PROCESS FOR PREPARING BISPHOSPHONIC ACIDS

• US 20070142636A1
• Filed: 10/18/2006
• Published: 06/21/2007
• Est. Priority Date: 10/20/2005
• Status: Active Grant

• Current Assignee: Dr. Reddy's Lab., Inc. (Dr. Reddy's Laboratories Ltd.), Dr. Reddy's Laboratories Ltd.
• Original Assignee: Dr. Reddy's Lab., Inc. (Dr. Reddy's Laboratories Ltd.), Dr. Reddy's Laboratories Ltd.
• Inventors: Manne, Nagaraju, Singam Setty, Radha Krishna, Mandava, Venkata Naga Brahmeswara
• Granted Patent: US 8,003,820 B2
• Time in Patent Office: Days
• US Class Current: 546/22
• CPC Class Codes: C07F 9/025 Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds of natural phosphatides C07F9/103; phosphines C07F9/5095
• CPC Class Codes: C07F 9/3873 containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
• CPC Class Codes: C07F 9/58 Pyridine rings
• CPC Class Codes: C07F 9/6506 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Abstract

A process for preparing a bisphosphonate compound comprises reacting a carboxylic acid with a phosphonating agent, in a cresol solvent.

Claims

1. A process for preparing a bisphosphonic acid or a salt thereof, comprising reacting a carboxylic acid with a phosphonating agent, in a cresol solvent.

2. The process of claim 1, wherein a carboxylic acid comprises at least one of 4-aminobutyric acid, 3-aminopropionic acid, 3-pyridylacetic acid, 1 -imidazolylacetic acid, N-(n-pentyl)-N-methyl-3-aminopropionic acid, 2-(imidazo[1,2-a]pyridin-2-yl)ethanoic acid, and 3-(dimethylamino) propionic acid.

3. The process of claim 1, wherein a carboxylic acid comprises 4-aminobutyric acid.

4. The process of claim 1, wherein a phosphonating agent comprises a combination of phosphorous acid and at least one of phosphorous trichloride, phosphorous pentachloride, phosphorous pentachloride, phosphorous tribromide, phosphorous pentabromide, and phosphorous oxybromide.

5. The process of claim 1, wherein a phosphonating agent comprises a combination of phosphorous acid and phosphorous trichloride.

6. The process of claim 1, wherein a cresol comprises p-cresol.

7. The process of claim 1, further comprising reacting a bisphosphonic acid with a base to form a salt.

8. The process of claim 1, further comprising reacting a bisphosphonic acid with an alkali metal hydroxide to form a salt.

9. A process for preparing a bisphosphonic acid or a salt thereof, comprising reacting an acid having a formula:

wherein;

X is a straight chain alkyl, a branched alkyl, or a cyclic alkyl chain having 1 to about 10 carbon atoms, which can optionally contain 1 to 3 nitrogen, oxygen, or sulfur atoms in the chain; and

Y is an alkyl, aralkyl, aromatic or hetero aromatic group, which can be optionally substituted by a group having a formula;

wherein R¹and R² are independently hydrogen or straight chain, branched, or cyclic alkyl groups, each independently having 1 to about 10 carbon atoms;

or a salt thereof, with a phosphonating agent, in a cresol solvent.

10. The process of claim 9, wherein a carboxylic acid comprises at least one of 4-am inobutyric acid, 3-aminopropionic acid, 3-pyridylacetic acid, 1-imidazolylacetic acid, N-(n-pentyl)-N-methyl-3-aminopropionic acid, 2-(imidazo[1,2-a]pyridin-2-yl)ethanoic acid, and 3-(dimethylamino) propionic acid.

11. The process of claim 9, wherein a carboxylic acid comprises 4-aminobutyric acid.

12. The process of claim 9, wherein a phosphonating agent comprises a combination of phosphorous acid and at least one of phosphorous trichloride, phosphorous pentachloride, phosphorous pentachloride, phosphorous tribromide, phosphorous pentabromide, and phosphorous oxybromide.

13. The process of claim 9, wherein a phosphonating agent comprises a combination of phosphorous acid and phosphorous trichloride.

14. The process of claim 9, wherein a cresol comprises p-cresol.

15. The process of claim 9, further comprising reacting a bisphosphonic acid with a base to form a salt.

16. The process of claim 9, further comprising reacting a bisphosphonic acid with an alkali metal hydroxide to form a salt.

17. A process for purifying a salt of a bisphosphonic acid having a formula:

wherein;

X is a straight chain alkyl, a branched alkyl, or a cyclic alkyl chain having 1 to about 10 carbon atoms, which can optionally contain 1 to 3 nitrogen, oxygen, or sulfur atoms in the chain; and

Y is an alkyl, aralkyl, aromatic or hetero aromatic group, which can be optionally substituted by a group having a formula;

wherein R¹and R² are independently hydrogen or straight chain, branched, or cyclic alkyl groups, each independently having 1 to about 10 carbon atoms;

comprising crystallizing from a mixture of a ketone and water.

18. The process of claim 17, wherein a ketone comprises methyl ethyl ketone.

19. The process of claim 17, wherein a ratio of water to ketone in the mixture is about 4:

1 to 1;

1 by volume.

20. The process of claim 17, wherein a salt is formed by reacting a bisphosphonic acid with sodium hydroxide.