Process for the preparation of enantiomerically pure 1-substituted-3-aminoalcohols

1. A process for the preparation of N-monosubstituted β-aminoalcohol sulfonates of formula

wherein R 1 is C 6-20 aryl or C 4-12 heteroaryl, each optionally being substituted with one or more halogen atoms and/or one or more C 1-4 alkyl or C 1-4 alkoxy groups, R 2 is selected from the group consisting of C 1-4 alkyl, C 3-8 cycloalkyl and C 6-20 aryl, each aryl optionally being substituted with one or more halogen atoms and/or one or more C 1-4 alkyl or C 1-4 alkoxy groups, and wherein R 3 is selected from the group consisting of C 1-18 alkyl, C 6-20 cycloalkyl, C 6-2 O aryl and C 7-20 aralkyl residues,

comprising the steps of

a) reacting a mixture comprising

(i) a methyl ketone of formula

wherein R 1 is as defined above,

(ii) a primary amine of formula

H 2 N—R 2   V,

wherein R 2 is as defined above, and

(iii) formaldehyde or a source of formaldehyde selected from the group consisting of formaldehyde in aqueous solution, 1,3,5-trioxane, paraformaldehyde and mixtures thereof,

in the presence of a sulfonic acid of the formula

R 3 —SO 2 —OH  VI

wherein R 3 is as defined above,

optionally in an organic solvent, said organic solvent optionally containing water, to afford a β-aminoketone sulfonate of formula

wherein R, R 2 and R 3 are as defined above,

and

b) asymmetrically hydrogenating said sulfonate, to afford a β-aminoalcohol sulfonate of formula I, wherein R 1 , R 2 and R 3 are as defined above, in the presence of a base and a catalyst, the catalyst comprising a transition metal and a diphosphine ligand, at a hydrogen pressure of 5 to 50 bar, in a polar solvent, optionally in the presence of water.

2. A process for the preparation of N-monosubstituted β-aminoalcohol sulfonates of formula

wherein R 1 is C 6-20 aryl or C 4-12 heteroaryl, each optionally being substituted with one or more halogen atoms and/or one or more Ci −4 alkyl or C 1-4 alkoxy groups, R 2 is selected from the group consisting of C 1-4 alkyl, C 3-8 cycloalkyl and C 6-20 aryl, each aryl optionally being substituted with one or more halogen atoms and/or one or more C 1-4 alkyl or C 1-4 alkoxy groups, and wherein R 3 is selected from the group consisting of Ci −18 alkyl, C 6-20 cycloalkyl, C 6-20 aryl and C 7-20 aralkyl residues,

comprising asymmetrically hydrogenating a β-aminoketone sulfonate of formula

wherein R, R and R are as defined above,

in the presence of a base and a catalyst, the catalyst comprising a transition metal and a diphosphine ligand, at a hydrogen pressure of 5 to 50 bar, in a polar solvent, optionally in 1 o the presence of water.

3. The process of claim 1 , wherein R 1 is 2-thienyl, optionally being substituted with one or more halogen atoms, and R 2 is selected from the group consisting of methyl, ethyl, tert-butyl and cyclopropyl.

4. The process of claim 1 , wherein the β-aminoalcohol of formula I is selected from the group consisting of (<S)-(−)-3-iV-methylamino-1-(2-thienyl)-1-propanol, (,S)-(−)-3-7V-methyl-amino-1-(3-chloro-2-thienyl)-1-propanol, (i?)-(+)-3-iV-methylamino-1-(2-thienyl)-1-propanol and (i?)-(+)-3-N-methylamino-1-(3-chloro-2-thienyl)-20 1-propanol.

5. The process of claim 1 , wherein R 3 of the sulfonic acids of the formula VI is selected from the group consisting of

i) linear or branched alkyl residues, consisting of 1 to 18 carbon atoms, containing one 15 or more substituents of the group consisting of amino, halogen and hydroxy,

ii) cycloalkyl residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxy, and

iii) mono- or polycyclic aromatic or araliphatic residues, consisting of 6 to 20 carbon so atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxy.

6. The process of claim 1 , wherein the base, is a metal carbonate.

7. The process of claim 1 , wherein the transition metal is selected from the group consisting of rhodium, ruthenium or indium, preferably rhodium.

8. The process of claim 1 , wherein the diphosphine ligand is selected from the group consisting of

9. β-Aminoalcohol sulfonates of the formula

wherein R 1 is C 6-20 aryl or C 4-12 heteroaryl, each optionally being substituted with one or more halogen atoms and/or one or more C 1-4 -alkyl or C 1-4 -alkoxy groups, R 2 is C 1-4 -alkyl or C 6-20 aryl, each aryl optionally being substituted with one or more halogen atoms and/or one or more C 1-4 alkyl or C 1-4 alkoxy groups, and wherein R 3 is selected from the group consisting of C 1-18 alkyl, C 6-20 cycloalkyl, C 6-20 aryl and C 7-20 aralkyl residues.

10. The process of claim 2 , wherein R.sup.1 is 2-thienyl, optionally being substituted with one or more halogen atoms, and R.sup.2 is selected from the group consisting of methyl, ethyl, tert-butyl and cyclopropyl.

11. The process of claim 2 , wherein the .beta.-aminoalcohol of formula I is selected from the group consisting of (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol, (S)-(−)-3-N-methyl-amino-1-(3-chloro-2-thienyl)-1-propanol, (R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol and (R)-(+)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol.

12. The process of claim 3 , wherein the .beta.-aminoalcohol of formula I is selected from the group consisting of (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol, (S)-(−)-3-N-methyl-amino-1-(3-chloro-2-thienyl)-1-propanol, (R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol and (R)-(+)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol.

13. The process of claim 10 , wherein the .beta.-aminoalcohol of formula I is selected from the group consisting of (S)-(−)-3-N-methylamino-1-(2-thienyl)-1-propanol, (S)-(−)-3-N-methyl-amino-1-(3-chloro-2-thienyl)-1-propanol, (R)-(+)-(3)-N-methylamino-1-(2-thienyl)-1-propanol and (R)-(+)-3-N-methylamino-1-(3-chloro-2-thienyl)-1-propanol.

14. The process of claim 2 , wherein R.sup.3 of the sulfonic acids of the formula VI is selected from the group consisting of

i) linear or branched alkyl residues, consisting of 1 to 18 carbon atoms, containing one or more substituents of the group consisting of amino, halogen and hydroxyl,

ii) cycloalkyl residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxyl, and

iii) mono- or polycyclic aromatic or araliphatic residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxyl.

15. The process of claim 12 , wherein R.sup.3 of the sulfonic acids of the formula VI is selected from the group consisting of

i) linear or branched alkyl residues, consisting of 1 to 18 carbon atoms, containing one or more substituents of the group consisting of amino, halogen and hydroxyl,

ii) cycloalkyl residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxyl, and

iii) mono- or polycyclic aromatic or araliphatic residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxyl.

16. The process of claim 13 , wherein R.sup.3 of the sulfonic acids of the formula VI is selected from the group consisting of

i) linear or branched alkyl residues, consisting of 1 to 18 carbon atoms, containing one or more substituents of the group consisting of amino, halogen and hydroxyl,

ii) cycloalkyl residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents, of the group consisting of amino, halogen and hydroxyl, and

iii) mono- or polycyclic aromatic or araliphatic residues, consisting of 6 to 20 carbon atoms, optionally containing one or more nitrogen or oxygen atoms and/or one or more substituents of the group consisting of amino, halogen and hydroxyl.

17. The process of claim 2 , wherein the base is a metal carbonate.

18. The process of claim 15 , wherein the base is a metal carbonate.

19. The process of claim 16 , wherein the base is a metal carbonate.

20. The process of claim 2 , wherein the transition metal is selected from the group consisting of rhodium, ruthenium or iridium, preferably rhodium.

21. The process of claim 18 , wherein the transition metal is selected from the group consisting of rhodium, ruthenium or iridium, preferably rhodium.

22. The process of claim 19 , wherein the transition metal is selected from the group consisting of rhodium, ruthenium or iridium, preferably rhodium.

23. The process of claim 2 , wherein the diphosphine ligand is selected from the group consisting of

24. The process of claim 21 , wherein the diphosphine ligand is selected from the group consisting of

25. The process of claim 22 , wherein the diphosphine ligand is selected from the group consisting of