Title of Invention	CHROMAN DERIVATIVES AND A PROCESS FOR PREPARING THE SAME
Abstract	Chroman derivatives of the formula I in which R1 is acyl having 1-6 carbon atoms, -CO-R5, phenylacetyl, phenoxyacetyl, methoxycarbonyl, ethyoxy-carbony, 2,2,2- trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxy-carbonyl, 4-methoxybenzyloxycarbonyl, 9- fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl, R2 is H or alkyl having 1-6 carbon atoms, R3 and R4 are each, independently of one another, H, alkyl having 1-6 carbon atoms, CN, Hal or COOR2, R5 is phenyl which is unsubstituted or monosubstituted or disubstituted by alkyl having 1-6 carbon atoms, OR2 or Hal, X is H,H or O, Hal is F,Cl,Br or I, and salts thereof where N-(chroman-2-ylmemyl)cyclopropanecarboxamide is excluded.

Title of Invention

CHROMAN DERIVATIVES AND A PROCESS FOR PREPARING THE SAME

Abstract

Chroman derivatives of the formula I in which R1 is acyl having 1-6 carbon atoms, -CO-R5, phenylacetyl, phenoxyacetyl, methoxycarbonyl, ethyoxy-carbony, 2,2,2- trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxy-carbonyl, 4-methoxybenzyloxycarbonyl, 9- fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl, R2 is H or alkyl having 1-6 carbon atoms, R3 and R4 are each, independently of one another, H, alkyl having 1-6 carbon atoms, CN, Hal or COOR2, R5 is phenyl which is unsubstituted or monosubstituted or disubstituted by alkyl having 1-6 carbon atoms, OR2 or Hal, X is H,H or O, Hal is F,Cl,Br or I, and salts thereof where N-(chroman-2-ylmemyl)cyclopropanecarboxamide is excluded.

Full Text	Chroman derivatives The invention relates to chroman derivatives of the formula I in which R1 is acyl having 1-6 C atoms, -CO-R5 or an amino protective group, R2 is H or alkyl having 1-6 C atoms, R3, R4 in each case independently of one another are H, alkyl having 1-6 C atoms, CN, Hal or COOR2, R5 is phenyl which is unsubstituted or mono- or disubstituted by alkyl having 1-6 C atoms, OR2 or Hal, X is H,H or O, Hal is F, C1, Br or I, and their salts. The invention also relates to the optically active forms, the racemates, the enantiomers and also the hydrates and solvates, e.g. alcoholates, of these compounds. Similar compounds are disclosed in EP 0 707 007. The invention was based on the object of finding novel compounds which can be used, in particular, as intermediates in the synthesis of medicaments. It has been found that the compounds of the formula I and their salts are important intermediates for the preparation of medicaments, in particular of those which show, for example, actions on the central nervous system. - 2 – The invention relates to the chroman derivatives of the formula X and their salts. Above and below, the radicals R1, R2, R3, R4, R5 and X have the meanings indicated in the formulae I and II, if not expressly stated otherwise. In the above formulae, alkyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms. Alkyl is preferably methyl or ethyl, furthermore propyl, isopropyl, in addition also butyl, isobutyl, sec-butyl or tert-butyl. Acyl has 1 to 6, preferably 1, 2, 3 or 4, C atoms. Acyl is in particular acetyl, propionyl or butyryl. R2 is preferably H, in addition also methyl, ethyl or propyl. R3 and R4 are preferably H. R5 is preferably, for example, phenyl, o-, m- or p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-fluorophenyl. The radical Rl is acyl, -CO-R5 or else an amino protective group which is known per se; acetyl is particularly preferred. The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise uncritical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" is to be interpreted in the widest sense in connection with the present process and the present compounds. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in - 3 - particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro- ethoxycarbony1, BOC (tert-butoxycarbonyl) , 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (carbobenzoxycarbonyl, also called "Z"), 4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxy-carbonyl) ; arylsulfonyl such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protective groups are BOC and Mtr, in addition CBZ or FMOC. The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms. The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I according to Claim 1 and also of their salts, in which X is 0, characterized in that a compound of the formula II in which R1, R2, R3, R4 have the meanings indicated in Claim 1 and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst. The invention also relates to a process for the preparation of chroman derivatives of the formula I - 4 – according to Claim 1 and also of their salts, in which X is H,H, characterized in that a compound of the formula II in which R1, R2, R3, R4 have the meanings indicated in Claim 1 and X is 0, is hydrogenated with the aid of an enantiomerically enriched catalyst, and then reduced in the customary manner. In particular, it has been found that (2-acetylaminomethyl)chromen-4-one can be hydrogenated using various enantiomerically pure rhodium-diphosphane complexes to give enantiomerically enriched (2-acetylaminomethyl)chroman-4-one. The invention also relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the enantiomerically enriched catalyst is a transition metal complex. Particularly preferably, the catalyst is a transition metal complex comprising a metal selected from the group rhodium, iridium, ruthenium and palladium. The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the catalyst is a transition metal complex in which the transition metal is complexed with a chiral diphosphane ligand. The ligands below may be mentioned by way of example: - 5 - - 6 - Depending on the choice of the (R) or (S) enantiomer of the ligand in the catalyst, the (R) or (S) enantiomer is obtained in an excess. Precursors used for the chiral ligands are compounds such as, for example, Rh(COD)2OTf (rhodium-cyclooctadiene triflate), [Rh(COD)Cl]2, Rh(COD)2BF4, [Ir(COD)Cl]2, Ir(COD)2BF4 or [Ru(COD)Cl2]x. The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), mainly under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail. - 7 - If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I. The compounds of the formula II are known in some cases; the unknown compounds can easily be prepared analogously to the known compounds. The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is O is carried out according to the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as, for example, methanol or ethanol. Suitable inert solvents are furthermore, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as isopropanol, n-propanol, n-butanol or tert- butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, and optionally also mixtures of the solvents mentioned with one another or mixtures with water. The reaction time of. the enantioseleetive hydrogenation, depending on the conditions used. is between a few minutes and 14 days; the reaction - 8 – temperature is between 0 and 150°, normally between 20 and 130°. Customarily, the catalyst/substrate ratio is between 1:2000 and 1:50, particularly preferably to 1:1000 and 1:100. The reaction time is then, for example, between 3 and 20 hours. The hydrogenation is carried out under 1-200 bar of hydrogen, preferably at 3-100 bar. The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is H,H is carried out according to the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as methanol or ethanol, such as described above, followed by a conversion of the 4-oxo group into a methylene group according to known conditions. The reduction is preferably carried out using hydrogen gas under transition metal catalysis (for example by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol) . The conversion of compounds of the formula I in which R3, R4 is COOalkyl into compounds of the formula I in which R3, R4 is COOH is carried out, for example, using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100°. The removal of a radical R1 from a compound of the formula I is carried out - depending on the protective group used - for example using strong acids, expediently using TFA (trifluoroacetic acid) or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic - 9 – acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are possible. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures are expediently between approximately 0 and approximately 50°; the reaction is preferably carried out between 15 and 30°. The BOC group is preferably removed using TFA in dichloromethane or using approximately 3 to 5 N hydrochloric acid in dioxane at 15-30°. The removal of the acetyl group is carried out according to customary methods (P.J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994). Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100° and pressures between approximately 1 and 200 bar, preferably at 20-30° and 1-10 bar. A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are particularly those which yield physiologically acceptable salts. Thus inorganic acids - 10 – can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid . or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids and laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I. On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, using bases (e.g. sodium - or potassium hydroxide or carbonate), or into the corresponding ammonium salts. The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments. Appropriate medicaments are described, for example, in EP 0 707 007. The invention accordingly relates in particular to the use of the compounds of the formula I according to Claim 1 in the synthesis of (R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]- chroman and its salts, characterized in that a) a compound of the formula II - 11 - in which R1 has the meaning indicated in Claim 1, R2, R3 and R4 are H and X is 0, is hydrogenated with the aid of an enantiomerically enriched catalyst, b) in that, from the enantiomerically enriched mixture of the (R) and (S) compounds of the formula I thus obtained, in which R1 has the meaning indicated in Claim 1, R2, R3 and R4 are H and X is 0, the enantiomerically pure (R) compound of the formula I, in which R1 has the meaning indicated in Claim 1, R2, R3 and R4 are H and X is 0, is obtained by crystallization, in that c) the enantiomerically pure (R) compound of the formula I, in which R1 has the meaning indicated in Claim 1, R2, R3 and R4 are H and X is 0, is then reduced in the customary manner, in that d) the radical R1 in which R1 has the meaning indicated in Claim 1, R2, R3 and R4 are H and X is H,H, is removed from the (R) compound of the formula I thus obtained, in that e) the (R)-(chroman-2-ylmethyl)amine thus obtained is converted into its acid addition salt and this is reacted in a known manner to give (R)-2-[5-(4- fluorophenyl)-3-pyridylmethylaminomethyl]chroman and, if appropriate, converted into its acid addition salt, - 12 – where the recovery of the (R) enantiomer can also be carried out fay crystallization from the enantimerically enriched (R,S) mixture after stage c) or after stage d). The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments which show actions on the central nervous system-Above and below, all temperatures are indicated in °C. In the following examples, "customary working up" means: if necessary, water is added, the mixture is adjusted, if necessary, depending on the constitution of the final product, to a pH of between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Rf values on silica gel. Examples Experimental data (complex preparation, hydrogenation, analytical methods): All reactions were carried out under inert conditions (i.e. anhydrous and oxygen-free reaction conditions). 1. Preparation of the catalyst/substrate solution: - 13 - 1.1 Example: 11.2 mg. of Rh(COD)2OTf (rhodium-cyclooctadiene triflate) were dissolved in 5 ml of methanol and cooled to 0°C. A cooled solution of 1.1 eq of bisphosphane (e.g. 12.6 mg of (R,R)-Skewphos) in 5 ml of methanol was then added. After stirring at room temperature for, 10 min, the complex solution was treated with the substrate solution consisting of 110 mg of (2- acetylaminomethyl)chromen-4-one in 10 ml of methanol. 1.2. Example: 51.4 mg of [Hh(COD)Cl]2 were dissolved in 4 ml of the solvent mixture toluene/methanol 5:1 and treated with a solution consisting of 5 ml of toluene, 1 ml of methanol and 1.1 eq of bisphosphane (e.g. 130.6 mg of (R)-BINAP). 1 ml of this catalyst complex solution was added to 510.8 mg of (2-acetylaminomethyl)chromen-4-one, dissolved in 15 ml of toluene and 3 ml of methanol. 2. Enantioselective hydrogenation The catalyst/substrate solution to be hydrogenated was filled into an autoclave in a countercurrent of protective gas. The protective gas atmosphere was replaced by flushing several times with hydrogen . (1-5 bar H2 atmosphere) . The batches analogous to 1.1. reacted even at room temperature and 5 bar of hydrogen. The catalysts analogous to 1.2- afforded the best results at 50°C and 80 bar of hydrogen. As a rule, the hydrogenation was terminated after 15 hours. 3. Sampling and analytical methods A sample was taken in a countercurrent of protective gas. The complex was separated off by column chromatography on silica gel (eluent: ethyl acetate) before the determination of the enantiomeric excesses. - 14 – The enantiomeric excess of the hydrogenation product was determined on the chiral HPLC phase; Column: Daicel Chiralcel OJ (I.D. x length/mm; 4.6 x 250) Eluent: n-hexane: i-propanol =9:1 Flow: 0.8 ml/min (18 bar, 28°C) Detection: UV 250 nm Retention: Rc (R) = 27 min; Rc(S) = 29 min The concentration of the crude hydrogenation solution led to the precipitation of the product. An increase in the enantiomeric excess was detected by means of fractional crystallization. 4. Further reduction After complete conversion was detected, the reduction of the keto group was carried out by means of palladium-carbon as a one-pot process. The crude ketone solution resulting from the homogeneous hydrogenation was treated with 10% by weight water-moist palladium-carbon (e.g. 100 mg of water-moist Pd/C to 1 g of (2-acetylaminomethyl)chromen-4-one) and 1 ml of glacial acetic acid. Hydrogenation was carried out at a hydrogen pressure of 7 bar and 50°C for 14 h. 5. Work-up and analytical methods The palladium-carbon was removed by filtration. The enantiomeric excess of the hydrogenation product was determined on a chiral HPLC phase: Column: Daicel Chiralcel OJ (I.D. x length/mm: 4.6 x 250) Eluent: n-hexane: i-propanol = 9:1 Flow: 0.8 ml/min -(18 bar, 28°C) Detection: UV 250 nm Retention: Rt(R) = 25 min; Rc(S) = 27 min - 15 - During the reduction with palladium-carbon, the enantiomeric excess remained unchanged. The concentration of the crude hydrogenation solution led to the precipitation of the product. An increase in the enantiomeric excess was detected by means of fractional crystallization. - 16 – Enantioselectivities of the homogeneous hydrogenation: Efafo No. Complexmetal anion ligand (addition) Solvent Pressure %ee 1. 18 Rh-OTf-(R,R)-EtDuphos CH2C12 55 S 2. 13 Rh-OTf-(R,R)-EtDuphos THF 44S 3. 14 Rh-OTf-(R,R)-EtDuphos McOH 64S 4. 15 Rh-OTf-(R,R)-EtDuphos EE 33 S 5. 6 Rh-OTf-(R,R)-EtDuphos iPrOH 20 S 6. 23a Rh-OTf-(R,R)-EtDuphos MeOH 34 S 7. 23b Rh-OTf-(R,R)-EtDuphos McOH 36 S 8. 23c Rh-OTf-(R,R)-EtDuphos MeOH 45 S 9. 23d Rh-OTf-(R,R)-EtDuphos MeOH 31 S 10, 12 Ru-Cl2-(R)-BINAP (AgOOCCF3) iPrOH 50 S 11. 19 Rh-ClO4(S.S)-Chiraphos iPrOH - 12. 20 Rh-OTf-(S.S)-D1OP THF rac. 13. 20 Rh-OTf-(S.S)-DIOP THF 8R 14. 21 Rh-OTf-(R.R)-Skewphos THF - 15. 22b Rh-OTf(S.S)-BPPM MeOH 7S 16. 24a Rh-OTf(R.S)BPPFOH MeOH 54 R 17. 24b Rh-OTf-(R.S)-BPPFOH MeOH 54 R 18. 24c Rh-OTf-(R.S)-BPPFOH MeOH 63 R 19. 25a Rh-OTf-(R)-BINAP MeOH 1R 20. 25b Rh-OTf-(R)-BINAP MeOH 5 rac. 21. 26a Rh-OTf-(S.S)Norphos MeOH 42 R 22. 26b Rh-OTf-(S.S)-Norphos MeOH 5 60 R 23. 26c Rh-OTf-(S.S)-Norphos iPrOH 5 12 R 24. 26d Rh-OTf-(S.S)Norphos THF 5 3R 25. 27a Rh-OTf-(S.S)Norphos MeOH 8 64R 26. 27b Rh-Cl-(S.S).-Norphos MeOH 8 40 R 27. 27c Rh-OTf-(S.S)-Norphos MeOH 30 65 R 28. 27d Rh-OTf-(S.S)-Norphos MeOH 60 64R 29. 28a Rh-OTf-(R.R)-EtDUphos MeOH 10 16 S 30. 28b Rh-OTf-(R.R)-EtDUPhos MeOH 30 28 S 31. 29a Rh-OTf-(R.S)-BPPFOH MeOH 10 55 R 32. 29b Rh-OTf-(R.S)BPPFOH MeOH 30 56 R 33. 37 Rh-ClO-(S.S)-Chiraphos MeOH 10 30 R 34." 38 Rh-OTf-(S.S)-DIOP MeOH 10 rac. 35. 39 Rh-OTf-(R.R)-Skewphos MeOH 10 46 S 36. 40 Rh-OTf-(S.S)-BPPM MeOH 10 9S 37. 41 Ir-Cl-(S.S)-DIOP MeOH 10 8R 38. 42 lr-Cl-(S.S)-DIOP CH2Cl2 10 7S - 17 - 0. 43 Ir-Cl-(S.S)-DIOP(+I) MeOH 10 1. 44 Ir-Cl-(S.S)-DIOP(+I) MeOH 30 2. 45 Ir-Cl-(S.S)-DIOP(+I) MeOH 10 +CH3COOH) 3. 46 Ir-Cl-(S.S)-DIOP MeOH 10 11R 4. 47 Ir-Cl-(S.S)-DIOP(+I) MeOH 10 39 R 5. 49 Rh-OTf-(S.S)-Norphos MeOH 10, RT 57 R 6. 50 Rh-OTf-(S.S)-Norphos MeOH 10,50°C 60 R 7. 52 Rh-BF4-(R,S)-PFctB MeOH 10, 50°C 33 S 8. 54 Rh-Cl-(R)-BINAP Tol:MeOH 5:1 80,50°C 91S 9. 59 Rh-Cl-(S.S)-Norphos Tol:MeOH 5:1 80,50°C 19 R 10. 62 crude 59//Pd/C Tol:MeOH 5:l 7,50°C 18 R 18- Wc Claim: 1. Chroman derivatives of the formula I in which R1 is acyl having 1-6 carbon atoms, -CO-R5, phenylacetyl, phenoxyacetyl, methoxycarbonyl, ethyoxy-carbony, 2,2,2- trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxy-carbonyl, 4-methoxybenzyloxycarbonyl, 9- fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl, R2 is H or alkyl having 1-6 carbon atoms, R3 and R4 are each, independently of one another, H, alkyl having 1-6 carbon atoms, CN, Hal or COOR2, R5 is phenyl which is unsubstituted or monosubstituted or disubstituted by alkyl having 1-6 carbon atoms, OR2 or Hal, X is H,H or O, Hal is F, Cl, Br or I, and salts thereof, where N-(chroman-2-ylmemyl)cyclopropanecarboxamide is excluded. 19- 2. Enantiomers of the compounds of the formula I as claimed in claim 1. 3. Compounds of the formula I as claimed in claim 1 a) N-(4-oxochroman-2-ylmethyl)acetamide; b) N-(chroman-2-ylmethyl)acetamide; c) (S)-N-(4-oxochroman-2-ylmethyl)acetamide; d) (R)-N-(4-oxochroman-2-ylmethyl)acetamide; e) (S)-N-(chroman-2-ylmethyl)acetamide; f) (R)-N-(chroman-2-ylmethyl)acetamide; and salts thereof 4. Process for the preparation of chroman derivatives of the formula I as claimed in claim 1 and salts thereof, in which X is O, wherein a compound of the formula II in which R1, R2, R3 and R4 are as claimed in claim 1, and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst. -20- 5. Process for the preparation of chroman derivatives of the formula I as claimed in claim 1 and salts thereof, in which X is H, H, wherein a compound of the formula H in which R1, R2, R3 and R4 are as claimed in claim 1, and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst and subsequently reduced in a conventional manner. 6. Process for the preparation of chroman derivatives of the formula I as claimed in claim 4 or 5, wherein the enantiomericaUy enriched catalyst is a transition-metal complex. 7. Process for the preparation of chroman derivatives of the formula I as claimed in claim 4, 5 or 6, wherein the catalyst is a transition-metal complex containing a metal selected from the group consisting of rhodium, iridium, ruthenium and palladium. - 21- 8. Process for the preparation of chroman derivatives of the formula I as claimed in claim 4, 5, 6 or 7, wherein the catalyst is a transition-metal complex in which the transition metal is complexed to a chiral diphosphine ligand. 9. Process for the preparation of (R 0)-2-[5-(4-fluorophenyl)-3-pyridyl-methylaminomethyl]-chroman and salts thereof, wherein a) a compound of the formula II n. in which R1 is as claimed in claim 1, R2,R3 and R4 are and is O, is hydrogenated with the aid of an enantiomerically enriched catalyst, b) in that the enantiomerically pure (R) compound of the formula I in which R1 is as claimed in claim 1, R2, R3 and R4 are H and X is 0, by crystallization, in that -22- c) the enantiomerically pure (R) compound of the formula I in which R1 is as claimed in claim 1, R2,R3 and R4 are H and X is O, is subsequently reduced in a conventional manner, in that d) the radical R1 is cleaved off from the resultant (R) compound of the formula I in which R1 is as claimed in claim 1, R2, R3 and R4 are H and X is H, H, in that e) the resultant (R)-(chroman-2-ylmethyl)amine is converted into its acid-addition salt, and the latter is converted in a known manner into (R)-2-[5-(4-fluorophenyl)-3- pyridylmethylaminomethyl]chroman and, if desired, converted into its acid-addition salt, where the isolation of the (R ) enantiomer from the enantiomerically enriched (R,S) mixture by crystallization can also be carried out after step c) or after step d). Chroman derivatives of the formula I in which R1 is acyl having 1-6 carbon atoms, -CO-R5, phenylacetyl, phenoxyacetyl, methoxycarbonyl, ethyoxy-carbony, 2,2,2- trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl, carbobenzoxy-carbonyl, 4-methoxybenzyloxycarbonyl, 9- fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl, R2 is H or alkyl having 1-6 carbon atoms, R3 and R4 are each, independently of one another, H, alkyl having 1-6 carbon atoms, CN, Hal or COOR2, R5 is phenyl which is unsubstituted or monosubstituted or disubstituted by alkyl having 1-6 carbon atoms, OR2 or Hal, X is H,H or O, Hal is F,Cl,Br or I, and salts thereof where N-(chroman-2-ylmemyl)cyclopropanecarboxamide is excluded.

Full Text

Chroman derivatives
The invention relates to chroman derivatives of the formula I

in which
R1 is acyl having 1-6 C atoms, -CO-R5 or an amino
protective group, R2 is H or alkyl having 1-6 C atoms, R3, R4 in each case independently of one another are
H, alkyl having 1-6 C atoms, CN, Hal or COOR2, R5 is phenyl which is unsubstituted or mono- or
disubstituted by alkyl having 1-6 C atoms, OR2
or Hal, X is H,H or O, Hal is F, C1, Br or I, and their salts.
The invention also relates to the optically active forms, the racemates, the enantiomers and also the hydrates and solvates, e.g. alcoholates, of these compounds.
Similar compounds are disclosed in EP 0 707 007.
The invention was based on the object of finding novel compounds which can be used, in particular, as intermediates in the synthesis of medicaments.
It has been found that the compounds of the formula I and their salts are important intermediates for the preparation of medicaments, in particular of those which show, for example, actions on the central nervous system.

- 2 –
The invention relates to the chroman derivatives of the formula X and their salts.
Above and below, the radicals R1, R2, R3, R4, R5 and X have the meanings indicated in the formulae I and II, if not expressly stated otherwise.
In the above formulae, alkyl has 1 to 6, preferably 1,
2, 3 or 4, C atoms. Alkyl is preferably methyl or
ethyl, furthermore propyl, isopropyl, in addition also
butyl, isobutyl, sec-butyl or tert-butyl. Acyl has 1 to
6, preferably 1, 2, 3 or 4, C atoms. Acyl is in
particular acetyl, propionyl or butyryl.
R2 is preferably H, in addition also methyl, ethyl or
propyl.
R3 and R4 are preferably H.
R5 is preferably, for example, phenyl, o-, m- or
p-tolyl, o-, m- or p-hydroxyphenyl, o-, m- or
p-methoxyphenyl, o-, m- or p-fluorophenyl. The radical
Rl is acyl, -CO-R5 or else an amino protective group
which is known per se; acetyl is particularly
preferred.
The expression "amino protective group" is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their nature and size is otherwise uncritical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression "acyl group" is to be interpreted in the widest sense in connection with the present process and the present compounds. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and also, in

- 3 -
particular, alkoxycarbonyl, aryloxycarbonyl and
especially aralkoxycarbonyl groups. Examples of acyl
groups of this type are alkanoyl such as acetyl,
propionyl, butyryl; aralkanoyl such as phenylacetyl;
aroyl such as benzoyl or toluyl; aryloxyalkanoyl such
as phenoxyacetyl; alkoxycarbonyl such as
methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloro-
ethoxycarbony1, BOC (tert-butoxycarbonyl) , 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (carbobenzoxycarbonyl, also called "Z"), 4-methoxybenzyloxycarbonyl, FMOC (9-fluorenylmethoxy-carbonyl) ; arylsulfonyl such as Mtr (4-methoxy-2,3,6-trimethylphenylsulfonyl). Preferred amino protective groups are BOC and Mtr, in addition CBZ or FMOC.
The compounds of the formula I can have one or more chiral centres and therefore occur in various stereoisomeric forms. The formula I includes all these forms.
The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I according to Claim 1 and also of their salts, in which X is 0, characterized in that a compound of the formula II

in which R1, R2, R3, R4 have the meanings indicated in Claim 1 and X is O,
is hydrogenated with the aid of an enantiomerically enriched catalyst.
The invention also relates to a process for the preparation of chroman derivatives of the formula I

- 4 –
according to Claim 1 and also of their salts, in which X is H,H, characterized in that a compound of the formula II

in which R1, R2, R3, R4 have the meanings indicated in
Claim 1 and X is 0,
is hydrogenated with the aid of an enantiomerically
enriched catalyst,
and then reduced in the customary manner.
In particular, it has been found that (2-acetylaminomethyl)chromen-4-one can be hydrogenated using various enantiomerically pure rhodium-diphosphane complexes to give enantiomerically enriched (2-acetylaminomethyl)chroman-4-one.
The invention also relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the enantiomerically enriched catalyst is a transition metal complex.
Particularly preferably, the catalyst is a transition metal complex comprising a metal selected from the group rhodium, iridium, ruthenium and palladium.
The invention furthermore relates to a process for the preparation of chroman derivatives of the formula I, characterized in that the catalyst is a transition metal complex in which the transition metal is complexed with a chiral diphosphane ligand.
The ligands below may be mentioned by way of example:

- 5 -

- 6 -
Depending on the choice of the (R) or (S) enantiomer of the ligand in the catalyst, the (R) or (S) enantiomer is obtained in an excess.
Precursors used for the chiral ligands are compounds such as, for example, Rh(COD)2OTf (rhodium-cyclooctadiene triflate), [Rh(COD)Cl]2, Rh(COD)2BF4, [Ir(COD)Cl]2, Ir(COD)2BF4 or [Ru(COD)Cl2]x.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), mainly under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.

- 7 -
If desired, the starting substances can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
The compounds of the formula II are known in some cases; the unknown compounds can easily be prepared analogously to the known compounds.
The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is O is carried out according to the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as, for example, methanol or ethanol.
Suitable inert solvents are furthermore, for example,
hydrocarbons such as hexane, petroleum ether, benzene,
toluene or xylene; chlorinated hydrocarbons such as
trichloroethylene, 1,2-dichloroethane, carbon
tetrachloride, chloroform or dichloromethane; alcohols
such as isopropanol, n-propanol, n-butanol or tert-
butanol; ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran (THF), or dioxane; glycol ethers
such as ethylene glycol monomethyl or monoethyl ether
(methyl glycol or ethyl glycol), ethylene glycol
dimethyl ether (diglyme); ketones such as acetone or
butanone; amides such as acetamide, dimethylacetamide
or dimethylformamide (DMF); nitriles such as
acetonitrile; sulfoxides such as dimethyl sulfoxide
(DMSO); carbon disulfide; nitro compounds such as
nitromethane or nitrobenzene; esters such as ethyl
acetate, and optionally also mixtures of the solvents
mentioned with one another or mixtures with water.
The reaction time of. the enantioseleetive hydrogenation, depending on the conditions used. is between a few minutes and 14 days; the reaction

- 8 –
temperature is between 0 and 150°, normally between 20 and 130°.
Customarily, the catalyst/substrate ratio is between 1:2000 and 1:50, particularly preferably to 1:1000 and 1:100. The reaction time is then, for example, between 3 and 20 hours. The hydrogenation is carried out under 1-200 bar of hydrogen, preferably at 3-100 bar.
The conversion of a compound of the formula II in which X is O into a compound of the formula I in which X is H,H is carried out according to the invention using hydrogen gas with the aid of an enantiomerically enriched catalyst in an inert solvent such as methanol or ethanol, such as described above, followed by a conversion of the 4-oxo group into a methylene group according to known conditions. The reduction is preferably carried out using hydrogen gas under transition metal catalysis (for example by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol) .
The conversion of compounds of the formula I in which R3, R4 is COOalkyl into compounds of the formula I in which R3, R4 is COOH is carried out, for example, using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100°.
The removal of a radical R1 from a compound of the formula I is carried out - depending on the protective group used - for example using strong acids, expediently using TFA (trifluoroacetic acid) or perchloric acid, but also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic

- 9 –
acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide, halogenated hydrocarbons such as dichloromethane, in addition also alcohols such as methanol, ethanol or isopropanol and also water. In addition, mixtures of the abovementioned solvents are possible. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures are expediently between approximately 0 and approximately 50°; the reaction is preferably carried out between 15 and 30°.
The BOC group is preferably removed using TFA in dichloromethane or using approximately 3 to 5 N hydrochloric acid in dioxane at 15-30°.
The removal of the acetyl group is carried out according to customary methods (P.J. Kocienski, Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994).
Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100° and pressures between approximately 1 and 200 bar, preferably at 20-30° and 1-10 bar.
A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are particularly those which yield physiologically acceptable salts. Thus inorganic acids

- 10 –
can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid . or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids and laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, using bases (e.g. sodium - or potassium hydroxide or carbonate), or into the corresponding ammonium salts.
The invention furthermore relates to the use of the
compounds of the formula I as intermediates for the
synthesis of medicaments. Appropriate medicaments are
described, for example, in EP 0 707 007.
The invention accordingly relates in particular to the
use of the compounds of the formula I according to
Claim 1 in the synthesis of
(R)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-
chroman and its salts, characterized in that
a) a compound of the formula II

- 11 -
in which
R1 has the meaning indicated in Claim 1,
R2, R3 and R4 are H and X is 0,
is hydrogenated with the aid of an enantiomerically
enriched catalyst,
b) in that, from the enantiomerically enriched mixture
of the (R) and (S) compounds of the formula I thus
obtained, in which
R1 has the meaning indicated in Claim 1,
R2, R3 and R4 are H and X is 0,
the enantiomerically pure (R) compound of the formula
I, in which
R1 has the meaning indicated in Claim 1,
R2, R3 and R4 are H and X is 0,
is obtained by crystallization,
in that
c) the enantiomerically pure (R) compound of the
formula I, in which
R1 has the meaning indicated in Claim 1, R2, R3 and R4 are H and X is 0, is then reduced in the customary manner, in that
d) the radical R1 in which
R1 has the meaning indicated in Claim 1,
R2, R3 and R4 are H and X is H,H,
is removed from the (R) compound of the formula I thus
obtained,
in that
e) the (R)-(chroman-2-ylmethyl)amine thus obtained is
converted into its acid addition salt and this is
reacted in a known manner to give (R)-2-[5-(4-
fluorophenyl)-3-pyridylmethylaminomethyl]chroman and,
if appropriate, converted into its acid addition salt,

- 12 –
where the recovery of the (R) enantiomer can also be carried out fay crystallization from the enantimerically enriched (R,S) mixture after stage c) or after stage d).
The invention furthermore relates to the use of the compounds of the formula I as intermediates for the synthesis of medicaments which show actions on the central nervous system-Above and below, all temperatures are indicated in °C. In the following examples, "customary working up" means: if necessary, water is added, the mixture is adjusted, if necessary, depending on the constitution of the final product, to a pH of between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization. Rf values on silica gel.
Examples
Experimental data (complex preparation, hydrogenation, analytical methods):

All reactions were carried out under inert conditions (i.e. anhydrous and oxygen-free reaction conditions).
1. Preparation of the catalyst/substrate solution:

- 13 -
1.1 Example:
11.2 mg. of Rh(COD)2OTf (rhodium-cyclooctadiene
triflate) were dissolved in 5 ml of methanol and cooled
to 0°C. A cooled solution of 1.1 eq of bisphosphane
(e.g. 12.6 mg of (R,R)-Skewphos) in 5 ml of methanol
was then added. After stirring at room temperature for,
10 min, the complex solution was treated with the
substrate solution consisting of 110 mg of (2-
acetylaminomethyl)chromen-4-one in 10 ml of methanol.
1.2. Example:
51.4 mg of [Hh(COD)Cl]2 were dissolved in 4 ml of the solvent mixture toluene/methanol 5:1 and treated with a solution consisting of 5 ml of toluene, 1 ml of methanol and 1.1 eq of bisphosphane (e.g. 130.6 mg of (R)-BINAP). 1 ml of this catalyst complex solution was added to 510.8 mg of (2-acetylaminomethyl)chromen-4-one, dissolved in 15 ml of toluene and 3 ml of methanol.
2. Enantioselective hydrogenation
The catalyst/substrate solution to be hydrogenated was filled into an autoclave in a countercurrent of protective gas. The protective gas atmosphere was replaced by flushing several times with hydrogen . (1-5 bar H2 atmosphere) . The batches analogous to 1.1. reacted even at room temperature and 5 bar of hydrogen. The catalysts analogous to 1.2- afforded the best results at 50°C and 80 bar of hydrogen. As a rule, the hydrogenation was terminated after 15 hours.
3. Sampling and analytical methods
A sample was taken in a countercurrent of protective gas. The complex was separated off by column chromatography on silica gel (eluent: ethyl acetate) before the determination of the enantiomeric excesses.

- 14 –
The enantiomeric excess of the hydrogenation product was determined on the chiral HPLC phase;
Column: Daicel Chiralcel OJ (I.D. x length/mm;
4.6 x 250)
Eluent: n-hexane: i-propanol =9:1
Flow: 0.8 ml/min (18 bar, 28°C)
Detection: UV 250 nm Retention: Rc (R) = 27 min; Rc(S) = 29 min
The concentration of the crude hydrogenation solution led to the precipitation of the product. An increase in the enantiomeric excess was detected by means of fractional crystallization.
4. Further reduction
After complete conversion was detected, the reduction of the keto group was carried out by means of palladium-carbon as a one-pot process. The crude ketone solution resulting from the homogeneous hydrogenation was treated with 10% by weight water-moist palladium-carbon (e.g. 100 mg of water-moist Pd/C to 1 g of (2-acetylaminomethyl)chromen-4-one) and 1 ml of glacial acetic acid. Hydrogenation was carried out at a hydrogen pressure of 7 bar and 50°C for 14 h.
5. Work-up and analytical methods
The palladium-carbon was removed by filtration.
The enantiomeric excess of the hydrogenation product
was determined on a chiral HPLC phase:
Column: Daicel Chiralcel OJ (I.D. x length/mm:
4.6 x 250)
Eluent: n-hexane: i-propanol = 9:1
Flow: 0.8 ml/min -(18 bar, 28°C)
Detection: UV 250 nm Retention: Rt(R) = 25 min; Rc(S) = 27 min

- 15 -
During the reduction with palladium-carbon, the enantiomeric excess remained unchanged.
The concentration of the crude hydrogenation solution led to the precipitation of the product. An increase in the enantiomeric excess was detected by means of fractional crystallization.

- 16 –
Enantioselectivities of the homogeneous hydrogenation:

Efafo No. Complexmetal anion ligand (addition) Solvent Pressure %ee
1. 18 Rh-OTf-(R,R)-EtDuphos CH2C12 55 S
2. 13 Rh-OTf-(R,R)-EtDuphos THF 44S
3. 14 Rh-OTf-(R,R)-EtDuphos McOH 64S
4. 15 Rh-OTf-(R,R)-EtDuphos EE 33 S
5. 6 Rh-OTf-(R,R)-EtDuphos iPrOH 20 S
6. 23a Rh-OTf-(R,R)-EtDuphos MeOH 34 S
7. 23b Rh-OTf-(R,R)-EtDuphos McOH 36 S
8. 23c Rh-OTf-(R,R)-EtDuphos MeOH 45 S
9. 23d Rh-OTf-(R,R)-EtDuphos MeOH 31 S
10, 12 Ru-Cl2-(R)-BINAP (AgOOCCF3) iPrOH 50 S
11. 19 Rh-ClO4(S.S)-Chiraphos iPrOH -
12. 20 Rh-OTf-(S.S)-D1OP THF rac.
13. 20 Rh-OTf-(S.S)-DIOP THF 8R
14. 21 Rh-OTf-(R.R)-Skewphos THF -
15. 22b Rh-OTf(S.S)-BPPM MeOH 7S
16. 24a Rh-OTf(R.S)BPPFOH MeOH 54 R
17. 24b Rh-OTf-(R.S)-BPPFOH MeOH 54 R
18. 24c Rh-OTf-(R.S)-BPPFOH MeOH 63 R
19. 25a Rh-OTf-(R)-BINAP MeOH 1R
20. 25b Rh-OTf-(R)-BINAP MeOH 5 rac.
21. 26a Rh-OTf-(S.S)Norphos MeOH 42 R
22. 26b Rh-OTf-(S.S)-Norphos MeOH 5 60 R
23. 26c Rh-OTf-(S.S)-Norphos iPrOH 5 12 R
24. 26d Rh-OTf-(S.S)Norphos THF 5 3R
25. 27a Rh-OTf-(S.S)Norphos MeOH 8 64R
26. 27b Rh-Cl-(S.S).-Norphos MeOH 8 40 R
27. 27c Rh-OTf-(S.S)-Norphos MeOH 30 65 R
28. 27d Rh-OTf-(S.S)-Norphos MeOH 60 64R
29. 28a Rh-OTf-(R.R)-EtDUphos MeOH 10 16 S
30. 28b Rh-OTf-(R.R)-EtDUPhos MeOH 30 28 S
31. 29a Rh-OTf-(R.S)-BPPFOH MeOH 10 55 R
32. 29b Rh-OTf-(R.S)BPPFOH MeOH 30 56 R
33. 37 Rh-ClO-(S.S)-Chiraphos MeOH 10 30 R
34." 38 Rh-OTf-(S.S)-DIOP MeOH 10 rac.
35. 39 Rh-OTf-(R.R)-Skewphos MeOH 10 46 S
36. 40 Rh-OTf-(S.S)-BPPM MeOH 10 9S
37. 41 Ir-Cl-(S.S)-DIOP MeOH 10 8R
38. 42 lr-Cl-(S.S)-DIOP CH2Cl2 10 7S

- 17 -
0. 43 Ir-Cl-(S.S)-DIOP(+I) MeOH 10
1. 44 Ir-Cl-(S.S)-DIOP(+I) MeOH 30
2. 45 Ir-Cl-(S.S)-DIOP(+I) MeOH 10
+CH3COOH)
3. 46 Ir-Cl-(S.S)-DIOP MeOH 10 11R
4. 47 Ir-Cl-(S.S)-DIOP(+I) MeOH 10 39 R
5. 49 Rh-OTf-(S.S)-Norphos MeOH 10, RT 57 R
6. 50 Rh-OTf-(S.S)-Norphos MeOH 10,50°C 60 R
7. 52 Rh-BF4-(R,S)-PFctB MeOH 10, 50°C 33 S
8. 54 Rh-Cl-(R)-BINAP Tol:MeOH 5:1 80,50°C 91S
9. 59 Rh-Cl-(S.S)-Norphos Tol:MeOH 5:1 80,50°C 19 R
10. 62 crude 59//Pd/C Tol:MeOH 5:l 7,50°C 18 R

18-
Wc Claim:
1. Chroman derivatives of the formula I

in which
R1 is acyl having 1-6 carbon atoms, -CO-R5, phenylacetyl,
phenoxyacetyl, methoxycarbonyl, ethyoxy-carbony, 2,2,2-
trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl,
carbobenzoxy-carbonyl, 4-methoxybenzyloxycarbonyl, 9-
fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl,
R2 is H or alkyl having 1-6 carbon atoms,
R3 and R4 are each, independently of one another, H, alkyl having 1-6
carbon atoms, CN, Hal or COOR2,
R5 is phenyl which is unsubstituted or monosubstituted or disubstituted
by alkyl having 1-6 carbon atoms, OR2 or Hal,
X is H,H or O,
Hal is F, Cl, Br or I,
and salts thereof, where N-(chroman-2-ylmemyl)cyclopropanecarboxamide is excluded.

19-
2. Enantiomers of the compounds of the formula I as claimed in claim 1.
3. Compounds of the formula I as claimed in claim 1

a) N-(4-oxochroman-2-ylmethyl)acetamide;
b) N-(chroman-2-ylmethyl)acetamide;
c) (S)-N-(4-oxochroman-2-ylmethyl)acetamide;
d) (R)-N-(4-oxochroman-2-ylmethyl)acetamide;
e) (S)-N-(chroman-2-ylmethyl)acetamide;
f) (R)-N-(chroman-2-ylmethyl)acetamide;
and salts thereof
4. Process for the preparation of chroman derivatives of the formula I
as claimed in claim 1 and salts thereof, in which X is O, wherein a
compound of the formula II

in which R1, R2, R3 and R4 are as claimed in claim 1, and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst.

-20-
5. Process for the preparation of chroman derivatives of the formula I
as claimed in claim 1 and salts thereof, in which X is H, H,
wherein a compound of the formula H

in which R1, R2, R3 and R4 are as claimed in claim 1, and X is O, is hydrogenated with the aid of an enantiomerically enriched catalyst and subsequently reduced in a conventional manner.
6. Process for the preparation of chroman derivatives of the formula I as claimed in claim 4 or 5, wherein the enantiomericaUy enriched catalyst is a transition-metal complex.
7. Process for the preparation of chroman derivatives of the formula I as claimed in claim 4, 5 or 6, wherein the catalyst is a transition-metal complex containing a metal selected from the group consisting of rhodium, iridium, ruthenium and palladium.

- 21-
8. Process for the preparation of chroman derivatives of the formula I as claimed in claim 4, 5, 6 or 7, wherein the catalyst is a transition-metal complex in which the transition metal is complexed to a chiral diphosphine ligand.
9. Process for the preparation of (R 0)-2-[5-(4-fluorophenyl)-3-pyridyl-methylaminomethyl]-chroman and salts thereof, wherein
a) a compound of the formula II
n.
in which
R1 is as claimed in claim 1,
R2,R3 and R4 are and is O,
is hydrogenated with the aid of an enantiomerically enriched
catalyst,
b) in that the enantiomerically pure (R) compound of the formula I
in which
R1 is as claimed in claim 1, R2, R3 and R4 are H and X is 0, by crystallization, in that

-22-
c) the enantiomerically pure (R) compound of the formula I in
which
R1 is as claimed in claim 1,
R2,R3 and R4 are H and X is O,
is subsequently reduced in a conventional manner, in that
d) the radical R1 is cleaved off from the resultant (R) compound of
the formula I in which
R1 is as claimed in claim 1,
R2, R3 and R4 are H and X is H, H, in that
e) the resultant (R)-(chroman-2-ylmethyl)amine is converted into
its acid-addition salt, and the latter is converted in a known
manner into (R)-2-[5-(4-fluorophenyl)-3-
pyridylmethylaminomethyl]chroman and, if desired, converted
into its acid-addition salt,
where the isolation of the (R ) enantiomer from the enantiomerically enriched (R,S) mixture by crystallization can also be carried out after step c) or after step d).
Chroman derivatives of the formula I
in which
R1 is acyl having 1-6 carbon atoms, -CO-R5, phenylacetyl,
phenoxyacetyl, methoxycarbonyl, ethyoxy-carbony, 2,2,2-
trichloroethoxycarbonyl, tert-butoxycarbonyl, 2-iodoethoxycarbonyl,
carbobenzoxy-carbonyl, 4-methoxybenzyloxycarbonyl, 9-
fluorenylmethoxycarbonyl or 4-methoxy-2,3,6-trimethyl-phenylsulfonyl,
R2 is H or alkyl having 1-6 carbon atoms,
R3 and R4 are each, independently of one another, H, alkyl having 1-6
carbon atoms, CN, Hal or COOR2,
R5 is phenyl which is unsubstituted or monosubstituted or disubstituted
by alkyl having 1-6 carbon atoms, OR2 or Hal,
X is H,H or O,
Hal is F,Cl,Br or I,
and salts thereof where N-(chroman-2-ylmemyl)cyclopropanecarboxamide
is excluded.

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Patent Number

201436

Indian Patent Application Number

IN/PCT/2001/00733/KOL

PG Journal Number

08/2007

Publication Date

23-Feb-2007

Grant Date

23-Feb-2007

Date of Filing

13-Jul-2001

Name of Patentee

MERCK PATENT GMBH

Applicant Address

FRANKFURTER STRESSE 250, D-64293 DARMSTADT,

Inventors:

#	Inventor's Name	Inventor's Address
1	BOKEL, HEINZ-HERMANN	GUNDOLFSTRASSE 2, D-64287 DARMSTADT
2	MACKERT, PETER	BAHANSTRASSE 4, D-63329 EGELBACH,
3	MURMANN, CHRISTOPH	UEBERAUER STRSSE-4, D-64354 REINHEIM,
4	SCHWEICKERT, NORBERT	ALSBACHERSTRASSE 17, D-64342 SEEHEIM-JUGENHEIM,

PCT International Classification Number

C07D 311/22; 311/58;

PCT International Application Number

PCT/EP99/09333

PCT International Filing date

1999-12-01

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	198 58 341.9	1998-12-17	Germany