A NEW AND IMPROVED PROCESS FOR THE PREPARATION OF
IBANDRONATE SODIUM MONOHYDRATE
This application is a patent of addition of the earlier patent
(Application No: 189/CHE/2008)
TECHNICAL FIELD OF THE INVENTION
The present invention is directed to a new, improved, safe and industrially feasible process for manufacturing of Ibandronate monosodium monohydrate [3-(N-methyl-N-pentyl)amino-l-hydroxypropane-14-diphosphonic acid monosodium mono hydrate] of formula-I
The further aspect of the invention is to provide a new and cost effective process for preparation of substantially pure 3-(N-methyl-N-pentylamino)propionic acid hydrochloride of formula-II
BACKGROUND OF THE INVENTION
Ibandronate is one of the most potent antiresorptive drugs that directly inhibit osteoclast activity and present an effective pharmacologic alternative for controlling hypercalcemia. Ibandronate binds to hydroxyapatite in calcified bone, rendering it resistant to hydrolytic dissolution by phosphatases, thereby inhibiting both normal and abnormal bone resorption. This drug increases bone mass and decreases the risk of fractures and is therefore particularly well adapted to bone and calcium metabolic diseases such as for instance osteoporosis or Paget's disease (EP-A 0252504).
Different processes were reported for the preparation of ibandronic acid and it's pharmaceutically accaptable salts. However they have some disadvantages associated with safety, quality and yield. A brief summary of the synthetic methods of ibandronic acid, known in the prior art, are projected herein.

US4927814 discloses the process of preparation of the Ibandronic acid in two different synthetic routes. Route I: According to the process (scheme-i) disclosed in this patent, benzaldehyde of formula-Ill was reacted with N-pentylamine of formula-IV to get the corresponding benzylidene derivative of the formula-V. Reduction of double bond of benzylidine compound provided an intermediate of formula-VI, which on methylation gave N-benzyl-N-methylpentylamine of the formula-VII. Reductive debenzylation gave the secondary amine of formula-VIIL Addition of N-methylpentylamine to methyl acrylate gave the β-alanine derivative of formula-IX, which on hydrolysis gave 3-(N-methyl-N-pentylamino)propionic acid of formula-X. Reaction of this acid with phosphorous acid and phosphorous trichloride gave the Ibandronic acid of formula-XL The crude Ibandronic acid was isolated by purification through an ion exchange column.

Route II: According to the process (scheme-ii) disclosed in this patent, a carboxylic acid chloride of formula-XII reacted with trialkylphosphite of formula-XIII to give acylphosp-honate of formula-XIV, which on reaction with dialkylphosphite gave diphosphonic ester of formula-XV. This ester on saponification gave Ibandronic acid of formula-XI,


WO2006045578 discloses the process of preparation of the Ibandronate sodium monohydrate and according to the process (scheme-iii), benzaldehyde of formula-Ill reacted with N-pentylamine of formula-IV to get N-benzyledene-N-pentylamine of formula-V, which on reduction gave N-metyl-N-pentylamine of formula-VIIL The resulting amine was reacted with methylacrylate of formula-XVI gave N-methyl-N-pentyl-β-alaninemethyl ester of formula-XVII, which was subjected to hydrolysis to give 3-(N-methyl-N-pentylamino)propionicacid hydrochloride salt of formula-II. This acid subsequently reacted v^th phosphoric acid and phosphorous halide to get Ibandronate sodium monohydrate of formula-I.

WO2007013097 discloses another process for preparation of Ibandronate sodium. According to the process disclosed (scheme-iv) in this patent, acrylonitrile of formula-XVIII was reacted with methylamine of formula-XIX to give 3-methylaminopropionitrile of formula-XX, which on reaction with N-pentylhalide of formula-XXI gave N-methyl-N-pentylamino propionitrile of formula-XXIL Hydrolysis of the resulting nitrile provided N-methyl-N-pentylaminepropionic acid hydrochloride of formula-II, which on reaction with phosphoric acid and phosphorous trichloride followed by hydrolysis and reaction with sodium hydroxide gave Ibandtonate sodium of formula-I.


The above mentioned methods contain number of steps like protection, deprotection, and hydrogenation to get the required intermediate secondary amine. And also involves the usage of acrylonitrile which sometimes undergoes explosive polymerization and releases toxic fumes of hydrogen cyanide and oxides of nitrogen,
OBJECTIVE OF THE PRESENT INVENTION
The main objective of the present invention is to provide a new, safe and improved process for the preparation of Ibandronate monosodium monohydrate in high yield, which would be easy to implement on a commercial scale production.
The other objective of the present invention is to provide a new process for the preparation of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride salt in high yield and high purity,
SUMMARY OF THE INVENTION
In accordance with the principle of the present invention, it is provided a new, safe and improved process for the preparation the Ibandronate monosodium monohydrate of formula-I.
Another embodiment of the present invention provides a new process for preparation of substantially pure 3-(N-methyl-N-pentylamino)propionic acid hydrochloride salt of formula-II in high yield.

The process of the present invention is shown in the following scheme

The method of making 3-(N-methyl-N-pentylamino)propionic acid hydrochloride (II) and Ibandronate sodium monohydrate (I) comprising the following steps
A) Preparation of 3-(N-methvl-N-pentvlamino)propionic acid hydrochloride (11)
a) reaction of pentylamine of formula-IV with ethylacrylate of formula-XXIII in
an organic solvent to give N-pentyl-β-alanine ethyl ester of formula-XXIV,
b) reaction of N-pentyl-β-alanine ethyl ester of formula-XXIV with formic acid
and formaldehyde to provide N-methyl-N-pentyl-β-alanine ethyl ester of
formula-XXV,
c) hydrolysis of N-Methyl-N-pentyl-β-alanine ethyl ester of formula-XXV in
aqueous medium to give N-methyl-N-pentyl propionic acid, and subsequent
reaction with hydrochloric acid to give 3-(N-methyl-N-pentylamino)propionic
acid hydrochloride of formula-II,
B) Preparation of Ibandronate monosodium monohydrate (I)
d) reaction of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride of
formula-II with phosphorous acid and phosphorous trichloride in absence of any
organic solvent,
e) heating the reaction mass of step d) in 6N aqueous hydrochloric acid,
f) pH adjustment of the reaction mass of step e) with aqueous sodium hydroxide
solution and subsequent dilution with methanol to provide Ibandronate sodium
monohydrate of formula-I,

DESCRITPON OF THE FIGURES
Figure 1. X-ray powder diffraction pattern of Ibandronate sodium monohydrate polymorph B prepared according to example-4.
Figure 2. X-ray powder diffraction pattern of Ibandronate sodium monohydrate polymorph A prepared according to example-5.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the principle of the present invention, it is provided a new, improved and safe process for the preparation of Ibandronate sodium monohydrate 3-(N-methyl-N-pentyl)amino-l-hydroxypropane-l,l-diphosphonic acid monosodium mono hydrate) of formula-I,

said process comprises;
a) reaction of pentylamine (IV) with ethylacrylate (XXIII) in an organic solvent to
give N-pentyl-β-alanine ethyl ester of formula-XXIV,

b) methylation of N-pentyl-β-alanine ethyl ester (XXIV) to give N-methyl-N-
pentyl-β-alanine ethyl ester of formula-XXV,

c) hydrolysis of N-methyl-N-pentyl-β-alanine ethyl ester (XXV) to provide 3-(N-
methyl-N-pentylamino)propionic acid hydrochloride of formula-II,


d) bisphosphorylation of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride (II) with phosphorous acid and phosphorous trichloride followed by hydrolysis and subsequent treatment with base to give Ibandronate monosodium monohydrate of formula-L
In step (a), the solvents used are selected from the group consisting of aliphatic alcohols like methanol, ethanol, isopropanol, n-butanol, t-butanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; aromatic solvents like toluene, xylene. The most preferable solvent used in this step is toluene. The reaction is carried out at a temperature range of about 0°C to about 50°C, most preferably at about 10°C to about 30°C. The isolation of the product can be performed by the known techniques, preferably by distillation,
Ethylacrylate is added to pentylamine in toluene medium at 10°C to 15°C in about two to two and half hours. After complete addition of the ethylacrylate, reaction mass is maintained at a temperature range of 25°C to 30°C for a period of twelve to fifteen hours, then solvent is distilled off under vacuum at a temperature range of 70°C to 75°C to give N-pentyl-β-alanine ethyl ester.
In step (b), methylation is performed with a mixture of formic acid and formaldehyde in an aqueous medium. The reaction is carried out at a temperature range of about 10°C to about 100°C, preferably at about 500°C to about 90°C, most preferably at about 60°C to about 70°C. The product is isolated by extraction with an organic solvent, preferably with methylenedichloride followed by distillation of the solvent.
N-pentyl-β-alanine ethyl ester is added slowly to a mixture of formic acid and formaldehyde in water at 40°C to about 50°C for a period of one to two hours. The reaction mixture is heated to 60°C to about 65°C for a period of three to three and half hours. Reaction mass is cooled to 25°C to 30°C and pH is adjusted to 9 to 9.5 with aqueous ammonium hydroxide. The product is extracted with methylenedichloride and solvent is distilled off to give N-methyl-N-pentyl-β-alanine ethyl ester.

In step (c), the hydrolysis of N-methyl-N-pentyl-β-alanine ethyl ester is carried out by heating at 90 to 100°C for about five to fifteen hours, most preferably for ten to twelve hours in water medium. The reaction mass is treated with hydrochloric acid and water is removed by azeotropic distillation to provide 3-(N-methyl-N-pentylamino)propionic acid hydrochloride.
N-methyl-N-pentyl-β-alanine ethyl ester is added to the water and heated at 90°C to 100°C for a period often to twelve hours. Water is distilled off under vacuum at below 75°C. Hydrochloric acid is added to the reaction mixture followed by methylisobutyl-ketone. Water is distilled off azeotropically and the separated solid product is isolated by filtration. The product is purified by recrystallizion from acetone to give pure N-methyl-N-pentylamine propionic acid hydrochloride.
In step (d), 3-(N-methyl-N-pentylamino)propionic acid hydrochloride is reacted with phosphorous acid and phosphorous trichloride at a temperature range of about 50°C to about 95°C, preferably at about 60°C to about 70°C, in the absence of a solvent. The hydrolysis is carried out in water or an acid, preferably 6N hydrochloric acid. The base used for pH adjustment of the reaction mass is sodium carbonate or sodium hydroxide, preferably sodium hydroxide.
Phosphorous acid is added to 3(N-methyl-N-pentylamino)propionic acid hydrochloride and heated to 60°C to 65°C. Phosphorous trichloride is added to the reaction mass at 60°C to 65°C and heated at 70°C to 75°C for a period of twenty hours. Unreacted phosphorous trichloride is distilled off at 50°C to 55°C under vacuum. The reaction mass is cooled to 20°C to 25°C and 6N hydrochloric acid is added. The reaction mass is heated at 90°C to 95°C for a period of seven to eight hours. Then cooled to 20°C to 30°C and the pH is adjusted to 4.30 to 4.40 with aqueous sodium hydroxide solution. The reaction mass is treated with activated carbon and the solution is diluted with methanol to separate solid Ibandronate sodium. The product is recrystallized from aqueous methanol to provide pure Ibandronate monosodium monohydrate of purity above 99% (HPLC).
The details of the process of invention are described in the following examples, which are illustrative only, and which are not intended to limit the scope of the subject matter described in the claims.

Example 1
Preparation of N-pentvl-β-alanine ethyl ester (XXIV)
Into a IL, four necked RB flask was charged 350 ml of toluene and 100 gm (1.15 mol) of
N-pentylamine at 25°C to 30°C. The reaction mass was cooled to 10°C, a mixture of
135.6 gm (1.35 mol) of ethylacrylate and 100 ml toluene was added at 10°C to 15°C in 1
hour. The temperature of the reaction mass was raised to 25°C to 30°C and maintained for
a period of 12 to 15 hours. Toluene was distilled off under vacuum at 70°C to 75°C to get
206 gm of title compound (yield 95.8%).
Example 2
Preparation of N-methvl-N-pentvl-β-alanine ethyl ester (XXV)
Into a 2L, four necked RB flask was charged with 412 ml of water and 178.8 gm (3.30
mol) of (85%) formic acid. The reaction mass is cooled to 20°C to 25°C and 133.9 gm
(1.65mol) of formaldehyde (37%) was added. The temperature of the reaction mass was
raised to 40°C to 50°C and 206 gm (1.10 mol) of N-pentyl-β-alanine ethyl ester prepared
as per the process described in example 1 was added. The temperature of the reaction
mass was raised to 60°C to 65°C and stirred for a period of three hours. The reaction
mixture is cooled to 25°C to 28°C and pH was adjusted to 9 to 9.3 with ammonium
hydroxide (20%), The product was extracted with methylene dichloride and the solvent
was distilled off to give 208 gm of title compound (yield 94,0%).
Example 3
Preparation of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride (ID
Into a 2L, four necked RB flask was charged with 208 gm (1,03 mol) of N-methyl-N-
pentyl-β-alanine ethyl ester prepared as per the process described in example 2 and 403.5
ml of water. The reaction mass was slowly heated to reflux temperature and stirred for a
period of ten to twelve hours at 98°C to 100°C, After completion of the reaction, about
50% of water was distilled off under vacuum at 70°C to 75°C. A mixture of water (104
ml) and hydrochloric acid (32%, 104 ml) was added. Water was distilled off under
vacuum at 70°C to 75°C and methyl isobutyl ketone (500 ml) was added. Residual water
was removed from the reaction mass by azeotropic distillation. The reaction mass was
cooled to 30°C to 35°C and the crystalline solid product was filtered. The product was
recrystallized from acetone (640 ml) to get 147 gm of title compound as white crystalline

solid (yield 67.8%). Melting point of product is 98°C to 100°C. IR(KBr): 3562, 3200, 2972, 2879, 2723, 2668, 1733, 1469, 1417, 1366, 1284, 1190, 1095, 1047, 1021, 965, 800, and 654cm-1 1H-NMR (D2O): 3.39-3.42 (t, 2H, -NCH2-); 3.20-3.39 (t, 2H, -NCH2-); 2.99-3.06 (m, 5H, N-CH3 and CH2COOH); 2.722-2.75 (m, 2H), 1.19-1.59 (m, 4H, -CH2-CH2); 0.72-0.75 (t, 3H, .CH3).
Example 4
Preparation of Ibandronate sodium monohvdrate (3-(N-methvl-N-pentvnamino-l-hvdroxvpropane-1,1-diphosphonic acid monosodium monohvdrate) (I) Into a 2L, four necked RB flask was charged with 100 gm (0.48 mol) of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride prepared as per the process described in example 3 and 58.4 gm (0,71 mol) of phosphorous acid. The reaction mass temperature was raised 60°C to 65°C under nitrogen atmosphere. After complete liquification of the reaction mass, 191.6 gm (1.39 mol) of phosphorous trichloride was added at 60°C to 65°C for a period of 50 to 60 minutes. The reaction mass temperature was raised to 70°C to 75°C and maintained for a period of 20 hours at the same temperature. The unreacted phosphorous trichloride was distilled off at 50°C to 55°C under vacuum. The reaction mass was cooled to 20°C to 30°C and hydrochloric acid (6N, 658 ml) was added. The reaction mass was heated to 90°C to 95°C for seven to eight hours. Then it was cooled to 20T to 30°C and pH of the reaction mass was adjusted to 4,30 to 4.35 with aqueous sodium hydroxide solution (40%). The reaction mass was treated with activated carbon. The filtrate was diluted with methanol to isolate crystalline solid, which was recrystallized from aqueous methanol to give 141 gm of a pure white crystalline Ibandronate sodium monohydrate. The product is confirmed as polymorph B by XRD (yield 82.23%). IR(KBr): 3163, 2963, 1491, 1093, and 759 cm-1 1H-NMR (D2O): 0.72-0.75, (t, 3H, -CH3); 1.17-1.20 (m, 4H, -CH2-CH2); 1.56-1.57 (m, 2H, -CH2-); 2,19-2.22 (m, 2H, -CH2), 2.69 (s. 3H, -NCH3); 2.90-2.91 (m, H); 3.06-3.07 (m, H); 3.16-3,20 (m, H); 3.39-3.41 (m,H).

Example 5
Preparation of Ibandronate sodium monohvdrate polymorph A
Into a IL four necked RB flask was charged with 150 gm of Ibandronate sodium monohydrate prepared as per the process described in example 4 and 390ml of water at 25°C to 30°C, temperature was raised to 90°C and maintained for a period of forty five minutes. After distillation of the half quantity of water, the reaction mixture was cooled to 25°C to 30°C and maintained for a period of five hours to get crystals of 90 gm of titled compound of Ibandronate sodium monohydrate polymorph A (yield 60%).

Claims
1) A process for the preparation of 3-(N-methyl-N-pentyl)amino-l-hydroxypropane-l-
diphosphonic acid monosodium monohydrate of the formula-I

said process comprises:
a) reaction of pentylamine (IV) with ethylacrylate (XXIII) in the presence of a
solvent to give N-pentyl-p-alanine ethyl ester of formula-XXIV,

b) methylation of N-pentyl-p-amine ethyl ester (XXIV) to give N-methyl-N-
pentyl-p-alanine ethyl ester of formula-XXV,

c) hydrolysis of N-Methyl-N-pentyl-P-alanine ethyl ester (XXV) and subsequent formation of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride of formula-II,
d) bisphosphorylation of compound 3-(N-methyl-N-pentylamino)propiomc acid hydrochloride (II) with phosphorous acid and phosphorous trichloride followed by hydrolysis and subsequent treatment with base to give 3-(N-methyl-N-pentyl)amino-l-hydroxy propane-l,l-diphosphonic acid mono sodium monohydrate of formula-L
2) Process according to claim 1, characterized in that the reaction in step a) is performed
in a suitable solvent selected form alcohols like methanol, ethanol, isopropanol,

n-butanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; aromatic compoxmds like toluene, xylene, preferably toluene,
3) Process according to claim 1to 2 wherein in step a) is performed at a temperature range of about 0°C to 50°C, most preferably at about 10°C to about 30°C.
4) Process according to claim 1 to 3, characterized in that methylation in step b) is performed with a mixture of formic acid and formaldehyde at a temperature range of about 10°C to about 100°C, most preferably at about 60°C to about 70°C,
5) Process according to claim 1 to 4, characterized in that the methylation in step b) is performed in polar medium, preferably water.
6) Process according to claim 1 to 5, characterized in that the hydrolysis in step c) is performed in aqueous medium followed by treatment with hydrochloric acid and the reaction is carried out at a temperature range of about 90°C to about 100°C.
7) Process according to claim 1 to 6, characterized in that the bisphosphorylation in step d) the process is carried out in the absence of a solvent at a temperature range of about 50°C to about 95°C, most preferably at about 60°C to about 70°C.
8) Process according to claim 1 to 7, characterized in that the hydrolysis in step d) is carried out with an acid preferably 6N hydrochloric acid, and the base used after hydrolysis is sodium carbonate or sodium hydroxide, preferably sodium hydroxide.
9) Process of preparation of 3-(N-methyl-N-pentylamino) propionic acid hydrochloride of compound of formula -II

said process comprises;
a) reaction of pentylamine (IV) with ethylacrylate (XXIII) in the presence of
solvent to give N-pentyl-p-alanine ethyl ester of formula-XXIV,

b) methylation of N-pentyl-p-alanine ethyl ester (XXIV) to give N-methyl-N-
pentyl-p-alanine ethyl ester of formula-XXV,


c) hydrolysis of N-Methyl-N-pentyl-p-alanine ethyl ester (XXV) and subsequent formation 3-(N-methyl-N-pentylamino)propionic acid hydrochloride of formula -11,
10) Process according to claim 9, characterized in that the reaction in step a) is
performed in a suitable solvent selected form alcohols like methanol, ethanol,
isopropanol, n-butanol; ketones like acetone, methyl ethyl ketone, methyl isobutyl
ketone; aromatic compounds like toluene, xylene, preferably toluene,
11) Process according to claim 9 to 10 wherein in step a) is performed at a temperature
range of 0°C to about 50°C, most preferably at about 0°C to about 30°C.
12) Process according to claim 9 to 11, characterized in that methylation in step b) is performed with a mixture of formic acid and formaldehyde at a temperature range of about 10°C about to 100'°C, most preferably at about 60°Cto about 70°C.
13) Process according to claim 9 to 12, characterized in that the methylation in step b) is performed in an aqueous medium.
14) Process according to claim 9 to 13, characterized in that the hydrolysis in step c) is
performed in aqueous medium water followed by treatment with hydrochloric acid
and the reaction is carried at a temperature range of about 90°C to about 100°C.
15) Process according to claim 1 to 7, 3-(N-methyl-N-pentyl)amino-l-hydroxy propane-
1,1-diphosphonic acid monosodium monohydrate of formula-I prepared is dissolved
in water at a temperature of 25°C to 30°C, then temperature was raised to 90°C
followed by distillation of the half quantity of water and cooled to the temperature
of 25°C to 30°C to give Ibandronate monosodium monohydrate polymorph A.