80 - 2.13 (m,4H), 2.70 and 2.73 (2 NMe rotamer Singlets, 3H) , 2.78 - 2.93 (m,2H) , 4.73 - 4.81 and 5.71 - 5.79 (2 rotamer multiplets, 1H) , 7.02 - 7.25 (m,4H), 8.30 and 8.34 (2 for yl CH rotamer singlets, 1H) p.p.m.

EXAMPLE 3 (R) (+)-N-(1,2,3,4-Tetrahydro-4-keto-l-naphthyl)-N-methylformami de

To a chilled solution of (R) (+)-N-(1,2,3,4-tetrahydro-l- raphthyl)-N-metoyl^ormamide (19.1 g) in acetone (430 ml) was added magnesium sulphate heptahydrate (57 g) , water (143 ml) and then, portionwise over 1 hour, potassium permanganate (76 g) . Ihe mixture was stirred for 5.5 hours with water bath cooling to keep the reaction teirperature below 34 C, filtered and the cake washed with acetone (2 x 100 ml) . Ihe filtrate and washes were combined and treated with 10% aqueous sodium metabisulphate solution (140 ml) , then the mixture refiltered and extracted with dichloromethane (400 ml and then 200 ml) . The cxmbined extracts were evaporated under vacuum to an oil (14.7 g) -which was dhro-αratographed on silica (274 g) , eluting with a dichlorciϊuiethane/πiethanol mixture (98:2) to give the product as an oil (8.2 g, 40%); Rf 0.18 (silica; ethyl acetate) and 0.58 (silica; chloroform, methanol; 95:5) .

A sample of the product (1.1 g) was triturated with diethyl ether (20 ml) to induce crystallisation giving a purified sample of the title compound (0.72 g) , m.p. 92-93°C; [α]_ + 54.9° (c = 0.5, EtOH). Found: C,70.68; H,6.4l; N,6.86. H NO requires C,70.92; H,6.45; N,6.64%. ^•* Η-πmr (300 MHz, CDC1 ₃ , :

S = 2.17 - 2.56 (m,2H), 2.68 - 2.99 (m,2H) , 2.79 and 2.83 (2 NMe rotamer singlets, 3H) , 4.96 - 5.04 and 5.92 - 6.01 (2 rotamer

quartets, IH) , 7.10 - 7.24 (q,lH), 7.40 - 7.53 (m,lH), 7.55 - 7.68 (m,lH), 8.07 - 8.16 (t,lH), 8.38 and 8.40 (2 formyl CH rotamer singlets, IH) p.p.m.

EXAMPLE 4 (IR,4S) (-)-N-T4-(3.4-Dichlorophenyl)-1,2.3,4-tetrahvdro-4-hvdroxy- 1-naphthyll-N-methylformamide

Magnesium turnings (0.89 g) and a crystal of iodine were stirred in dry diethyl ether (25 ml) as a solution of l,2-dichloro-4-iodobenzene (10.07 g) in dry diethyl ether (25 ml) was added over 20 minutes. After the exotherm subsided the ^• πiixture was heated under reflux for a further 25 minutes to complete the consumption of the magnesium metal. Ihe mixture was then chilled to 5°C, blanketed with nitrogen gas and a solution of (R) (+)-N-(1,2,3,4-tetr hydrc>-4-keto-l-naphthyl)-N-methylfonriamide (5 g) in dry toluene (100 ml) was added over 15 minutes. After being stirred for 20 hours the resulting mixture was poured into 10% aqueous ammonium chloride solution (200 ml) . Ihe -phases were separated, the aqueous layer was washed with toluene (25 ml) and the cxarnbined organic layers were evaporated under vacuum to give a mixture of (1R,4S)- and (lR,4R)-isomers (ratio 87:13 respectively by nmr spectroscopy techniques) as a dark oil (10.17 g) -which was chrcmatographed on silica (320 g) . Elution with hexane-ethyl acetate mixtures (1:1 to 1:4) gave the title coπpound as a foam (3.94 g, 45.7%), Rf 0.34 (silica; ethyl acetate) and 0.50 (silica; chloroform, methanol; 95:5) -which was sufficiently pure for use in the next step.

A sample of the product (0.92 g) was purified by slow crystallisation from di-2-propyl ether giving the title ccϊipound (0.46 g, 50% recovery) as white crystals, m.p. 123-125 C, [α] -31.6° (c = 0.5, EtOH) . Found: C,61.79; H,5.07; N,3.90. C _lg H ₁₇ Cl ₂ N0 ₂ requires C,61.72; 'H,4.89; N,4.00%. ^•* Η-πmr (300 MHz. CDC1 ₃ ) : ό ^" = 1.60 - 2.01 (m,2H), 2.12 - 2.37 (m,2H) , 2.38 (s,lH), 2.69 and 2.73 (2 NMe rotamer singlets, 3H) , 4.78 - 4.86 and 5.75 - 5.83 (2 rotamer quartets, IH) , 6.89 - 7.04 (m,lH), 7.05 - 7.42 (m,6H), 8.25 and 8.30 (2 formyl CH rotamer singlets, IH) p.p.m.

EXAMPLE 5 trans-OR,4S) (+)-N-l ^* 4-(3,4-dic lorophenyl)-1,2,3.4- tetrahvdro-1-na-ohthy1 ^" )-N-methylformamide To a solution of (1R,4S) (+)-N-[4-(3,4-dichlorophenyl)- 1,2,3,4-teta.Bhydro-4-hydrOxy-l-rja-ch-th.yl]-N-methylfo-nrn amide (0.175 g) in dichlorcarrethane (10 ml) was added triethylsilane (0.13 g) in dic-hloromethane (1 ml) . The resulting solution was cooled to -40°C and stirred as boron trifluoride (0.08 g) in dichloromethane (6.5 ml) was added over 30 minutes. The solution was allowed to warm to room temperature over 90 minutes and then treated with fΛirther triethylsilane (0.13 g) in dichloromethane (1 ml) followed by further boron trifluoride (0.54 g) in dichloromethane (43.5 g) . After overnight stirring at room temperature a third addition of triethylsilane (0.13 g) was made and the solution was gassed with boron trifluoride for about 1 minute. The resulting solution was washed with 2M aqueous sodium carbonate solution (22 ml) and then

saturated brine (25 ml) , and the aqueous phases were combined and back-washed with diethyl ether (2 x 25 ml) . The combined organic extracts were dried over magnesium sulphate and evaporated under vacuum to give an oil (0.17 g) "hich was percolated through a column of silica (16 g) eluting with 1:1 ethyl acetate-hexane to remove the low level of recovered starting material. Evaporation under vacuum of the requisite fractions gave the crude product as an oil (154 g, 92%) . A ^" Η-nmr assay of this material showed it to be an 86:14 mixture of the required (1R,4S) trans-isomer (δ = 4.04 - 4.14 p.p.m., m, for the H proton) and the (1R,4R) cis-isomer (δ = 4.18 - 4.27 p.p.m., m, for the H. proton), respectively.

The separation of trans and cis-isomers is most efficiently achieved after removal of the for yl group. However, crystallisation of a sample of the crude product from 1:3 άit ilorcfmethane-hexane provided a reference sample of the title crarnpound as -white crystals, m.p. 110 - 112°C; Rf 0.62 (silica; chloroform, methanol; 95:5); [α] _D +100.8° (c = 1.03, EtOH) . Found: C,64.66; H,5.37; N,4.12. C^H^C^NO requires C,64.67; H,5.13; N,4.19%. ^** ϊ-πmr (300 MHz. CDC1 ₃ ) : δ = 1.88 - 2.18 (m,3H), 2.21 - 2.37 (m,lH), 2.73 and 2.78 (2 NMe rotamer singlets, 3H) , 4.04 - 4.14 (ra,lH), 4.90 - 4.98 and 5.84 - 5.96 (2 rotamer multiplets, H) , 6.77 - 6.85 (t,lH), 6.91 -7.03 (m,lH), 7.05 - 7.34 (m,4H), 7.36 - 7.47 (m,lH), 8.34 and 8.38 (2 foriπyl CH -rotamer singlets, IH) p.p.m.

EXAMPLE 6 trans- (1R,4S) (+)-N→fethyl-4-(3,4-dichlorophenyl)-1,2,3,4- tetrahvάro-l-naphthylamine hydrochloride A solution of trans-(1R,4S) (+)-N-[4-(3,4- dichlorophenyl)-l,- 2,3,4-tet-rahyάro-l-naphrJyl]-N-methylfo-α^^ (0.15g of 86:14 trans-cis mixture from Example 5) in 2-propanol• (1.5ml) was treated with concentrated aqueous hydrochloric acid (0.45ml) and heated under reflux for 12.5 hours. The solution was refrigerated overnight, then the resulting mixture granulated at 0°C for several hours. Filtration gave the product (O.llOg, 71.4%) as white crystals, m.p. 253-255°C; Rf 0.09 (silica; chloroform, methanol; 90:10); [α] _D +41.4°(c=l, MsOH) .

N.B. N-Me-hyl-l,2,3,4-tetrahydro-l-naphthylamine (ccimpound IIIA) is obtainable according to Coll. Czech. Chem. Ctommun., 1973, 38, 1159.