MXPA97003989A - Procedures and intermediaries to prepare cis (+) 3- [4, 6-dihydroxicroman-3-ilmetil] -4-metoxianil - Google Patents

Abstract

The present invention relates to a process for preparing the compound of formula II: which comprises treating the compound of formula IIIA, wherein YH is (R) -CSA or L-DTTA, with a base to form the compound of formula IIID and treating the compound of formula IIID with hydrogen in the presence of a nob metal catalyst.

Description

PROCEDURES AND INTERMEDIARIES PRRfl PREPARE CIS (+) 3-C4,6- DIHIDROXICROMAN-3-ILMETIL3-4-METQXIANILINA BACKGROUND OF THE INVENTION The present invention relates to compounds of formula (+) wherein fir is an optionally substituted 5 to 8 membered heteroaryl or optionally substituted heteroaryl ring fused to optionally substituted benzene, wherein said heteroaryl ring comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; and pharmaceutically acceptable salts and prodrugs thereof (hereinafter "the active compounds"). More particularly, it relates to methods and intermediates useful in the preparation of the compound of formula < +) which are useful intermediates in the preparation of the compounds of formula T. The active compounds, which are described in International Patent Application No. PCT / US93 / 09171 (the application '171) (assigned to the assignee of this application and incorporated in the present reference), inhibit the production of leukotrienes and / or block the leukotriene receptors and are useful in the prevention or treatment of asthma, arthritis, psoriasis, ulcers, myocardial infarction and related pathological conditions in mammals. U.S. Patent No. 4,661,596, refers to compounds that are disubstituted n-ters, dihydronaphatalenes or tetralins having the formula where dotted lines represent optional double bonds, R "is 2 ~ pyridyl, 2-qui or! il, 2-? irazinyl, 2-quinoxalinyl, 2-thiazolyl, 2-benzothiazolyl, 2-oxazoliol, 2-benzoxazolyl , l-alkyl-2 ~ imidazolyl or l-alkyl-2-benznidazolyl, and Rb is hydroxyl, lower alkoxy, lower alkyl or perfluoroalkyl. U.S. Patent No. 5,059,609 relates to substituted tetralins, chronomania and related compounds. It is claimed that the compounds of these patents inhibit the lipoxygenase enzyme and antagonize the effects of leukotriene 1) 4 and, therefore, are useful in the prevention and treatment of asthma.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to processes and intermediates useful in the preparation of the compound of formula II above. More particularly, the invention relates to a process for the preparation of the compound of formula II comprising the steps of a) treating the compound of formula with L-Selectride (registered trademark) or NaBH <; and CeCl3, to form the compound of formula (±) and treating the compound of formula IVB with acid (R) to phonic camphor, C (R) -CGfi], (±) b) 1) i) treating the compound of formula IVA with a base, preferably Na 2 C 3, to form again the compound of formula IB and ii) treating the compound of formula IVB formed in this step, with ditoluyl-L-tartaric acid CL-DTTA3 to form the compound of formula (+) or 2) treating the compound of formula TVft with hot acetone to isolate the compound of formula (+) and c) treating the compound of formula IIIB or IIIC with a base to form the compound of formula and then treating the compound of formula IIID with H2 on a noble metal catalyst, preferably Pd (0H) 2, to form the compound of formula II. The invention also comprises a compound selected from the group consisting of (±) (±) (+) DETAILED DESCRIPTION OF THE INVENTION The preparation of the compound of formula II, and certain of the starting materials used therein, are illustrated in the following reaction scheme. All articles, books, patents and patent applications cited in the following discussion are incorporated by reference.

SCHEME SCHEME (CONTINUED) -CS0 4 SCHEME (CONTINUED) 5 4 where Ar is as defined above, Compound 1_ is converted to compound 2_ by means of treatment with a hydride reducing agent. Preferred reducing agents are CeCl3 / NaBr- and L-Selectp of. When using CeCl3 / NaBr-corno reducing agent, the reduction is effected in solvent solvents with alcohols and ethers and mixtures thereof. There are no temperature or pressure conditions with this reducing agent. The only condition is that none of the solvents is reactive with the reactants or products of the reaction. A preferred solvent is a mixture of methanol and THF. When L-Selec + pde is the reducing agent, the reduction is preferably carried out at a temperature below about 0 ° C in an inert atmosphere. Preferably, the reduction is carried out at a temperature between about -70 and about -80 ° C in an inert atmosphere such as dry nitrogen or argon. The preferred reducing agent is L-Selectride, which is used at a temperature below -70 ° C under a nitrogen atmosphere. Compound 1 is prepared from known starting materials, by methods known in the art. Compound 3_ is prepared by treating compound 2_ with (R) -alphafor sulfur acid. The reaction is carried out at a temperature between about -20 and about + 50 ° C in a polar solvent such as an ether, ester or alcohol. Preferably, the reaction is carried out at room temperature in ethyl acetate. Compound 2 does not need to be isolated from the reaction mixture of the previous step, and this procedure It can be done directly on the map. The preparation of compound 5_ from the compound 3 is effected by treating compound 3_ with an inorganic base such as a hydroxide, carbonate or bicarbonate of an alkali metal, such as sodium or potassium, or an alkaline earth metal, such as calcium or magnesium in a mixture of water and a polar solvent such as an ester or ether for regenerating compound 2. Preferably, the reaction is carried out in a mixture of water and ethyl acetate. A preferred base is sodium bicarbonate. Compound 2 is then treated with? DTTA in ethyl acetate to form the compound. The reaction can be carried out at a temperature between about zero and about 78 ° C, preferably at room temperature. The compound 2 does not need to be isolated from the reaction mixture of the previous step, and this can be carried out directly on it. Compound 5 is converted to compound 6 under the same conditions as above for the conversion of compound 3_ to compound 2. It is not necessary to isolate compound 6_ from the reaction mixture, which can be used directly in the next step of hydrogenolysis. Alternatively, compound 3_ can be converted to compound 6 by the following method. Compound 4_ is obtained by resolution of compound 3_ by hot acetone. A preferred resolving agent is aqueous acetone wherein the ratio of acetone to water is < le aprimamement f) 5:15 to approximately 99: 1. A preferred ratio Acetone: water is 93: 7. Compound 3_ is dissolved in hot aqueous acetone at about 50 to 55 ° C and, upon cooling of the solution, crystallized the desired, less soluble compound 4. Then, the compound _ is converted to the compound ñ by treatment with a base, ba or the same conditions < As indicated above, for the conversion of compound 5_ to compound 6 and the reaction mixture can be used directly in the next step without previous isolation of compound ñ_. Compound 6 is converted to compound 7 by reduction with hydrogen in the presence of a noble metal hydrogenolesis catalyst. A preferred hydrogenase catalyst is Pd (0H) 2. Preferably, the reaction is carried out at a hydrogen pressure of about 1.05 to about 7 kg / cm2 in the presence of a solvent such as a lower alkanol, ether or ester at room temperature. Most preferably, the reduction is carried out at a pressure of 2.8 g / cm2 in a solvent comprising a mixture of ethanol and ethyl acetate. Preferably, the solvent consists of methanol. Compound 7 can be converted to compound 1_ by means of the methods described in Examples 9 and 10 below, or in Example 18 of the '171 patent. For use in the prevention or treatment of asthma, l arthritis, psoriasis and gastrointestinal ulcers in a mammal, including man, a compound of formula T is given in an inhibitory amount of 5-1 ipoxygenase and / or leukotpene receptor blocker of about 0.5-50 rng / 1-g / d In a single dose or in divided doses daily .. A preferred dosage scale is 2-20 rng / kg / day, although in private homes, dosing may be required outside the larger scale, at the discretion of the attending physician. The preferred route of administration is usually oral, but in < Special SOS parenteral administration (eg, intramuscular, intravenous, intradermal) is preferred, for example when oral absorption is impaired, as is the case with disease, or when the patient is unable to swallow. The active compounds of the invention can be administered orally, topically, parenterally, by means of aerosol inhalation or rectally in unit dosage formulations containing conventional non-toxic pharmaceutically acceptable vehicles and adjuvants. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular injection, intrasternal injection or infusion techniques. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example as tablets, troches, lozenges, or aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, or syrups. or elixirs The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, sabotagers, coloring agents and preservatives, to provide pharmaceutically elegant and pleasant preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulation and disintegration agents, for example corn starch, or algimic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a material such as glyceryl monostearate or glycemic distearate may be used to retard time. They can also be coated by means of the techniques described in, for example, U.S. Patent Nos. 4,256,108; 4,166.45 ?; and 4,265,874 to form osmotic therapeutic tablets for release controlled Hard capsules for oral use can be presented as gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or wherein the soft capsules can be presented as co-or capsules. gelatin capsules wherein the active ingredient is mixed with water or an oily medium, for example peanut oil, ina liquid or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, sodium carboxy ethylcellulose, rilethylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example full polyoxie stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols , for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as monooleate or polyoxyethylene sorbitol, or condensation products of ethylene oxide products with partial esters derived from fatty acids and anhydrides of hexitol, for example polyethylenesorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl p-hydroxybenzoate or n-propyl, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffm. The oily suspensions may contain a weighing agent, for example beeswax, solid paraffin or cetyl alcohol. To provide a pleasant oral preparation, sweetening agents and flavoring agents, such as those set forth above, may be added. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid. The powders and dispersible granules suitable for the preparation of an aqueous suspension by means of the addition of water, provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example sabotagers, sweeteners and colorants. The pharmaceutical compositions of the invention they may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or liquid oil, a mineral oil such as liquid paraffm or mixtures thereof. Suitable emulsifying agents can be natural gum, for example gum acacia or gum tragacanth; naturally occurring phosphatides such as, for example, soya and lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan inonooleate. The emulsions may also contain sweetening and sabotagents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and sabotage agents and dyes. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known technique using the appropriate wetting or dispersing agents and suspending agents that have been mentioned above. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic reactive diluent or solvent, for example, as a solution in 1,3-butanedione. Among the vehicles and acceptable solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil including synthetic mono or diglycerides can be employed. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables. The active compounds of the invention can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is a solid at ordinary temperature but is liquid at the rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc. are used, which contain the active compounds of the invention. For administration by inhalation, the active compounds of the invention are conveniently released in the form of an aerosol spray presentation of packets under pressure or a nebulizer. The preferred composition for inhalation is a powder that can be formulated as a cartridge from which the powder composition can be inhaled with the aid of a suitable device. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to release a measured quantity.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending on the patient being treated and the particular administration mode. Dosage levels in the order of approximately 0.05 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the conditions indicated above (approximately 2.5 mg to approximately 7 grams per patient per day). For example, inflammation can be effectively treated with the administration of about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 0.5 g to about 3.5 g per patient per day). The present invention is illustrated with the following examples, but is not limited to the details thereof.

EXAMPLE 1 3-r4-Oxo-6-benzyl? Chroman-3? L? Denmet?] -4-metho? An? Trobenzene A slurry suspension was heated at 50 ° C for 24 hours. 6-benzo-lchroman-4-one (44.96 g, 1.77 moles) in a methanolic solution (6.9 1) containing 2-rnetox-4-n? Trobenzaldehyde (319.98 g, 1.77 moles) and pyrrolidine (147.19 ml) 1.77 moles). The reaction mixture was allowed to cool to 22 ° C for 18 hours. The solid yellow product was isolated by filtration. Produced (dry weight) 657.55 g (89%). P.f. = 156-57 ° C. 13c NMR 6 181. 7, 162.7, 156.1, 153.7, 140.9, 136.6, 133.1, 130.9, 128.1, 127.6, 126.8, 126.0, 125.6, 124.1, 121.8, 119..4, 110.7, 109.6, 70.6, 67.6, 56.5.

EXAMPLE 2 3- [4 ~ 0xo-6-benzyloxycortan-3-i.lmethyl-3-4-nitroxyaniline The title compound of example 1 (35.lg, 85 immoles), dissolved in tetrahydrofuran (TF) (1.5 1), was hydrogenated at 3.5 kg / cpv2, for 4 hours, on 5% of Pt in C ( 7.08 g, humidity 50% water). The reaction mixture was filtered through Celite (trademark). The volume of the reaction mixture was reduced by means of vacuum distillation at 140 rnl and 210 ml of isopropyl ether (IPE) were then added to the reactor. Then 210 ml of solvent were removed, by means of vacuum distillation, and 210 ml of IPE were added to the reactor. Then another 140 ml of solvent was removed, by means of vacuum distillation, and 500 rnl of IPE was added to the reactor. The product began to crystallize and heating was stopped. The reaction mixture was allowed to cool to 24 ° C for 16 hours. The separated white solid product was collected by vacuum filtration and dried to yield 27.42 g (83%), 13 C NMR (CD3) 2S03 6 193.6, 156.1, 153.0, 149.2, 142.5, 137.4, 128.0, 126.9, 125.4, 120.6, 119.5, 117.4, 113.4, 112.5, 109.6, 70.1, 56.0, 45.8, 27.4, 23.2.

EXAMPLE 3 Salt of cis (+) 3-r4-hydroxy-6-benzyloxy-chroman-3-yl-methyl-4-methoxyaniline (R) -alphaforphonic acid A. Heptahydrate cerium heptachloride was added (766.2 g, 2.05 moles) to a tetrahydrofuran (71) / methanol (2.4 L) solution of the title compound of Example 2 (400 g, 1.02 mol). The reaction mixture was cooled to < -70 ° C, and sodium borohydride (38.88 g, 1.02 mol) was added in four portions at 5 minute intervals. The reduction was completed by means of TLC in 1.5 hours and the reaction mixture was stirred an additional 18 hours during which it was heated to 23 ° C. Acetate (600 nmol) was added and the reaction mixture was stirred for 1 hour to quench any remaining borohydride. The solvents were removed under vacuum and dissipated twice with 800 i of ethyl acetate. Then ethyl acetate (4 1), saturated ammonium chloride (2550 ml), and Celite (50 g) were added, and the reaction mixture was stirred for 15 minutes. The mixture was filtered through Celite, the liquid phases were separated and the ethyl acetate layer was washed with water (2550 ml). The organic phase was treated with magnesium sulfate, and the volume was reduced under vacuum to 4 1. (R) -alphaforphosulphonic acid (214.98 g, 0.925 mol) was added and a solid precipitated in 15 minutes. The resulting mixture was stirred overnight and filtered. The precipitate was washed with acetone (1.8 1) and dried under vacuum. A white solid was isolated, yield: 516 g, 80%. This material contained approximately 15% of the trans isomer. The removal of the trans isomer was achieved by suspending in methanol (2.5 1) for 18 hours. The residue was filtered and dried to yield the title compound co or a white solid (382.8 g, 74%). B. The title compound was also prepared as follows. The title compound of Example 2 (3.0 g, 7.71 mmol) was dissolved in TF (50 nmol) and cooled to about -70 ° C or less. L-Selectride (registered trademark) (1 M, 11 ml, 11 mmol) was added dropwise while maintaining the temperature at about -70 ° C or less. The reaction mixture was stirred for 45 minutes, tri-ethylamine N-oxide dihydrate (3.7 g, 33 mmol) was added and the cooling bath was removed. After heating to 20 ° C, the reaction mixture was heated to reflux for 5 hours and stirred at 23 ° C for 18 hours. Aqueous ammonium chloride and ethyl acetate were added. After separation of the phases, the organic phase was washed with aqueous ammonium chloride and brine, treated with magnesium sulfate and the solvent was evaporated to yield an oil (4.5 g). The oil was dissolved in methanol (6 mL) and ethyl acetate (54 mL). (R) -alphaforphosulonic acid (1.7 g 7.32 mmol) was added to the solution which was stirred for 3 hours during which a precipitate formed. The precipitate was recovered by filtration and dried to yield 3.68 g (77%) of the title compound as a white solid containing less than about 5% of the isomer trans EXAMPLE 4 ci (+) 3- [4-H? Drox? -6-benzyloxy-chroman-3-ylmethi] -4-methox? Anil i a The title compound of Example 3 (9 g) was suspended in ethyl acetate (90 ml) and treated twice with 30 ml of aqueous sodium carbonate. The aqueous layer was washed with water (30 ml) and dried over magnesium sulfate. The solvent was removed under vacuum to yield the title compound as a thick yellow oil. 13 C NMR [(CD3) 2 0ld 152.2, 149. 4, 148.3, 142.4, 137.9, 128.8, 128.5, 128.1, 128.0, 126.6, 117. 5, 117.0, 116.5, 116.3, 112.5, 70.1, 64.9, 6.46, 56.2, 38.9, 27.7.

EXAMPLE 5 Salt of cis ("•) 3-C4-hydroxy-6-benzyloxy chroman-3-ylmethi] 4-rnetoxyanilindindoluyl-L-tartaric acid A. The title compound of Example 3 (40 g, 64 mmol) was suspended in ethyl acetate (400 mL) and the suspension was stirred twice with 700 mL of saturated aqueous sodium bicarbonate. The ethyl acetate solution containing the aniline free base was washed with water (162 ml) and treated with magnesium sulfate. The volume was reduced under vacuum to 251 ml and the resulting solution was treated with acid.

? R d? -? - tolu? l-L-tartáp co (24.28 g, 62.8 rn oles). A precipitate formed immediately and the mixture was stirred for 18 hours and then filtered. The precipitate (36.9 g) was suspended twice with ethyl acetate (550 ml and 150 ml, respectively), which had no trans isomer and an enantiorneric purity of about 98.4%. B. The title compound was also prepared as follows: The title compound of Example 3 (20 g, 32 rnmoles) was suspended in ethyl acetate (200 rnl) and stirred twice with 323 ml of saturated aqueous sodium bicarbonate. The ethyl acetate solution containing the free base of aniline was washed with 81 rnl of water and dried with magnesium sulfate. The volume was reduced to 125 ml under vacuum, and the resulting solution was treated with di-p-toluyl-L-tartaric acid (7.44 g, 19.2 rnmoles). A precipitate formed and the mixture was stirred immediately for 18 hours. The precipitate (10.59 g) was suspended in ethyl acetate (52 ml), and dried either ba or vacuum to yield a white solid (8.65 g, 82% of theory) which had a trans isomer content of about 0.2% and an enantiomépca purity of approximately 98.6%. C. Alternatively, the title compound of Example 3 is dissolved in ethyl acetate and treated, as indicated above in sections A and B, with di-p-toluyl-L-tartaric acid to form the title compound of this example.

EXAMPLE 6 cis (+) 3-C4-Hydroxy-6-benzyloxy-horroroan-3-ylmethyl-3-4-hydroxyaniline A suspension of the title compound of Example 5 (88 mg) in ethyl acetate was treated twice with 2 mL of saturated aqueous sodium carbonate. The organic layer was separated, washed with water (2 rnl) and treated with magnesium sulfate. The solvent was removed under vacuum to produce a thick oil. Ca] D - +128.9 (c = 0.35, CH30H).

EXAMPLE 7 Salt of cis (+) 3- [4-hydroxy-6-benzyloxy-chroman-3-yl-ethyl] -4-methoxyanilin- (R) -camphorsulfonic acid The title compound of example 3 (13.4 g) was dissolved in acetone (405 ml) and water (54 ml) at 50 ° C. Complete solution was obtained after 45 minutes and then the solution was allowed to cool to room temperature and stirred for 18 hours. The title compound was isolated by vacuum filtration as a white solid (3.15 g, 23%) Ca] D = + 36.4 (c = 0.45, CH 3 OH).

EXAMPLE 8 cis (+) 3C, 6-Dihydroxy-roman-3-ylmethyl-3-4-methoxyaniline A. The title compound of example 4 or 5 (77 g, 99 mmol) was suspended in a mixture of ethyl acetate (770 ml) and saturated sodium bicarbonate (250 ml) and stirred vigorously for 15 minutes. The layers were separated and the organic phase was washed with saturated sodium bicarbonate (250 ml) and water (250 ml) and then treated with magnesium sulfate. The volume was reduced under vacuum to 390 nl. Methanol (390 ml) and Pd (0H) 2 (11.62 g, 50% moisture water) were added to the mixture and the content was hydrogenated at 2.8 kg / cm for 2 hours. The reaction mixture was filtered through Celite and the solvent was removed from the filtrate under vacuum to give the crude product as a pale pink solid (25.8 g., 86%). This solid was suspended in methanol (12 ml) / methylene chloride (129 rnl) for 1 hour, filtered and dried ba or vacuum to give 22.57 g (88%) of the title compound as a separate white solid Cpf = 195-96 ° C, L "aJD = +122.3 (c = 0.81, TF] .Al.Cal. For C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C, 67.65; H, 6.37; N, 4.63. B. Alternatively, the title compound of Example 6 was dissolved in methanol and treated with H in the presence of Pd (0H) 2, ba or the conditions described in section A to produce the title compound of this example.

EXAMPLE 9 cis (+) 3- [4-Hydroxy-6- (7-chloroquinolin-2-yl) methoxy chroman-3-ylmethyl-4-roethoxyaniline To a solution of the title compound of Example 8 (25 g, 83 mol) in dirnetilformarni da (DMF) (125 ml) was added potassium t-butoxide (9.775 g, R7 rnmoles) in one portion. The reaction mixture was stirred for 1 hour, 7-chloroquinoline-2-yl-methyl-4-chloride (17.6 g, 83 mmol) in DMF (0.25 mmol) was added dropwise over 2 hours and the reaction mixture was stirred by 18 additional hours. Ethyl acetate (300 mL) and water (1250 mL) were added to the reaction mixture which was stirred 15 minutes and filtered through Celite. The phases were separated and the aqueous phase was extracted again with ethyl acetate (300 ml). The combined organic extracts were washed 2 times with 500 ml of water, twice with 500 ml of aqueous sodium carbonate (20% solution) and once with brine (500 nl) and then treated with magnesium sulfate. The solvent was removed under vacuum to give a light yellow solid residue (38.2 g, 96%). The residue was pulped again in methanol (79 rnl) and isopropyl ether (711 ml) for 18 hours. The title compound was recovered after filtration, and dried as a white solid. Yield 31.2 g (79%). 13C NMR (CDC1-3) 6 159.5, 152.0, 150.3, 149.0, 147. B, 140.4, 136.7, 135.5, 128.9, 128.2? 127.9, 127.4, 125.9, 124.2, 119.3, 118.5, 117.5, 117.1, 116.0, 114.2, 112.2, 71.5, 65.4, 64.5, 56.3, 40. 3, 27.0.

EXAMPLE 10 cis (+) 3- [4-Hydroxy-6- (5,6-difluoro-benzothiazol-2-yl) -? -toxy-chroman-3-ylmethyl-34-methoxyaniline Potassium t-butoxide (1.56 g, 14 mmol) was added in one portion to a solution of the title compound of Example 8 (4 g, 13.2 rnmoles) in DMF (20 rnl) at 23 ° C. The contents were agitated for 1 hour. A solution of 5,6-difluorobenzothiazol-2-yl ethyl chloride ("the chloride") (2.92 g, 13.2 rnmoles) in DMF (20 mL) was added over a period of 1 h and the reaction mixture was stirred by 18 additional hours. Potassium t-butoxide (298 g, 2.5 mrnol) was added again in one portion and the contents were stirred for 1 hour. Additional chloride (583 mg, 2.6 mmol) was added in one portion and the contents were stirred for 1 hour. Ethyl acetate (50 mL) and water were added to the reaction mixture, which was stirred 15 minutes and filtered through Celite. The phases were separated and the aqueous phase was extracted again with ethyl acetate (50 mL). The combined organic extracts were washed twice with 50 ml of water, twice with 50 ml of aqueous sodium carbonate (20% solution), once with brine (50 ml) and then treated with magnesium sulfate. The volume of solvent was reduced under vacuum to 20 ml. Drop by drop, hexane (60 nl) was added to the extract, and a precipitate formed. The mixture it stirred for 18 hours. The precipitate was recovered by means of fi- ration and dried to give a tan solid (5.84 g, 91%). The precipitate was pulped again in isopropanol (29 rnl) for 18 hours, recovered by filtration and dried to yield 4.51 g (70%) of the title compound as a light yellow solid.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing the compound of formula which comprises treating the compound of formula 3 I l l And H (+) where YH is (R) -CSA or L-DTTA, with a base to form the compound of formula and treating the compound of formula IIID with hydrogen in the presence of a noble metal catalyst.

2. The process according to claim 1, further characterized in that said catalysts Pd (0H) 2.

3. The method according to claim 1, further characterized in that YH is L-DTTA.

4. The process according to claim 1, further characterized in that YH is (R) -CSA.

5. The process according to claim 3, further characterized in that the compound of formula IIIA is prepared by treating the compound of formula (±) a) when YH is L-DTTA, i) with a base to form the compound of formula (±); and 11) treating the compound of formula IVB with L-DTTA; or b) when YH is (R) -CSA, with hot aqueous acetone and recover the product from the acetone solution by means of cooling and filtration.

6. The method according to claim 5, further characterized in that the compound of formula IVA is prepared by treating the compound of formula (±) with a reducing agent selected from NaBH "/ CeCl3 or L-Selectride, to form the compound of formula IVB and then triact the compound of formula EVB with (R) -CSA to form the compound of formula IVA.

7. The method according to claim 6, further characterized in that said reducing agent is L-Selectride.

8. - A procedure p > to prepare the compound of formula (+) which comprises the steps of a) treating the compound of formula with a reducing agent- selected from L-Seiectpde and NaBH «/ CeCl3, and treating the resulting product with (R) ~ phonyl-camphor-sulphonic acid to form the compound of formula (±) b) prepare the formula compound wherein YH is L-DTTA or (R) -CSR, treating the compound of formula IVA, i) when YH is L-DTTA; 1) with a base for form the compound of formula (±) and 2) treating the compound of formula IVB with ditoluyl-L tartaric acid to form the compound of formula (+) or ii) when YH is (R) -CSA, with hot acetone and cooling the hot acetone solution to produce, after filtration, the compound of formula (+) and c) treating the compound of formula IIIA, wherein YH is as defined above, with a base to form the compound of ITID formula, followed by treatment of the compound of formula IIID with hydrogen in the presence of a noble metal catalyst to form the compound of formula II.

9. The process according to claim 8, further characterized in that said catalysts Pd (OH) 2-

10. The compound of formula wherein YH is (R) -CSA, L-DTTA or is absent, and the racemates and (+) forms of the mimes provided that when YH is L-DTTA, the compound of formula IIIA is in the (+) form.

11. The compound according to claim 10, further characterized in that YH is L-DTTA.

12. The compound according to claim 10, further characterized in that YH is (R) ~ CSA and the compound is in the (+) form.

13. The compound according to claim 10, further characterized in that YH is (R) -CSA and the compound is present co or racerna.

14. The compound according to claim 10, further characterized in that YH is not present and the compound is in the (+) form.

15. The compound according to claim 10, further characterized in that YH is not present and the compound is present as r-acernate.