WO1999001453A1 - A process for the manufacture of optically active chromanylpyridine derivatives - Google Patents
A process for the manufacture of optically active chromanylpyridine derivatives Download PDFInfo
- Publication number
- WO1999001453A1 WO1999001453A1 PCT/EP1998/003944 EP9803944W WO9901453A1 WO 1999001453 A1 WO1999001453 A1 WO 1999001453A1 EP 9803944 W EP9803944 W EP 9803944W WO 9901453 A1 WO9901453 A1 WO 9901453A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- signifies
- process according
- formula
- corresponds
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention is concerned with a novel, catalytic process for the manufacture of optically active compounds of the general formula
- 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 -CH 2 F;
- n 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.
- 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.
- 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
- L signifies a neutral ligand
- A signifies an anion of an oxygen acid or complex acid
- Cl signifies benzene p-cymene, xylene, hexamethylbenzene
- 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
- R 2 signifies cycloalkyl or Ci- 8 -alkyl
- R 3 signifies hydrogen, cycloalkyl or Ci- 8 -alkyl
- R 4 and R 4 ' signify Ci.s-alkyl or C ⁇ _ 8 -alkoxy
- R 5 , R 5 ' and R 6 signify aryl, heteroaryl, Ci- 8 -alkyl, cycloalkyl, whereby the residues R 5 and R 5 ' can be the same or different, R 7 and R 8 each independently signify Ci- 8 -alkyl, Ci- 8 -alkoxy, hydroxy, protected hydroxy or R 7 and R 8 together signify
- R 4 ' and R 8 signify a benzo or benzofuran condensed system
- R 9 and R 10 each independently signify aryl, Ci- 8 -alkyl, cycloalkyl, a
- RU signifies C ⁇ . 8 -alkyl, benzyl, -COOR 6 , -COON(R 3 ) 2 , and
- R12 signifies -COR 6 , -COOR 6 , -CON(R 3 ) 2 , -SO 2 R 6 or
- 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.
- carboxylic acid residue used with respect to the term “anionic coordinating ligand” refers to groups Ci- ⁇ alkyl-COO-, the alkyl moiety being unsubstituted or substituted by halogen"
- oxygen acid or complex acid signifies in the scope of the present invention acids from the group of H2SO4, HCIO4, HBr ⁇ 4, HIO4, HNO3, H3PO4, H3PO3, CF3SO3H, C 6 H 5 SO 3 H as well as halogen complexes with the elements boron, phosphorus arsenic antimony or bismuth.
- Preferred representatives are HCIO4, CF3SO3H, HPF 6 , HBF 4 , HB(Ph) 4 , HB(3,5(CF 3 ) 2 - C 6 H 3 )4, HSbF 6 and HAsF 6 .
- halogen embraces fluorine, bromine, chlorine and iodine, chlorine, bromine or iodine is preferred.
- 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.
- 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.
- alkyl (sic) groups with 1 to 4 carbon atoms.
- 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 "C ⁇ -8-alkylthio groups".
- 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.
- 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.
- 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.
- the term can signify naphthyl.
- aroyl signifies in the scope of the present invention benzoyl which may also be substituted.
- 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.
- di(C ⁇ .8-alkyl)carbamoyl embraces e.g. dimethylcarbamoyl, diethylcarbamoyl and the like.
- ether- forming groups such as e.g. benzyl, allyl, benzyloxymethyl, C i-8-alkoxymethyl or also 2-methoxyethoxymethyl and the like.
- 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.
- E signifies oxygen, sulphur or -NR 14 .
- R 14 signifies hydrogen, Ci-8- alkyl, especially methyl, or C i-8-alkoxy, especially methoxy
- R 13 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.
- 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.
- 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.
- suitable organic 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.
- 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.
- 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.
- 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,
- MeOBIPHEP (6,6'-Dimethoxybiphenyl-2,2'-diyl)bis-
- TriMeOBIPHEP (4,4',5,5 ⁇ 6,6'-Hexamethoxy-biphenyl-2,2'- diyl)bis(diphenylphosphine)
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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
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
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
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
Compound of formula I, wherein R is cyano, R' is methyl, R" is hydrogen, X is N-oxide.
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
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
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«3 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-╬▓-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)Ln]+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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP97110941.8 | 1997-07-02 | ||
| EP97110941 | 1997-07-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999001453A1 true WO1999001453A1 (en) | 1999-01-14 |
Family
ID=8227001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1998/003944 WO1999001453A1 (en) | 1997-07-02 | 1998-06-27 | A process for the manufacture of optically active chromanylpyridine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO1999001453A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0020018A1 (en) * | 1979-05-19 | 1980-12-10 | Beecham Group Plc | Chroman derivatives, processes for their preparation and pharmaceutical compositions containing them |
| EP0031877A1 (en) * | 1980-01-08 | 1981-07-15 | Degussa Aktiengesellschaft | Optically active 1,2-Bis-(diphenylphosphino)-compounds, metal complexes containing them as chiral ligands and their use |
| EP0298452A2 (en) * | 1987-07-06 | 1989-01-11 | F. Hoffmann-La Roche Ag | 2H-1-benzopyrane derivatives substituted in position 4 by aryl or N-heteroaryl |
| DE4115465A1 (en) * | 1991-05-11 | 1992-11-12 | Beiersdorf Ag | NEW 2H-BENZO (B) PYRANE DERIVATIVES SUBSTITUTED IN 4-POSITION BY ARYL OR N-HETEROARYL, METHODS FOR THEIR PRODUCTION AND THEIR USE AND THE PREPARATIONS CONTAINING THE COMPOUNDS |
| US5171892A (en) * | 1991-07-02 | 1992-12-15 | E. I. Du Pont De Nemours And Company | Chiral phospholanes via chiral 1,4-diol cyclic sulfates |
| EP0564406A1 (en) * | 1992-04-02 | 1993-10-06 | Ciba-Geigy Ag | Ferrocenyldiphosphine as ligands for homogeneous catalysts |
| US5470861A (en) * | 1994-08-04 | 1995-11-28 | Hoffmann-La Roche Inc. | Method of promoting hair growth |
-
1998
- 1998-06-27 WO PCT/EP1998/003944 patent/WO1999001453A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0020018A1 (en) * | 1979-05-19 | 1980-12-10 | Beecham Group Plc | Chroman derivatives, processes for their preparation and pharmaceutical compositions containing them |
| EP0031877A1 (en) * | 1980-01-08 | 1981-07-15 | Degussa Aktiengesellschaft | Optically active 1,2-Bis-(diphenylphosphino)-compounds, metal complexes containing them as chiral ligands and their use |
| EP0298452A2 (en) * | 1987-07-06 | 1989-01-11 | F. Hoffmann-La Roche Ag | 2H-1-benzopyrane derivatives substituted in position 4 by aryl or N-heteroaryl |
| DE4115465A1 (en) * | 1991-05-11 | 1992-11-12 | Beiersdorf Ag | NEW 2H-BENZO (B) PYRANE DERIVATIVES SUBSTITUTED IN 4-POSITION BY ARYL OR N-HETEROARYL, METHODS FOR THEIR PRODUCTION AND THEIR USE AND THE PREPARATIONS CONTAINING THE COMPOUNDS |
| US5171892A (en) * | 1991-07-02 | 1992-12-15 | E. I. Du Pont De Nemours And Company | Chiral phospholanes via chiral 1,4-diol cyclic sulfates |
| EP0564406A1 (en) * | 1992-04-02 | 1993-10-06 | Ciba-Geigy Ag | Ferrocenyldiphosphine as ligands for homogeneous catalysts |
| US5470861A (en) * | 1994-08-04 | 1995-11-28 | Hoffmann-La Roche Inc. | Method of promoting hair growth |
Non-Patent Citations (1)
| Title |
|---|
| M. R. ATTWOOD ET AL., TETRAHEDRON LETTERS, vol. 32, no. 6, 1991, pages 811 - 4, XP002082330 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11926616B2 (en) | 2018-03-08 | 2024-03-12 | Incyte Corporation | Aminopyrazine diol compounds as PI3K-γ inhibitors |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Mršić et al. | Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium Complexes of Monodentate BINOL‐Derived Phosphoramidites | |
| Loiseleur et al. | Enantioselective Heck reactions catalyzed by chiral phosphinooxazoline-palladium complexes | |
| Hansen et al. | Scalable, efficient process for the synthesis of (R)-3, 5-bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex | |
| Welter et al. | Enantioselective synthesis of (+)(R)-and (−)(S)-nicotine based on Ir-catalysed allylic amination | |
| CN1946730A (en) | Cycloolefin phosphine ligands and their use in catalysis | |
| Diéguez et al. | Modular Furanoside Diphosphite Ligands for Pd‐Catalyzed Asymmetric Allylic Substitution Reactions: Scope and Limitations | |
| Schmidt et al. | Diarylmethanols by catalyzed asymmetric aryl transfer reactions onto aldehydes using boronic acids as aryl source | |
| Song et al. | Asymmetric synthesis of highly functionalized spirothiazolidinone tetrahydroquinolines via a squaramide-catalyzed cascade reaction | |
| KR101287369B1 (en) | Sulphonylated diphenylethylenediamines, method for their preparation and use in trasfer hydrogenation catalysis | |
| Iglesias-Sigüenza et al. | N-Heterotricyclic cationic carbene ligands. Synthesis, reactivity and coordination chemistry | |
| CN103408573B (en) | Boric acid derivatives and its preparation method and application | |
| Popa et al. | Phosphinooxazolines Derived from 3‐Amino‐1, 2‐diols: Highly Efficient Modular P‐N Ligands | |
| Hilgraf et al. | Chiral bis (N-tosylamino) phosphine-and TADDOL-phosphite-oxazolines as ligands in asymmetric catalysis | |
| WO1999001453A1 (en) | A process for the manufacture of optically active chromanylpyridine derivatives | |
| CN103408572B (en) | Chiral aminoboronic acid derivative and its preparation method and application | |
| Xu et al. | Synthesis of new pryridyl alcohols and their use as catalysts in the asymmetric addition of diethylzinc to aldehydes | |
| Mata et al. | Pyranoside phosphite–phosphoroamidite ligands for Pd-catalyzed asymmetric allylic alkylation reactions | |
| US9328079B2 (en) | Process for producing optically active amine | |
| WO2020064818A1 (en) | Process for the preparation of sphingosine-1-phosphate receptor agonist | |
| Shi et al. | Asymmetric catalysis of Morita‐Baylis‐Hillman reactions by chiral phosphine Lewis bases bearing multiple phenol groups | |
| EP3781581A1 (en) | Novel ruthenium complexes and their use in olefin metathesis reactions | |
| EP3016961B1 (en) | Novel ruthenium catalysts and their use for asymmetric reduction of ketones | |
| CA2716694A1 (en) | Process | |
| US7642357B2 (en) | Iridium complexes | |
| Viso et al. | Synthesis of chiral sulfinamido-sulfonamides and their evaluation as ligands for the enantioselective ethylation of aldehydes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA CN JP KR MX US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: KR |
|
| NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 1999506297 Format of ref document f/p: F |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |