WO1999001453A1

WO1999001453A1 - A process for the manufacture of optically active chromanylpyridine derivatives

Info

Publication number: WO1999001453A1
Application number: PCT/EP1998/003944
Authority: WO
Inventors: Emil Albin Broger; Yvo Crameri; Philip Stephen Jones
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 1997-07-02
Filing date: 1998-06-27
Publication date: 1999-01-14

Abstract

A process for the manufacture of optically active chromanylpyridine derivatives of general formula (I), wherein X corresponds to N or N-oxide; R corresponds to cyano, hydrogen, halogen, trifluoromethyl, nitro, C1-8-alkyl, C1-8-alkoxycarbonyl, C1-8-alkylthio, C1-8-alkylsulphonyl, C1-8-alkanoyl, aroyl, carbamoyl, mono-(C1-8-alkyl)carbamoyl or di(C1-8-alkyl)carbamoyl; R' corresponds to hydrogen, C1-8-alkyl or -CH2F; R' corresponds to C1-8-alkyl, halogen, amino, -CO2(-C1-8-alkyl), hydroxy, C1-8-alkoxy, aryl or, when n=2, R' together with the group (II) correspond to a benz-fused system according to formulae (IIa) or (IIb) or (IIc) and n corresponds to 0, 1 or 2. Starting from a compound of general formula (III) wherein X, R, R', R' and n have the significances set forth above, [which] is assymetrically hydrogenated in the presence of a complex of an optically active diphosphine ligand with a Group VIII metal.

Description

A process for the manufacture of optically active chromanylpyridine derivatives

The present invention is concerned with a novel, catalytic process for the manufacture of optically active compounds of the general formula

wherein

X corresponds to N or N-oxide

R corresponds to cyano, hydrogen, halogen, trifluoromethyl, nitro, Ci-₈-alkyl, Ci-₈-alkoxycarbonyl, Ci-₈-alkylthio, Ci-8- alkylsulphonyl, Ci-₈-alkanoyl, aroyl, carbamoyl, mono- (Ci-₈-alkyl)carbamoyl or di(Ci-₈-alkyl)carbamoyl;

R' corresponds to hydrogen, Ci-₈-alkyl or -CH₂F; R" corresponds to Ci-₈-alkyl, halogen, amino, -CO2(-Ci-8- alkyl), hydroxy, Ci-₈-alkoxy, aryl or, when n = 2, R" together with the group

correspond to a benz-fused system according to the formulae

Ila lib lie

and n corresponds to 0, 1 or 2.

The compounds of formula I are valuable intermediates for pharmacologically usable end products or themselves represent active substances, e.g. as antihypertensives or hair growth agents, as described in US PS 5 470 861.

The object of the present invention is to find a direct access to optically active compounds of formula I which avoids a racemate resolution.

The process in accordance with the invention is characterized by asymmetrically hydrogenating a compound of the general formula

wherein X, R, R', R" and n have the above significance, in the presence of a complex of an optically active diphosphine ligand with a Group VIII metal.

As optically active metal-diphosphine complexes for the process in accordance with the invention there come into consideration especially optically active cationic and neutral rhodium and ruthenium complexes of the general formulae

[Rh(Y)(Ln)]+A- IV- a

[Rh(Y)(Ln) B] rv- b

[Ru(Y)]²+(A-)₂ IV- c

[Ru(Y)(B)₂] rv- d

[Ru(Y)(Cl)(C2)_2-rn](C3)_rn IV- e wherein

L signifies a neutral ligand

A signifies an anion of an oxygen acid or complex acid

B signifies an anionic coordinating ligand

Cl signifies benzene p-cymene, xylene, hexamethylbenzene

C^ signifies halogen

C^ signifies halogen or A n signifies 0, 1 or 2 m signifies 0, 1 or 2

Y signifies an optically active diphosphine of the formulae

wherein

R² signifies cycloalkyl or Ci-₈-alkyl,

R³ signifies hydrogen, cycloalkyl or Ci-₈-alkyl,

R⁴ and R⁴' signify Ci.s-alkyl or Cι_₈-alkoxy,

R⁵, R⁵' and R⁶ signify aryl, heteroaryl, Ci-₈-alkyl, cycloalkyl, whereby the residues R⁵ and R⁵' can be the same or different, R⁷ and R⁸ each independently signify Ci-₈-alkyl, Ci-₈-alkoxy, hydroxy, protected hydroxy or R⁷ and R⁸ together signify

-CH2-O-CH2- R⁴' and R⁷ and/or

R⁴' and R⁸ signify a benzo or benzofuran condensed system, R⁹ and R¹⁰ each independently signify aryl, Ci-₈-alkyl, cycloalkyl, a

5-membered heteroaromatic or a group of the formula

RU signifies Cι.₈-alkyl, benzyl, -COOR⁶, -COON(R³)₂, and

R12 signifies -COR⁶, -COOR⁶, -CON(R³)₂, -SO₂R⁶ or

-PO(R5)₂.

In connection with the compounds of formulae I to XV the following definitions of the general terms apply irrespective of whether or not the terms in question appear alone or in combination.

The term "anionic coordinating ligand" embraces e.g. halides, a carboxylic acid residue, a sulphonate residue such as e.g. tosylate or methanesulphonate, a 1,3-diketonate such as e.g. acetyl acetonate, an optionally substituted phenolate, hydroxy, nitrite, cyanate, rhodanide, cyanide, allyl and 2-methylallyl. The definition "carboxylic acid residue" used with respect to the term "anionic coordinating ligand" refers to groups Ci-β alkyl-COO-, the alkyl moiety being unsubstituted or substituted by halogen"

The term "oxygen acid or complex acid" signifies in the scope of the present invention acids from the group of H2SO4, HCIO4, HBrθ4, HIO4, HNO3, H3PO4, H3PO3, CF3SO3H, C₆H₅SO₃H as well as halogen complexes with the elements boron, phosphorus arsenic antimony or bismuth. Preferred representatives are HCIO4, CF3SO3H, HPF₆, HBF₄, HB(Ph)₄, HB(3,5(CF₃)₂- C₆H₃)4, HSbF₆ and HAsF₆.

The term "halogen" embraces fluorine, bromine, chlorine and iodine, chlorine, bromine or iodine is preferred.

The term "neutral ligand" signifies in the scope of the present invention readily replaceable ligands such as olefins, e.g. ethylene, propylene, cyclo- octene, 1,5-hexadiene, norbonadiene, or 1,5-cyclooctadiene, or benzene, hexamethylbenzene, p-cymene and the like, nitriles such as acetonitrile, benzonitrile, or also the solvent which is used, etc. This ligand can be replaced in the hydrogenation. Where several of such ligands are present, these can also be different from one another.

The term "Ci-8-alkyl" signifies in the scope of the present invention for all alkylene-containing systems hydrocarbons with 1 to 8 carbon atoms, i.e. straight-chain or branched alkyl groups such as, for example, methyl, ethyl propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl, iospentyl, neopentyl, hexyl, isohexyl, tert.hexyl, heptyl, isoheptyl, preferably alkyl (sic) groups with 1 to 4 carbon atoms.

The term "cycloalkyl" signifies in the scope of the present invention cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexyl, cycloheptyl and cyclooctyl.

Methylthio and ethylthio can be enumerated, for example, for the term "Cι-8-alkylthio groups".

The term "Ci-8-alkoxy" signifies a Ci.s-alkyl group as has been described above, which is bonded via an oxygen atom. Methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy and the like can be mentioned by way of example.

The term "Ci-8-alkanoyl" signifies a Ci-8-alkyl group as set forth above, which is bonded via a carbonyl function. Acetyl, propionyl, butyryl and the like can be mentioned by way of example. The term "aryl" signifies in the scope of the present invention especially the phenyl residue which can be not only unsubstituted, but also mono- or also multiply-substituted in the ortho-, meta- or para-position. Substituents which come into consideration here are phenyl, Ci-8-alkyl or Ci-8-alkoxy groups, preferably methyl or methoxy groups, or also di-Ci-8-alkylamino, preferably dimethylamino groups, as well as fluorine, trialkylsilyl, such as trimethylsilyl or also sulphamoyl such as e.g. N,N-dimethylaminosulphamoyl and the like. Moreover, the term can signify naphthyl.

The term "aroyl" signifies in the scope of the present invention benzoyl which may also be substituted. As substituents there come into consideration e.g. nitro and halogens. p-Nitrobenzoyl or o-, m- or p-nitrobenzoyl can be enumerated here by way of example.

The term "mono(Cι.8-alkyl)carbamoyl" signifies in the scope of the present invention, for example, methylcarbamoyl, ethylcarbamoyl and the like.

The term "di(Cι.8-alkyl)carbamoyl" embraces e.g. dimethylcarbamoyl, diethylcarbamoyl and the like.

As protecting groups for the hydroxy groups there come into consideration in the scope of the present invention especially the usual ether- forming groups such as e.g. benzyl, allyl, benzyloxymethyl, C i-8-alkoxymethyl or also 2-methoxyethoxymethyl and the like.

The term "heteroaryl" signifies in the scope of the present invention residues of 5- and/or 6-membered aromatics having one or two hetero atoms from the group of nitrogen, oxygen or sulphur. Pyridine, pyrimidine, furan, thiophene, pyrrole and the like can be mentioned by way of example. These can be substituted in accordance with the definition of the aryls.

Preferred heteroaryl residues are

Furthermore, in the substituents of formulae (a) to (d) E signifies oxygen, sulphur or -NR¹⁴. Here, the substituent R¹⁴ signifies hydrogen, Ci-8- alkyl, especially methyl, or C i-8-alkoxy, especially methoxy, and R¹³ stands for Ci-8-alkyl, preferably methyl. The optically active phosphine ligands of formulae V to XV are known compounds; thus, e.g. the ligands of formulae V and VI are described in US Pat. No. 5 171 892. The chiral ligands of formulae VII are also known compounds and can be prepared, for example, according to the process described in EP-A-031 877. The ligands of formula VIII can be obtained analogously to the method described in EP-A-564 406.

The diphosphine ligand of formula XV used in accordance with the invention are known compounds or analogues of known compounds which can be prepared readily in a manner analogous to the preparation of the known compounds.

The manufacture of the known compounds of the general formula III is described by M. R. Attwood et al., "Synthesis of the potent potassium channel opener Ro 31-6930 via Claisen rearrangement and tandem regio controlled cyclisation"; Tetrahydron Letters, Vol. 32, No. 6, pp 811-814, 1991.

The asymmetric hydrogenation in accordance with the invention of compounds of general formula III to compounds of formula I can be effected in suitable organic solvents which are inert under the reaction conditions. As such solvents there come into consideration especially lower alcohols such as methanol, ethanol, isopropanol; or halogenated hydrocarbons such as, for example, methylene chloride, chloroform and the like; or hydrocarbons such as, for example, toluene; or ethers such as, for example, diethyl ether, tetrahydrofuran or dioxan; or esters such as, for example, ethyl acetate, or also ketones such as, for example, acetone, methyl ethyl ketone or diethyl ketone. Furthermore, mixtures of these solvents with one another in any variation can be used.

The hydrogenation of chromenylpyridine N-oxides is preferably carried out in esters, hydrocarbons, chlorinated hydrocarbons, ethers or mixture thereof.

Chlorinated hydrocarbons, alcohols or mixtures thereof are especially suitable for the hydrogenation of chromenylpyridines.

The hydrogenation is conveniently carried out at temperatures in the range of about 0°C to 120°C, preferably 10 to 100°C, particularly in the temperature range of about 20°C to 80°C, and a pressure of about 1 to 200 bar, preferably 1 to 150 bar and particularly 10 to 80 bar.

The molar ratio (S/C) between the compounds of formula III to be hydrogenated and the metal complexes which are used as catalysts in accordance with formulae rV-a to rV-e conveniently lies between 20 to 30 000, preferably between 1000 to 6000. Rhodium-diphosphine complexes of formulae IV-a and IV-b are used for the hydrogenation preferably in a substrate-catalyst ratio of 100-25 000, particularly in a ratio of 1000 to 6000.

Ruthenium-diphosphine complexes of formulae TV-c to rV-e are preferably used in the hydrogenation in a substrate-catalyst ratio of 20-10 000, particularly in a ratio of 100 to 1000.

The complexes of formulae IV-a to IV-e can be prepared in a manner known per se.

The asymmetric hydrogenation of compounds of formula III in which X is N-oxide is preferably carried out in the presence of rhodium-diphosphine complexes of formula rV-a and rV-b.

For the asymmetric hydrogenation of compounds of formula III in which X is nitrogen, the reaction is preferably effected in the presence of a ruthenium-diphosphine complex of formula rV-c, rV-d or rV-e.

Examples of preferred ligands of formulae V to XIV are tert.-butyl 4-(5H-dibenzophosphol-5-yl)-2-(5H-dibenzophosphol-5- ylmethyl)-l-pyrrolidinecarboxylate,

5,5'-(6,6'-dimethyl-biphenyl-2,2'-diyl)-di-5H-benzo[b]-phosphindole, l,2-bis(2,5-dimethylphospholano)benzene, l,2-bis(2,5-dimethylphospholano)ethane, ethylene-bis-((2-methoxyphenyl)-phenyl-phosphine),

2,3-bis(diphenylphosphino)butane, l,2-bis-(diphenylphosphino)propane, l-benzyl-3,4-bis(diphenylphosphino)pyrrolidine,

2,3-bis(diphenylphosphino)-bicyclo(2.2.1)-hept-5-ene,

1- [bis-(3 ,5-dimethyl-phenyl)-phosphanyl] -2- [1- [bis-(3 ,5-dimethyl- phenyD-phosphanyl] -ethyl] -ferrocene, l-[bis-(4-trifluoromethyl-phenyl)-phosphanyl]-2-[l-diphenylphosphanyl- ethyl]- ferrocene, l-[bis-(3,5-dimethyl-phenyl)-phosphanyl]-ethyl}-l-diphenylphosphanyl- ferrocene,

2-{l-[bis-(2-methoxy-phenyl)-phosphanyl]-ethyl}-l-diphenylphosphanyl- ferrocene,

2-{l-[bis-(4-tert-butyl-phenyl)-phosphanyl]-ethyl}-l-diphenylphosphan- yl-ferrocene,

2-[l-dinaphthalen-2-ylphosphanyl-ethyl]-l-diphenylphosphanyl- ferrocene.

Examples of especially preferred ligands of formula XV are to

(6,6'-dimethylbiphenyl-2,2'-diyl)bis(diphenylphosphine),

(6,6'-dimethylbiphenyl-2,2'-diyl)bis(di-p-tolylphosphine),

(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(diphenylphosphine),

(6,6'-dimethoxybiphenyl-2,2'-diyl)bis(di-p-tolylphosphine),

(4,4',5,5',6,6'-hexamethoxy-biphenyl-2,2'-diyl)bis(diphenylphosphine).

The following Examples serve to illustrate the invention and are in no manner a limitation thereof. In these Examples the abbreviations used have the following significance:

HPLC High pressure liquid chromatography

RT Room temperature

HV High vacuum: 0.1 mbar

GC Capillary gas chromatography. e.e. Enatiomeric excess. (S,S)-BPPM-DIPHOL tert-Butyl (2S,4S)-4-(5H-dibenzophosphol-5- yl)-2-(5H-dibenzophosphol-5-ylmethyl)-l- pyrrolidinecarboxylate

(S)-BIPHEMP-DIPHOL 5,5'-[(S)-6,6'-Dimethyl-biphenyl-2,2'-diyl]-di-

5H-benzo [b] -phosphindole

(R,R)-MeDUPHOS l,2-Bis[(2R,5R)-2,5-dimethylphospholano]- benzene

(S,S)-MePHOS-Ethan l,2-Bis[(2S,5S)-2,5-dimethylphospholano]- ethane

(S,S)-DIPAMP Ethylene-bis-[(S)-(2-methoxy-phenyl)-phenyl- phosphine]

(S,S)-CHIRAPHOS (2S,3S)-2,3-Bis(diphenylphosphino)butane

(S)-PROPHOS (R)-l,2-Bis(diphenylphosphino)propane

(R,R)-PYRPHOS (3R,4R)-l-Benzyl-3,4-bis(diphenylphos- phino)pyrrolidine

(S,S)-NORPHOS (2S,3S)-2,3-Bis(diphenylphosphino)-bicyclo-

[2.2.1]-hept-5-ene

(R,S)-(3,5-Xyl)-PPF-P(3,5-Xyl)₂ (lR,2S)-l-[Bis-(3,5-dimethyl-phenyl)-phos- phanyl]-2-[(R)-l-[bis-(3,5-dimethyl-phenyl)- phosphanyl] -ethyl] -ferrocene

(R,S)-(pCF3-C6H )-PPF-P(Ph)2 (lR,2S)-l-[Bis-(4-trifluormethyl-phenyl)- phosphanyl]-2-[(R)-l-diphenylphosphanyl- ethyl] -ferrocene

(R,S)-PPF-P(3,5-Xyl)2 (lR,2S)-2-{(R)-l-[Bis-(3,5-dimethyl-phenyl)- phosphanyl]-ethyl}-l-diphenylphosphanyl- ferrocene

(R,S)-PPF-P(oAn)2 (lR,2S)-2-{(R)-l-[Bis-(2-methoxy-phenyl)- phosphanyl]-ethyl}-l-diphenylphosphanyl- ferrocene (R,S)-PPF-P(4tert.Bu-C6H4)2 (lR,2S)-2-{(R)-l-[Bis-(4-tert-butyl-phenyl)- phosphanyl]-ethyl}-l-diphenylphosphanyl- ferrocene

(R,S)-PPF-P(2-Naphtyl)2 (lR,2S)-2-[(R)-l-Dinaphthalen-2-ylphos- phanyl-ethyl]-l-diphenylphosphanyl-ferrocene

(Rh(COD)2)BF4 Bis-(cycloocta-l,5-diene)rhodium(I) tetrafluoro-borate

BIPHEMP (6,6'-Dimethylbiphenyl-2,2'-diyl)bis-

(diphenylphosphine) p-TolBIPHEMP (6,6'-Dimethylbiphenyl-2,2'-diyl)bis(di-p- tolylphosphine)

MeOBIPHEP (6,6'-Dimethoxybiphenyl-2,2'-diyl)bis-

(diphenylphosphine) p-TolMeOBIPHEP (6,6'-Dimethoxybiphenyl-2,2'-diyl)bis(di-p- tolylphosphine)

TriMeOBIPHEP (4,4',5,5\6,6'-Hexamethoxy-biphenyl-2,2'- diyl)bis(diphenylphosphine)

All temperatures are given in degrees Celsius.

Example 1

Compound of formula I, wherein R is cyano, R' is methyl, R" is hydrogen, X is N-oxide.

100 mg (0.359 mmol) of 2-(6-cyano-2,2-dimethyl-2H-l-benzopyran-4-yD- pyridine 1-oxide, 9 ml of toluene, 1 ml of dichloromethane, 5.8 mg (0.0144 mmol) of [Rh(COD)₂]BF and 6.1 mg (0.0144 mmol) of (S,S)- CHIRAPHOS in a 30 ml autoclave were placed in a glove box (O₂ content < 1 ppm). The autoclave was sealed and the hydrogenation was carried out while stirring at 40° and a pressure of 40 bar. The hydrogenation was interrupted after 20 hours. In order to determine the e.e. value and the conversion, a sample of the hydrogenation solution was evaporated and analyzed by HPLC on a chiral phase (Chiracel OD-H). (S)-2-(6-Cyano-3,4- dihydro-2,2-dimethyl-2H-l-benzopyran-4-yl)pyridine- 1-oxide was obtained in quantitative yield: e.e. = 98%; chem. purity > 99%.

Examples 2-15

The hydrogenations using the ligands listed in Table 1 in place of (S,S)- CHIRAPHOS were carried out in an analogous manner to Example 1.

Table 1

Example 16

2.5 g of 2-(6-cyano-2,2-dimethyl-2H-l-benzopyran-4-yl)pyridine 1-oxide were suspended in 48 ml of ethyl acetate in a 185 ml autoclave in a glove box (O₂ content < 1 ppm) and 5 ml of a catalyst solution prepared by dissolving 10.5 mg of [Rh(COD)₂]CF₃SO₃ and 9.6 mg of (S,S)-CHIRAPHOS in 50 ml of ethyl acetate were added. The autoclave was sealed and the hydrogenation was carried out while stirring at 40° at a constant pressure of 40 bar. The hydrogenation had finished within about 18 hours. After evaporation of the solvent there was obtained crude (S)-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H- l-benzopyran-4-yl)pyridine 1-oxide in quantative yield with 99% e.e. and a chemical purity of > 99 HPLC area %.

Examples 17-20

The hydrogenations using the cationic [Rh(S,S)-CHIRAPHOS]⁺A- complexes listed in Table 2 in place of [Rh(S,S)-CHIRAPHOS]+ CF3SO3 - were carried out in an analogous manner to Example 16. Table 2

1) Using (R,R)-CHIRAPHOS as the ligand

Example 21

Compound of formula I, wherein R is cyano, R' is methyl, R" is hydrogen, X is N.

100 mg of 2,2-dimethyl-4-(2-pyridyl)-2H-l-benzopyran-6-carbonitrile and 12.6 mg of Ru(S)-p-TolBIPHEMP)(OAc)₂ in 7.5 ml of dichloromethane were suspended in a 30 ml autoclave in a glove box (O₂ content < 1 ppm) and 0.5 ml of a solution of HCl in methanol (prepared by adding 97.8 mg of acetyl chloride in 20 ml of methanol) was added. The autoclave was sealed and the hydrogenation was carried out while stirring at 80° and a pressure of 40 bar. The hydrogenation had finished within 19 hours. After evaporation of the solvent there was obtained crude (R)-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)- 2H-l-benzopyran-6-carbonitrile in quantitative yield with 95% e.e. and a chemical purity of 99 HPLC area %. The determination of the e.e. value and the conversion was effected by HPLC on a chiral phase (Chiracel OD-H).

Examples 22-25

The hydrogenations using the ruthenium complexes listed in Table 3 in place of Ru((S)-pTolBIPHEMP)(OAc)₂ were carried out in an analogous manner to Example 21. Table 3

Example 26

Compound of formula I, wherein R is hydrogen, R' is methyl, R" is hydrogen, X is N-oxide.

0.50 g of 2-(2,2-dimethyl-2H-l-benzopyran-4-yl)-pyridine 1-oxide, 8 ml of ethyl acetate, 9.2 mg of [Rh(COD)₂]CF₃SO₃ and 8.4 mg of (S,S)-CHIRAPHOS in a 30 ml autoclave were placed in a glove box (O₂ content < 1 ppm). The autoclave was sealed and the hydrogenation was carried out while stirring at 40° and a pressure of 40 bar. The hydrogenation was interrupted after 20 hours, the reaction mixture was evaporated and the residue was chromato- graphed on silica gel (eluent: chloroform). There were obtained 320 mg (64%) of 2-(3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-4-yl)-pyridine 1-oxide with

[_α]_D) ²⁰ = +112.1° (c = 1%, EtOH). The enantio eric purity was > 94% e.e. (NMR analysis with l-(9-anthryl)-2,2,2-trifluro-ethanol as the chiral shift reagent).

An analogous reaction with (R,R)-CHIRAPHOS yielded 2-(3,4-dihydro-

20

2,2-dim meetthhyyll--22HH--ll--bbeennzzooppyyrraann--44--yyll))--ppyyrriiddiinnee 11--ooxxiiddee w with [α]_D, = -110.8° (c = 1%, EtOH). The enantiomeric purity was > 96% e.e.

Claims

Patent Claims

1. A process for the manufacture of optically active chromanylpyridine derivatives of the general formula

wherein

X corresponds to N or N-oxide

R corresponds to cyano, hydrogen, halogen, trifluoromethyl, nitro, Ci-8-alkyl, Ci-8-alkoxycarbonyl, Ci-8-alkylthio, Ci-8- alkylsulphonyl, Ci-8-alkanoyl, aroyl, carbamoyl, mono- (Ci-8-alkyl)carbamoyl or di(Ci-8-alkyl)carbamoyl;

R' corresponds to hydrogen, Ci-8-alkyl or -CH₂F; R" corresponds to Ci-8-alkyl, halogen, amino, -CO2-(Ci-8- alkyl, hydroxy, Ci.s-alkoxy, aryl or, when n = 2, R" together with the group

correspond to a benz-fused system according to the formulae

Ila lib lie

and n corresponds to 0, 1 or 2, characterized by asymmetrically hydrogenating a compound of the general formula

wherein X, R, R', R" and n have the significances set forth above, in the presence of a complex of an optically active diphosphine Hgand with a Group VIII metal.

2. A process according to claim 1, characterized in that the asymmetic hydrogenation is carried out in the presence of an optically active metal- diphosphine complex of one of the following formulae

[Rh(Y)(Ln)]+A- IV- a

[Rh(Y)(Ln) B] P7- b

[Ru(Y)]2+(A-)₂ IV- c

[Ru(Y)(B)₂] IV- d

[Ru(Y)(Cl)(C2)₂._m](C3)_m IV- e

wherein

L signifies a neutral ligand

A signifies an anion of an oxygen acid or complex acid

B signifies an anionic coordinating ligand

Cl signifies benzene p-cymene, xylene, hexamethylbenzene

C^ signifies halogen

C^┬½3 signifies halogen or A n signifies 0, 1 or 2 m signifies 0, 1 or 2

Y signifies an optically active diphosphine of the formulae

'7

wherein

R² signifies cycloalkyl or Ci-╬▓-alkyl, R³ signifies hydrogen, cycloalkyl or Ci-8-alkyl,

R⁴ and R⁴' signify Ci-8-alkyl or Ci-8-alkoxy,

R⁵, R⁵' and R⁶ signify aryl, heteroaryl, C ╬╣_8-alkyl, cycloalkyl, whereby the residues R⁵ and R⁵' can be the same or different, R⁷ and R⁸ each independently signify Ci-8-alkyl, C╬╣-8-alkoxy, hydroxy, protected hydroxy or R⁷ and R⁸ together signify

-CH2-O-CH2- R⁴' and R? and/or

R⁴' and R⁸ signify a benzo or benzofuran condensed system, R⁹ and R¹⁰ each independently signify aryl, Ci-8-alkyl, cycloalkyl, a

5-membered heteroaromatic or a group of the formula

RU signifies C╬╣.₈-alkyl, benzyl, -COOR⁶, -COON(R³)₂, and

R12 signifies -COR⁶, -COOR⁶, -CON(R³)₂, -SO₂R⁶ or

-PO(R5)₂.

3. A process according to one of claims 1 to 2, characterized in that rhodium complexes of the formula

[Rh(Y)L_n]+A- r " a

[Rh(Y)(Ln)B] IV- b

wherein the symbols are as defined in claim 2, are used for the asymmetric hydrogenation of compounds of formula III in which X is N-oxide.

4. A process according to one of claims 1 to 2, characterized in that ruthenium complexes of the formula

[Ru(Y)]2+(A-)₂ IV- c

[Ru(Y)(B)₂] IV- d

[Ru(Y)(Cl)(C2)₂._m](C³)_m IV- e

wherein the symbol are as defined in claim 2, are used for the asymmetric hydrogenation of compounds of formula III in which X is nitrogen.

5. A process for the manufacture of a compound of formula I according to claim 1, characterized in that the asymmetric hydrogenation is effected in a temperature range of 0 to 120┬░C, a pressure of 1 to 250 bar and a substrate to catalyst ratio of 20-30 000.

6. A process according to any one of claims 1 to 3, characterized in that the asymmetric hydrogenation in the case of the reaction of compounds of formula III in which X is N-oxide is carried out in a temperature range of 0 to 100┬░C and a pressure of 1 to 180 bar.

7. A process according to claim 6, characterized in that the molar ratio of substrate to catalyst for a catalyst of formulae IV-a and IV-b lies in the range of 20 to 30 000.

8. A process according to any one of claims 1, 2 or 4, characterized in that the asymmetric hydrogenation in the case of the reaction of compounds of formula III in which X is nitrogen is effected in a temperature range between 10-100┬░C and a pressue of 1-150 bar.

9. A process according to claim 8, characterized in that the molar ratio of substrate to catalyst for a catalyst of formulae rV-c to rV-e lies in the range of 20 to 10 000.

10. A process according to any one of claims 1 to 4, characterized in that the asymmetric hydrogenation of a compound of formula TV as defined in claim 2 is carried out in a solvent from the group of esters, hydrocarbons, chlorinated hydrocarbons, ethers, lower alcohols and mixtures thereof.

11. A process according to any one of claims 1 to 3, characterized in that esters, chlorinated or non-chlorinated hydrocarbons, ethers or mixtures thereof are used for the asymmetric hydrogenation of compounds of formula III in which X is N-oxide.

12. A process according to any one of claims 1,2 and 4, characterized in that chlorinated hydrocarbons, alcohols or mixtures thereof are used as the solvent for the asymmetric hydrogenation of compounds of formula III in which X is nitrogen.