FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
and
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10 and rule 13]
1. Title: Process for preparation of bisphosphonic acid derivatives.
2. Applicant: Claris Lifesciences Limited,
Claris Corporate Headquarters, Nr.Parimal Crossing, Ellisbridge, Ahmedabad-380 006, Gujarat, India.

The following specification particularly describes the invention and the manner in which it is to be performed.


DESCRIPTION
FIELD OF INVENTION:
The present invention relates to a improved process for the preparation of bisphosphonic acid derivatives, on reacting a substituted carboxylic acid with mixture of phosphonvlating agents a mixture of phosphorous acid and halophosphorous compound in presences of paraffin oil, then hydrolyzing the reaction mixture with water.
BACKGROUND OF THE INVENTION:
The biphosphonic acid derivatives are an important class of medicaments useful in the treatment of bone disorders such as Paget's disease and osteoporosis.
Several methods have been reported for preparing bisphosphonic acids. The synthesis are based on reacting a carboxylic acid with a phosphonvlating agents mixture of phosphorous acid and one of the following halophosphorous compound: phosphorous trichloride (PCl3), phosphorous oxychloride (POCI3), phosphorous pentachloride (PCI5), phosphorous tribromide (PBr3), phosphorous oxybromide (POBr3) or phosphorous pentabromide (PBr5), then hydrolyzing the reaction mixture with water, followed by heating to the phosphorous intermediates to the final product.


DE 2130794 discloses the process of preparation of 3-amino-I-hydroxypropane-l,l-diphosphonic acid mixing B-alanine, phosphorous trichloride and phosphorous acid in presence or absence of an organic diluent, chlorobenzene. However, yellow-red by-products in the form of amorphous phosphorus-oxygen compounds of unknown structure are formed in this reaction and their separation. Thus required separation of the by-product is not only difficult, but also leads to high production cost.
US 4939130 disclose use of chlorobenzene as diluent for the reaction of imidazol-1-ylacetic acid hydrochloride is with phosphorous bichloride and phosphoric acid at 100°C. The intermediates subsequently hydrolyzed with hydrochloric acid and dilution with acetone gave Zoledronic acid. When using this procedure, a semisolid sticky mass difficult to stir develops which prevents smooth heat transfer. The described process is not suitable for commercial scale preparations.
US 4407761 discloses use chlorinated hydrocarbons as diluents for the preparation of 4-amino-l_hydroxybutylidene-l,l- biphosphonic acid besides other bisphosphonic acids are described. The intermediates are hydrolyzed with strong acids, which is complicated. When using this procedure, a semisolid sticky mass difficult to stir develops which prevents smooth heat transfer. The described process is not suitable for commercial scale preparations.


US 4705651 a similar procedure is followed with different molar ratios and although some improvements were achieved, it is still unsuitable for industrial scale up.
US 4922007, US 5019651 and US 5510517 as well as J. Org. Chem. 60, 8310, (1995), discloses the use of methanesulphonic acid as reaction solvent. This makes it possible to obtain stirrable masses in the course of the reaction. However, this technique, as reported in J. Org. Chem. 60, 8310, (1995), involves risks of safety in that this solvent gives rise to uncontrollable reactions in the reaction conditions, when the temperature of the reacting mixtures exceeds 85° C.
EP 00945957 discloses the use of methanesulphonic anhydride as the solvent for producing alendronic acid, but the high cost of the solvent makes the process commercially less attractive.
US 5908959 disclose use of the poly (alkylene glycol) as a diluent, which solubilizes the reaction components, however still when the reaction mixture is decomposed with water, an agitation problem occurs. The viscous reaction mixture must be transferred into the water. To facilitate this, viscosity problem is solved by the addition of toluene. When using toluene, a safety problem arises and also an additional separation step is needed.


EP 98902890 discloses use of polyalkylene glycols as reaction solvents for synthesizing alendronic acid however, these solvents have a high cost and are difficult to eliminate from the finished product, given their high boiling point.
US 6201148 discloses starting from a nitrogen protected derivative of p-aminopropionic acid to prevent the known problems of stirrabilitv of the reaction mixture, use is made of orthophosphoric acid as the reaction means. The derivatization of the starting product in any case renders the method of synthesis unwieldy and involves the need for introducing additional steps for protection and deprotection.
US 5792885 disclose synthesizes of pamidronic acid starting from a nitrogen-protected derivative of aminobutyric acid, in aromatic hydrocarbons as the reaction solvents.
EP 02736468 discloses use of aralkyl or alkyl ethoxylates or triglycerides such as plant or animal oils as diluents for the reaction mixture.
US 6878846 disclose use of an amine hydrochloride in preparation of bisphosphonates from the reaction of a carbonyl, compound with a phosphorous halide. This process involves use of concentrated hydrochloric acid as a reactant.


US 7038083 disclose use of aromatic hydrocarbon or a silicone fluid as diluents for preparation of bisphosphonic acid derivatives.
The present invention provides a process wherein paraffin oil is used for preparation of bisphosphonic acid derivative. In prior art it is recorded use of may organic solvents such as 1,2-dimethoxyethane, 1, 4-dioxane, glymes such as diglyme, toluene, polyalkylene glycols, and the like can also be used for preparation of bisphosphonic acids, however paraffin oil was observed to provide superior yields. The intermediates subsequently hydrolyzed with water, without complicated hydrolysis and recovery steps and the final bisphosphonic acid derivatives product directly isolated from the reaction mixture.
The complexity and high cost of the prior art procedures has created a need for an improved process for the preparation of bisphosphonic acid derivatives. The present invention provides a solution to the problem presented by the prior art.


SUMMARY OF THE INVENTION:
A primary object of the present invention is to provide an improved process for the preparation of bisphosphonic acid derivatives or pharmaceutical acceptable salts thereof.
The main objective of the present invention is to provide an improved process using paraffin oil, for the preparation of bisphosphonic acid derivatives and its pharmaceutically acceptable salts thereof.
An object of the present invention is the development of a process for the production of bisphosphonic acid in good yields without complicated hydrolysis and recovery steps.
Another objective of the present invention is to provide a process for the preparation of bisphosphonic acid derivatives and its pharmaceutically acceptable salts thereof, which would be easy to implement on commercial scale.
Still another objective of the present invention is to provide a process for the preparation of bisphosphonic acid derivatives and its pharmaceutically acceptable salts in good yield and high purity Surprisingly, present invention is where the reaction is carried out in the presence of paraffin oil, operationally simple and easily adaptable at an industrial scale.


A further object of the present invention is to provide an improved process for preparing bisphosphonic acid derivatives, which is operationally simple, easy to handle and feasible at commercial scale.
DESCRIPTION OF THE INVENTION:
Object of the present invention is to provide an improved process for the preparation of bisphosphonic acid derivatives of structural formula (I), comprising a step of, reacting carboxylic acid of structural formula (II), with phosphonyiating agents mixture of hosphorous acid and halophosphorous compound, wherein halophosphorous compound is selected from the group comprising of PC13, PCI5, P0C13, PBr3, POBr3, and PBr5 in the presence of paraffin oil. Hydrolyzing the reaction mixture with water, and isolating from the aqueous phase with alcohols or acetone.
Accordingly, the present invention provides an improved process for the preparation of bisphosphonic acid derivatives. The method of making bisphosphonic acid derivatives of structural formula (I)



wherein R represents is hydrogen atom or C1-C6 alkyl group or amino substituted C1-C6 alkyl group or hetroaromatic five to six member ring optionally containing 1 to 3 hetroatoms selected from N,S,0 in hetroaromatic ring, as a rule, one of the hetroatom is a nitrogen atom.
Preferred C1-C6 alkyl group are methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.
Preferred amino substituted C1-C6 alkyl group are methylamine, ethylamine, dimethylamine, diethylamine, butylamine, pentylamine, methylethylamine, methyl pentyl amine.
Preferred hetroaromatic five to six member ring optionally containg 1 to 3 hetroatoms selected from N,S,0 in hetroaromatic ring, as a rule, one of the hetroatom is a nitrogen atom, groups are imidazole, pyrazol, pyrrole, benzimidazole, isoxazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole,
The suitable example of the R included but not limited to
H+ ETIDRONIC ACID

ZOLEDRON1C ACID

RISEDRONIC ACID
MINODRONIC ACID


PAMIDRONIC ACID


ALENDRONIC ACID


NERIDRONIC ACID


OLAPDROMC ACID


IBANDRONIC ACID

Comprising the steps of:
• Reacting carboxylic acid of structural formula (II),



Wherein R is defined herein above
With a phosphonylating agents mixture of phosphorous acid and halophosphorous compound in the presence of paraffin oil, at a temperature of about 80°C to 130°C.
• hydrolysing the reaction mixture with water, whereby an aqueous and a non - aqueous phase are formed.
• Separating the aqueous layer whereby aqueous layer comprises bisphosphonic acid derivatives, and add paraffin oil in aqueous layer for washing and removal of impurity.
• Isolating from the aqueous phase with alcohols or acetone whereby a suspension comprising bisphosphonic acid derivatives is formed, and filter the solution and collect wet cake for purification.
Purification of bisphosphonic acid derivatives or salts thereof by refluxing with water for 0.5 to 3 hours at temperature of 80°C to 120°C.
The process of preparation of bisphosphonic acid derivatives, having structural formula (I), can be illustrated by the following reaction scheme-



These and other objects of the invention will become more apparent as the description thereof proceeds.
The subject matter of the invention is, therefore, the preparation of compounds of bisphosphonic acid derivatives or pharmaceutical acceptable salts thereof, where by the reaction of an carboxylic acids of structural formula (II) with phosphonylating agents a mixture of phosphorous acid and halophosphorous compound, and


subsequent hydrolysis with water in presences of paraffin oil, at a temperature of about 80°C to 130°C.
More particularly, the present invention relates to a process for the preparation of a bisphosphonic acid derivatives, consisting essentially of the steps of reacting carboxylic acid of structural formula (II) with a phosphonating reactant selected from the group consisting of a mixture of phosphorous acid and phosphorous halides: phosphorous trichloride (PCI3), phosphorous oxychloride (POCl3), phosphorous pentachloride (PCI5), phosphorous tribromide (PBr3), phosphorous oxybromide (POBr3) or phosphorous pentabromide (PBr5), and hydrolyzing the reaction mixture with a water, and recovering said bisphosphonic acid derivatives.
The carboxylic acid of structural formula (II),

wherein R represents is hydrogen atom or C1-C6 alkyl group or amino substituted C1-C6 alkyl group or hetroaromatic five to six member ring optionally containg 1 to 3 hetroatoms selected from N,S,0 in hetroaromatic ring, as a rule, one of the hetroatom is a nitrogen atom.

Preferred C1-C6 alkyl group are methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.
Preferred amino substituted C1-C6 alkyl group are methylamine, ethylamine, dimethylamine, diethylamine, butylamine, pentylamine, methylethylamine, methyl pentyl amine.
Preferred hetroaromatic five to six member ring optionally containg 1 to 3 hetroatoms selected from N,S,0 in hetroaromatic ring, as a rule, one of the hetroatom is a nitrogen atom, groups are imidazole, pyrazol, pyrrole, benzimidazole, isoxazole, oxazole, thiazole, triazole, oxadiazole, thiadiazole,
The suitable example of the R included but not limited to

ETIDRONIC ACID ZOLEDRONIC ACID
RISEDRONIC ACID

PAMIDRONIC ACID


ALENDRONIC ACID


NERIDRONIC ACID


OLAPDRONIC ACID


IBANDROMC ACID

The suitable example of carboxylic acid included but not limited to
4-aminobutanoic acid, (3-pyridyl)ethanoic acid, (1-
imidazoyl)ethanoic acid, N-(n-pentyl)-N-methyl-3-
aminopropanoic acid, 2(imidazo[l,2-a]pyridin-3_yl)ethanoic acid, aminoethanoic acid, aminobutanoic acid, B-aminopropanic acid and 6~aminohexanoic acid.
The selection of appropriate carboxylic acid depends on the end of bisphosphonic acid derivatives to be prepared. The phosphonylation reaction generally takes place at temperatures of from 80°C to 130°C, preferably at about 90°C to 110°C


Preferably 2.5 to 4.5mol of H3 PO3 and 1.5 to 3.5mol of PC13 and/or PC15, or POCI3 are used per mol of carboxylic acid. It is of advantage if a mixture of carboxylic acid, H3PO3 and PCl3 in a molar ratio of 3.6:2.8:1.0 is prepared first.
The desired, paraffin oil, which do not solublize the reaction product, are particularly, paraffin oil are light paraffin oil or heavy paraffin oil can be used in the reaction.
In general, the hydrolysis with water is completed after about 1 to 10 hours boiling at 80°C to 130°C with constant stirring.
The reaction is carried out at temperature ranging 80°C. to 130°C. Preferable temperature range is 90°C. to 110°C. The reaction is carried out generally for about 1 to 10 hours. After completion of the reaction water is added, heated and optionally the reaction mixture is charcoalized.
After filtering, the aqueous layer and non-aqueous layer are separated. Aqueous layer is washed with paraffin oil to remove impurities, the aqueous layer and non-aqueous layer are separated and aqueous layer is filter and bisphosphonic acid derivatives is isolated.


Isolation of bisphosphonic acid derivatives from aqueous layer, by quenching of aqueous layer in acetone, whereby suspensions comprising bisphosphonic acid is formed and is filtered from the solution, and collect the wet cake for purification. Reflux the wet cake with water for 0.5 to 3 hours at temperature of 80°C to 120°C. filter the solution at hot condition. Collect the filtrate and discard the wet cake. Cool the filtrate at 0°C to 20°C for 0 to 2 hour with constant stirring. Filter the solution discard the filtrate, and the resultant isolated compound is dried at 60-65°C under vacuum until the loss on drying was less than 0.2%.
The present invention process has advantages over prior art such as-
1. It .provides a process, which is operationally simple and industrially applicable.
2. It involves less reaction time then prior art process.
3. It provides high yield.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example
Preparation of Zoledronic acid
In the suspension of 50 ml Heavy paraffin and 35 gm Phosphorus pentachloride (0.17M) 18.4 gm of phosphorus acid (0.22M) was


added in portion wise under constant stirring. Maintain the temperature less than 40°C during the addition. 10 gm of imidazol-1-ylacetic acid hydrochloride (0.06M) was added with constant stirring at less than 40°C. The reaction mixture was heated to 100-105°C within one hour & maintains this temperature for four hours. Reaction mixture was hydrolyzed by adding 70 ml water at 100-105°C. and stirring for another three hour at same temperature. Cool the solution at ambient temperature and charcolized with 2 gm of carbon. Two phases were separated and the aqueous phase washed with 25 ml of paraffin. Filtrated aqueous phase was added by drop wise into the 300 ml acetone. The solid product was collected by filtration and washed with the water and finally with methanol to obtain crude Zoledronic acid. The product was purified in hot water by crystallization and dried at 55-60°C under vacuum until the loss on drying was less than 0.2%. Yield 12.5 gm (68%). Purity by HPLC is 99.5%.


We Claim,
1. A process for preparation of bisphosphonic acid derivatives of structural formula (I)

wherein R represents is hydrogen atom or C1-C6 alkyl group or amino substituted C1-C6 alkyl group or hetroaromatic five to six member ring optionally containg 1 to 3 hetroatoms selected from N,S,0 in hetroaromatic ring, as a rule, one of the hetroatom is a nitrogen atom;
comprising a step of, reacting with carboxylic acid of structural formula (II),

Formula (II) wherein R is defined herein above, with a phosphonylating agents mixture of phosphorous acid and halophosphorous compound in the presence of paraffin oil at a temperature of

about 80°C to 130°C; hydrolysis with water, and isolating with alcohols or acetone.
2. The process according to Claim 1, wherein R represents C1-C6 alkyl group are methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl.
3. The process according to Claim 1, wherein R represents amino substituted C1-C6 alkyl group are methylamine, ethylamine, dimethylamine, diethylamine, butylamine, pentylamine, methylethylamine, methyl pentyl amine.
4. The process according to Claim 1, wherein R represents hetroaromatic five to six member ring optionally containing 1 to 3 hetroatoms selected from N,S,0.
5. The process according to Claim 4, wherein R represents hetroaromatic five to six member ring with, more than one hetroatom as nitrogen atom.
6. The process according to Claim 4, wherein R represents hetroaromatic five to six member ring groups are imidazole, pyrazol, pyrrole, benzimidazole, isoxazoie, oxazole, thiazole, triazole, oxadiazole, thiadiazole.


7. The process according to Claim 1, wherein R represents group mentioned below


ETIDRONIC ACID
ZOLEDRONIC ACID
RISEDRONIC ACID
MINODRONIC ACID


PAMIDRONIC ACID


ALENDRONIC ACID


NERIDRONIC ACID


OLAPDRONIC ACID


IBANDRONIC ACID

The process according to Claim 1, wherein halophosphorous compound is selected from the group phosphorous trichloride (PCl3), phosphorous oxychloride (P0C13), phosphorous pentachloride (PC15), phosphorous tribromide (PBr3), phosphorous oxybromide (POBr3) or phosphorous pentabromide (PBrs).
9. The process according to Claim 1, wherein paraffin oil are light paraffin oil or heavy paraffin oil or mixture thereof.
10. A process for Purification of bisphosphonic acid derivatives, the said process comprises,
a. refluxing with water for 0.5 to 3 hours at temperature
of 80°Cto 120°C;
b. filter the solution at hot condition, collect the filtrate
and discard the wet cake;
c. cool the filtrate at 0°C to 20°C for 0 to 2 hour with
constant stirring;
d. filter the solution discard the filtrate, and the resultant
isolated compound is dried 60-65°C under vacuum until
the loss on drying was less than 0.2%.
DATE and SIGNATURE

Date : 27th February 2009
Signature :
Name : Chetan S. Majmudar