FIELD OF THE INVENTION
The invention relates to an improved industrial process for the production of 4-amino-l-hydroxybutylidene-l,l-bisphosphonic acid or salts thereof.
BACKGROUND OF THE INVENTION
4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid commonly known as Alendronic acid is an antihypercalcemic agent effective in the treatment or prevention of diseases involving hypercalcemia of pregnancy, Paget's disease and osteoporosis
Alendronic acid is marketed as its monosodium salt trihydrate represented by formula (I) under the brand name FOSAMAX by
Merck.
Several methods are known in the art for the synthesis of -amino-1- hydroxyalkylidene-1,1-bisphosphonic acids in general and 4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid in particular. The synthesis consists of reacting the corresponding -amino acid with a mixture of phosphorus acid and one of the three phosphorus chlorides PCl3, POCl3 or PCl5, quenching the reaction mixture with water or a non-oxidizing aqueous acid followed by heating to hydrolyze the phosphorous intermediates to the final product.

US Patent No. 4,407,761 teaches a process to prepare 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid wherein the reaction is carried out at about 100 °C in chlorobenzene as a diluent which does not solubilize the reaction components and serves only as a heat transfer agent. The process is unsuitable for large scale production as the reaction remain a two phase system and gradually thickens into a non-stirrable mass with local solidification.
In US 4,922,007, the above said problem of solidifcation was overcome by using methanesulfonic acid to solubilize the reaction components and keep it fluid up to completion of the reaction.
However, the use of methanesulfonic acid has safety concerns. Methansulfonic acid reacts with PC13 and under adiabatic conditions the reaction becomes self-heating at 85 °C and an uncontrolled exotherm occurs at >140 °C. This fact was recognized by the inventors in Example 1 of US 4,922,007. The inventors in a subsequent publication J. Org. Chem., 1995, 60, 8310-8312 have mentioned about the safety concerns.It is evident from the above that there is a need for simple, safe and non hazardous process for the large scale production of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof.
OBJECT OF THE PRESENT INVENTION
The object of the present invention is to provide a process to prepare 4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid or salts that overcomes the non homogeneity, solidification and safety problems associated with prior art synthesis.

The inventors of present invention have found that the use of solvent such as sulfolane overcomes the non homogeneity, solidification and safety problems that are associated with prior art synthesis.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a process for the production of 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid or salts thereof which comprises:
(a) reacting 4-aminobutyric acid with a suitable phosphonating agent in a solvent such as sulfolane
(b) hydrolyzing the resulting reaction mixture by heating with water,
(c) recovering the said 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid or salts thereof.
DETEAILED DESCRIPTION OF THE INVENTION
The present invention involves the phosphonylation of 4-aminobutyric acid with a suitable phosphonating agent selected from: a mixture of phosphorous acid and PC13, a mixture of phosphorous acid and PC15, a mixture of phosphorous acid and POCl3 in a solvent such as sulfolane, diglyme and diphenyl oxide, followed by hydrolysis of the resulting mixture using water and then recovering 4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid or salts thereof. The phosphonylation reaction is carried out in a solvent such as sulfolane, diglyme and diphenyl oxide at a suitable temperature between 30 °C to 80 °C,

The reaction is schematically represented as follows:

The use of sulfolane overcomes the non homogeneity, solidification and safety problems.
The process of the present invention may also be carried out in other solvents such diglyme and diphenyl oxide.
The phosphonylation of 4-amino butyric acid is preferably carried out using phosphorous acid and phosphorous trichloride After the completion of the reaction, hydrolysis is carried out by adding water and heating to about 80 °C to 100 °C in water. The 4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid or its salt is isolated by adjusting the pH to 4 to 4.5 by the addition of a base such as aq. NaOH or aq. KOH.
In a preferred embodiment 4-amino-l-hydroxybutylidene-l, 1-bisphosphonic acid is isolated as its sodium salt.
Figure 1 shows the powder X-ray diffraction pattern for the 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid mono sodium trihydrate obtained by the process disclosed in the present invention.
4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid monosodium trihydrate in a pharmaceutical composition is useful for

treatment of some bone disorders, such as osteoporosis and hypercalcemia of malignancy.
The following example is illustrative of the practice of the invention without being limiting any way.
EXAMPLE
A mixture of 4-amino butyric acid (10 Kg, 97.0 mol) and phosphorous acid (28 Kg, 340.0 mol) in sulfolane (50 lit) was heated to 70-75 ° C for about 30 min and cooled to 40-45 ° C. PCl3 (33.28 Kg, 242.0 mol) was added dropwise at 40-45 °C and stirred at 60-65 °C for 12 hrs. After the completion of the reaction, reaction mixture was cooled to 40-45 °C and water (100 lit) was added and heated to 95-100 °C for 7 hrs. The reaction mixture was cooled, filtered, and the pH of the filtrate was adjusted to 4.3-4.4 with 50% aqueous NaOH. The formed crude product was filtered and recrystallized in water, washed with cold water (25 lit) followed by 95 % ethanol (25 lit) and dried under vaccum at 40 °C to get pure 4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid mono sodium trihydrate. Yield: 55% Purity by HPLC: 99.92%

WE CLAIM:
1. A process for the preparation of 4-amino-l-
hydroxybutylidene-1,1-bisphosphonic acid or salts thereof
which comprises:
(a) reacting 4-aminobutyric acid with a phosphonating agent in sulfolane
(b) hydrolyzing the resulting reaction mixture from step
(a) by heating with water,
(c) recovering said 4-amino-l-hydroxybutylidene-l
bisphosphonic acid or salts thereof.
2. The process according to claim 1, wherein the phosphonating agent is selected from: a mixture of phosphorous acid and PCl3, a mixture of phosphorous acid and PCl5, a mixture of phosphorous acid and POCl3.
3. The process according to claim 1 and claim 2, wherein the phosphonating agent is phosphorous acid and PCl3.
4. The process according to claim 1, wherein step (a) is conducted at a temperature of about 30 to 80 °C.
5. The process according to claim 1, wherein step (b) is conducted at a temperature of about 80 to 100 °C.
6. The process according to claim 1 wherein 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid is recovered as its monosodium salt trihydrate.

7. The process according to claim 1 wherein 4-amino-l-hydroxybutylidene-1,1-bisphosphonic acid is recovered.

A process is provided for the preparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof which comprises of: (a) reacting 4-aminobutyric acid with a mixture of phosphorous acid and phosphorous trichloride in solvent selected from sulfolane, diglyme and diphenyl oxide (b) hydrolyzing the resulting reaction mixture from step (a) with water (c) recovering the said 4-amino-l-hydroxybutylidene-l,1-bisphosphonic acid or salts thereof.