Method for preparing and purifying 3-hydroxyamidinophenylalanine compounds

1. A method for purifying a 3-hydroxyamidinophenylalanine compound having the formula (I):

in which R 1 is a group of the formula

in which R 4 is

(i) an unsubstituted C 1 -C 6 -alkyl residue, or a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted C 1 -C 6 -alkyl residue;

(ii) a saturated or unsaturated branched or unbranched C 1 -C 6 -alkoxy residue;

(iii) an unsubstituted phenoxy or benzyloxycarbonyl residue, a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted phenoxy or benzyloxycarbonyl residue;

(iv) phenyl, p-halophenyl, or naphthyl, or

(v) ethoxycarbonyl,

R 2 is an unsubstituted phenyl residue, or a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted phenyl residue,

R 3 is H or branched or unbranched C 1 -C 4 -alkyl,

n is 0 or 1, and

Z is CR 9 where R 9 is H,

comprising the steps of:

(a) forming a salt precipitate by adding an aromatic sulfonic acid to a solution of a contaminated 3-hydroxyamidinophenylalanine compound,

(b) separating said precipitate formed in step (a), and

(c) recovering a purified 3-hydroxyamidinophenylalanine compound from the precipitate.

2. The method as claimed in claim 1 , wherein the 3-hydroxyamidinophenylalanine compound is an N-α-(2,4,6-triisopropylphenylsulfonyl-3-hydroxyamidino-(D,L)-phenylalanine compound or a L enantiomer thereof.

3. The method of claim 1 , wherein R 4 is ethoxycarbonyl, phenyl, p-halophenyl, or naphthyl.

4. The method as claimed in claim 3 , in which the aromatic sulfonic acid in step (a) is Armstrong's acid.

5. The method as claimed in claim 3 , wherein a solution of the 3-hydroxyamidinophenylalanine compound in acetone is employed in step (a).

6. The method as claimed in claim 3 , wherein said separation of the precipitate in step (b) takes place by filtration.

7. The method as claimed in claim 3 , wherein the recovery in step (c) takes place by reaction with NaHCO 3 .

8. The method as claimed in claim 3 , wherein the 3-hydroxyamidinophenylalanine compound is obtained in a purity of more than 90%.

9. The method as claimed in claim 3 , wherein the 3-hydroxyamidinophenylalanine compound is obtained in a purity of more than 95%.

10. The method as claimed in claim 3 , wherein the hydroxyamidinophenylalanine compound is obtained in a purity of more than 99%.

11. The method of claim 3 , wherein R 2 is phenyl, 4-methylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, or 4-methoxy-2,3,6-trimethylphenyl.

12. A method for preparing a 3-hydroxyamidinophenylalanine compound having the formula (I):

in which R 1 is a group of the formula

in which R 4 is

(i) an unsubstituted C 1 -C 6 -alkyl residue, or a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted C 1 -C 6 -alkyl residue;

(ii) a saturated or unsaturated branched or unbranched C 1 -C 6 -alkoxy residue;

(iii) an unsubstituted phenoxy or benzyloxycarbonyl residue, a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted phenoxy or benzyloxycarbonyl residue,

(iv) phenyl, p-halophenyl, or naphthyl, or

(v) ethoxycarbonyl;

R 2 is an unsubstituted phenyl residue, or a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted phenyl residue,

R 3 is H or branched or unbranched

n is 0, and

Z is CR 9 where R 9 is H,

comprising the steps of:

(i) reacting an N-protected 3-cyanophenylalanine with a piperazine derivative to form an N-protected 3-cyanophenylalanine piperazide, wherein said piperazine derivative is of the formula:

(ii) deprotecting said N-protected 3-cyanophenylalanine piperazide to form an N-deprotected 3-cyanophenylalanine piperazide and reacting said N-deprotected 3-cyanophenylalanine piperazide with a phenylsulfonyl halide to form a compound, said phenylsulfonyl halide being optionally substituted with a substituent, wherein said substituent is C1-C6-alkyl, C1-C3-alkoxy, hydroxyl, carboxyl, nitro, cyano and/or halogen;

(iii) converting a cyano group of the compound formed in step (ii) into a hydroxyamidino group to form a 3-hydroxyamidinophenylalanine compound

(iv) purifying the 3-hydroxyamidinophenylalanine compound formed in step (iii) by:

(A) forming a salt precipitate by adding an aromatic sulfonic acid to a solution of said 3-hydroxyamidinophenylalanine compound;

(B) separating said precipitate formed in step (A); and

(C) recovering a purified 3-hydroxyamidinophenylalanine compound from the precipitate.

13. The method of claim 12 , wherein the piperazine derivative in step (i) is ethoxycarbonylpiperazine.

14. The method of claim 12 , wherein R 4 is ethoxycarbonyl, phenyl, p-halophenyl, or naphthyl.

15. The method of claim 14 wherein a Boc N-protected 3-cyanophenylalanine derivative is employed in step (i).

16. The method of claim 14 , wherein R 2 is phenyl, 4-methylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, or 4-methoxy-2,3,6-trimethylphenyl.

17. The method of claim 14 , wherein said phenylsulfonyl halide is 2,4,6-triisopropylbenzenesulfonyl chloride.

18. The method of claim 14 , wherein the cyano group in step (iii) is converted into a hydroxyamidino group by reaction with hydroxylamine hydrochloride in the presence of sodium carbonate or triethylamine.

19. The method of claim 14 , wherein the 3-hydroxyamidinophenylalanine compound is produced in a purity of more than 90%.

20. The method of claim 14 , wherein the 3-hydroxyamidinophenylalanine compound is produced in a purity of more than 95%.

21. The method of claim 14 , wherein the 3-hydroxyamidinophenylalanine compound is produced in a purity of more than 99%.

22. A process for preparing a 3-amidinophenylalanine compound comprising the steps of:

I) preparing a hydroxyamidinophenylalanine compound having the formula (I):

in which R 1 is a group of the formula

in which R 4 is

(i) an unsubstituted C 1 -C 6 -alkyl residue, or a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted C 1 -C o -alkyl residue;

(ii) a saturated or unsaturated branched or unbranched C 1 -C 6 -alkoxy residue;

(iii) an unsubstituted phenoxy or benzyloxycarbonyl residue, a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted phenoxy or benzyloxycarbonyl residue; or

(iv) an aryl residue,

R 2 is an unsubstituted phenyl residue, or a C 1 -C 6 -alkyl-, C 1 -C 3 -alkoxy-, hydroxyl-, carboxyl-, nitro-, cyano-, or/and halogen-substituted phenyl residue,

R 3 is H or branched or unbranched C 1 -C 4 -alkyl,

n is 0, and

Z is CR 9 where R 9 is H,

comprising the steps of:

(i) reacting an N-protected 3-cyanophenylalanine with a piperazine derivative to form an N-protected 3-cyanophenylalanine piperazide, wherein said piperazine derivative is of the formula:

(ii) deprotecting said N-protected 3-cyanophenylalanine piperazide to form an N-deprotected 3-cyanophenylalanine piperazide and reacting said N-deprotected 3-cyanophenylalanine piperazide with a phenylsulfonyl halide to form a compound, said phenylsulfonyl halide being optionally substituted with a substituent, wherein said substituent is C1-C6-alkyl, C1-C3-alkoxy, hydroxyl, carboxyl, nitro, cyano and/or halogen;

(iii) converting a cyano group of the compound formed in step (ii) into a hydroxyamidino group to form a 3-hydroxyamidinophenylalanine compound

(iv) purifying the 3-hydroxyamidinophenylalanine compound formed in step (iii) by:

(A) forming a salt precipitate by adding an aromatic sulfonic acid to a solution of said 3-hydroxyamidinophenylalanine compound;

(B) separating said precipitate formed in step (A); and

(C) recovering a purified 3-hydroxyamidinophenylalanine compound from the precipitate; and

II) converting a hydroxyamidino group of said 3-hydroxyamidinophenylalanine compound into an amidino group to form a 3-amidinophenylalanine compound.

23. The method as claimed in claim 22 , in which the hydroxyamidino group is converted into an amidino group in step (ii) by reaction with acetic anhydride and subsequent catalytic hydrogenation.

24. A method for purifying a 3-hydroxyamidinophenylalanine compound wherein the 3-hydroxyamidinophenylalanine compound is N-α-2,4,6-triisopropylphenylsulfonyl-3-hydroxyamidino-(D,L)-phenylalanine, 4-ethoxycarbonylpiperazine or a L enantiomer thereof,

comprising the steps of:

(a) forming a salt precipitate by adding an aromatic sulfonic acid to a solution of a contaminated 3-hydroxyamidinophenylalanine compound,

(b) separating said precipitate formed in step (a), and

(c) recovering a purified 3-hydroxyamidinophenylalanine compound from the precipitate.