# US 7,612,229 B2 · Industrial process for the synthesis of 2-substituted 1-(hydroxy-ethylidene)-1,1-bisphosfi- conic acids of high purity and the salts thereof

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- Number: US 7,612,229 B2
- Document ID: US7612229B2
- Status: Granted
- Kind: B2
- Application number: 10/541,866
- Filed: 2004-01-27
- Published: 2006-06-08
- Granted: 2009-11-03
- Earliest claimed: 2003-01-28
- Assignees: Richter Gedeon Vegyeszeti Gyar Rt.
- Inventors: Jozsef Neu; Janos Fischer; Tamas Fodor; Jozsef Törley; Tibor Gizur; Sandor Levai; Adam Demeter; Eva Perenyi
- Web page: https://patentgrep.com/patent/US7612229B2

## CPC

- 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)}
- C07F 9/58: Pyridine rings
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Process for the synthesis of high purity 2-substituted-1-(hydroxy-ethylidene)-1,1-bisphosphonic acid of formula (I), the salts and hydrates thereof—wherein the meaning of R is 3′-pyridyl or 2′-amino-ethylidene group—from compounds of formula (II)—wherein the meaning of R is as described above—or salts and hydrates thereof with phosphorous acid in the presence of methanesulfonic acid using phosphorus pentoxide as reagent and in given case the obtained acid is converted into a salt with base.

## Claims

### Claim 1

A process for preparing a compound of the Formula (I)
or a hydrate or a pharmaceutically acceptable salt or hydrate thereof in a purity of >99.9%, wherein
R is 3′-pyridyl or 2′-amino-ethylidene, which comprises the step of:
phosphonylating a compound of the Formula (II)
R—CH2—COOH
or a pharmaceutically acceptable salt or hydrate thereof in a reaction mixture with a chlorine-free phosphonylating agent comprising phosphorous acid in the presence of methanesulfonic acid and phosphorous pentoxide to obtain the compound of the Formula (I) or a hydrate thereof; and in the case where a pharmaceutically acceptable salt of the compound of the Formula (I) is desired, reacting the compound of the Formula (I) with a base.

### Claim 2 (depends on 1)

The process for preparing a compound of the Formula (I) defined in claim 1 wherein the molar ratio of methane sulfonic acid: phosphorous acid: and phosphorous pentoxide in the chlorine-free phosphonylating agent ranges between 1 to 5: 1: 0.25 to 1.

### Claim 3 (depends on 1)

The process for preparing a compound of the Formula (I) defined in claim 1 wherein the molar ratio of the compound of the Formula (II) and the phosphorous acid in the chlorine-free phosphonylating agent ranges between 1: 2 to 5.

### Claim 4 (depends on 2)

The process for preparing a compound of the Formula (I) defined in claim 2 wherein the molar ratio of the compound of the Formula (II) and the phosphorous acid in the chlorine-free phosphonylating agent ranges between 1: 2 to 5.

### Claim 5 (depends on 1)

The process for preparing a compound of the Formula (I) defined in claim 1 wherein the compound of the Formula (I) is isolated from the reaction mixture by hydrolyzing the compound of the Formula (I) with an equal volume mixture of water and methanesulfonic acid, followed by neutralization of the methanesulfonic acid with a base.