WO2007013097A1

WO2007013097A1 - Improved process for the preparation of ibandronate sodium

Info

Publication number: WO2007013097A1
Application number: PCT/IN2006/000251
Authority: WO
Inventors: Muddasani Pulla Reddy; Vattikuti Usharani; Nannapaneni Venkaiah Chowdary
Original assignee: Natco Pharma Limited
Priority date: 2005-07-25
Filing date: 2006-07-17
Publication date: 2007-02-01
Also published as: WO2007013097A8

Abstract

Present invention discloses an improved and commercial process for the preparation of ibandronic acid or its monosodium salt. According to the process 3-N-methylaminopropionitrile is reacted with n-pentylbromide to get the tertiary amine of formula-II. Hydrolysis of the nitrile compound of formula-II with hydrochloric acid gave the b-alanine derivative of formula-X. Bis-phosphonylation of the acid compound of formula-X with phorphorous trichloride and phosphorous acid, followed by water hydrolysis gave aqueous ibandronic acid. Treatment of this with sodium hydroxide, followed by dilution of the aqueous solution with methanol gave ibandronate monosodium of formula-Ia as white crystalline solid. Present process utilizes simple raw materials and avoids the column chromatography technique used in the prior art process for isolation of ibandronic acid. Overall yield of ibandronate is more than 60% from the nitrile intermediate of formula-II. Ibandronate is widely used as bone resorption inhibitor.

Description

IMPROVED PROCESS FOR THE PREPARATION OF

IBANDRONATE SODIUM FIELD OF INVENTION

The present invention relates to an improved process for the preparation of ibandronic acid sodium salt. The said process utilizes a novel compound, 3-(N-methyl-N- pentylamino)-proρionitrile of formula-II in making the ibandronic acid and its sodium salt. Ibandronic acid which is [l-hydroxy-3- (methylpentylamino)propylidene]- bisphosphonic acid has the formula-I given below.

Ibandronate sodium of formula-la is widely used as a bone resorption inhibitor.

BACKGROUND OF INVENTION

Ibandronic acid of the formula-I was reported in US pat. No. 4,927,814 by Boehringer Mann (Germany). According to the process (Scheme-I) disclosed in this patent benzaldehyde of formula-Ill is reacted with N-pentylamine of formula-IV to get the corresponding benzylidene derivative of the formula-V. Reduction of double and alkylation using formaldehyde/formic acid gave N-benzyl-N-methylpentylamine of the formula- VII. Reductive debenzylation gave the secondary amine of formula- VIII. Addition of N-methylpentylarnine to methyl acrylate gave the β-alanine derivative of formula-IX which on hydrolysis gave the corresponding β-alanine derivative. Reaction of this acid with phosphorous acid and phosphorous trichloride gave the ibandronic acid. The crude ibandronic acid was isolated by purification through an ion exchange column. The fractions collected were detected by electrophoresis and concentrated to get the ibandronic acid. However, no process for the preparation of pharmaceutically acceptable monosodium (Ia) salt of ibandronic acid is disclosed. There is a need to produce ibandronate monosodium in a reproducible, pure and crystalline form to enable formulations to meet exact pharmaceutical requirements and specifications.

Vl VIi

Scheme-I

Overall yield of the β-alanine derivative of the formula-X is 10.2%. Yield in the final step is not disclosed. The main drawback in this process is the usage of costly pentylamine. Also, the process uses a number of steps like protection and deprotection of pentylamine to get the required secondary amine of formula- VIII, hydrogenation, etc. Also, purification or handling of low boiling (118 °C) intermediate of formula- VIII is not suitable for commercial production. As there is no other process known for the preparation of the β-alanine derivative of formula-X or ibandronic acid available there is a need for commercial and cheap process for the preparation of ibandronic acid or its monosodium salt. Keeping in view of the drawbacks of the above mentioned procedure we aimed to develop a simple and easy to adapt process for the preparation of ibandronic acid of formula-I and its monosodium of formula-la.

Accordingly, main objective of the present invention is to develop a process for ibandronic acid of formula-I and its monosodium of formula-la, which does not require protection, or deprotection chemistry, hydro genation and costly chemicals.

Another objective of the present invention is to avoid the usage of ion exchange column while purifying ibandronic acid.

Still another objective of the present invention is to develop a process for the preparation of ibandronate monosodium, which avoids the isolation of intermediate ibandronic acid.

PROCESS OF PRESENT INVENTION

The carboxylic acid group present in compound of the formula-X can be obtained from the corresponding nitrile compound. The nitrile compound in turn can be obtained from acrylonitrile and methylamine. Therefore one can use the known 3-methylamino- propionitrile as a starting material for the preparation of the acid intermediate of formula- X and alkylate it with pentyl bromide to get the 3-(methylpentylamino)propionitrile of formula-II. Compound of formula-II or its acid addition salts are novel and prepared for the first time in making ibandronic acid.

Process of the present invention is shown in Scheme-II.

Scheme-II

Accordingly, the present invention provides an improved process for the preparation of ibandronic acid of the formula-I and its monosodium of formula-la,

which comprises:

(i) Reaction of 3-methylarninopropionitrile of formula-Xffl with n-pentyl halide in the presence of a base to get the compound of formula-II.

(ii) Hydrolysis of the nitrile compound of formula-II with a base or acid to get the acid compound of formula-X

(iii) Reaction of the acid compound of formula-X with phosphorous trihalide in the presence of phosphoric acid or phosphorous acid to get aqueous solution of ibandronic acid of formula-I. (iv) Reaction of aqueous ibandronic acid of formula-I with sodium hydroxide followed by dilution with a water miscible organic solvent to get the ibandronate monosodium of formula-la.

Aqueous ibandronic acid obtained in step (iii) above contains inorganic compounds such as phosphoric acid and phosphenic acid. Pure ibandronic acid shall be isolated as per the process disclosed in US pat. No. 4,927,814 by using ion exchange column. Alternatively, aqueous ibandronic acid obtained in step (iii) above can be treated with sodium hydroxide to get aqueous ibandronate sodium. This aqueous solution can be diluted with water miscible solvents such as acetone, methanol, isopropanol, n-butanol, acetonitrie, tetrahydrofuran, etc. to precipitate the ibandronate sodium. The precipitated ibandronate sodium can be isolated by simple filtration technique to get crude ibandronate sodium in the solid form. Neutralization of ibandronate monosodium with hydrochloric acid liberates pure ibandronic acid.

This crude ibandronate sodium can be recrystallized from a number of aqueous solvents such as methanol, ethanol, isopropanol, n-butanol, acetone, acetonitrile, tetrahydrofuran, etc. The recrystallized ibandronate sodium was found to be >99.8% by HPLC and contained one mole of water. Therefore, the present process produces ibandronate sodium of pharmaceutical grade directly from the reaction mass without isolating ibandronic acid. Overall yield of ibandronate sodium as monohydrate in this process is more than 85% from the acid intermediate of formula-X. Present process is also suitable for commercial scale and studied up to 50 kg ibandronate sodium per batch.

The starting compound, 3-methylaminopropionitrile used in the process can be made from acrylonitrile and methylamine by known processes (J. Am. Chem. Soc, 1950, 72, 828; Brit. Pat. 795,758 corresponding Chem. Abstr. Vol. 53, P418b). The base used in step (i) is selected from organic or inorganic base. The organic base includes trialkylamines, pyrrolidine, piperidine, alkyl substituted piperidine, pyridine or alkylated pyridine, etc. The inorganic base includes alkali or alkaline earth metal bicarbonate, ^" carbonate or hydroxide such as sodium, calcium or potassium. Preferred solvent of reaction can be a dipolar aprotic solvent such as DMF, DMAC, DMSO, or a hydrocarbon solvent such as cyclohexane, toluene, an ether solvent such as THF, dioxane. Preferred temperature of the reaction can be in the range of 20-80°C. Pentyl halide used in step (i) is preferably pentyl bromide or chloride.

The base used in hydrolysis step (ii) can be selected from alkali or alkaline earth metal bicarbonate, carbonate or hydroxide such as sodium, calcium or potassium, preferably sodium or potassium hydroxide. After the hydrolysis is over for the isolation of the acid intermediate of formula-X, an acid is required to convert the sodium or potassium salt derived from the hydrolysis into the free acid. Preferred acid can be hydrochloric acid, sulfuric acid, phosphoric acid, etc. preferably hydrochloric acid. The acid used in the hydrolysis step (ii) can be selected from hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, etc, preferably hydrochloric acid.

In the bis-phosphonylation step (ϋi) medium of the reaction can be methanesulfonic acid or an organic solvent such as chlorobenzene, fluorobenzene, toluene, cyclohexane, ethylene dichloride, and chloroform or neat without any solvent. After the bis- phosphonylation the intermediate chlorophosphonates can be hydrolyzed either with hydrochloric acid as mentioned in the prior art process or without hydrochloric acid. Temperature of the reaction during bis-phosphonylation is 50-95°C or the boiling point of the solvent employed.

Overall yield of the intermediate compound of formula-X according to the present process has improved considerably to more than 60%. Also, the yield of ibandronate monosodium is more than 85% from the intermediate compound of formula-X. The yield of ibandronic acid is more than 80%. Therefore, the process of present invention is an improvement over the known process for ibandronic acid. Also, a simple and high yielding process for the preparation of ibandronate monosodium as monohydrate is developed and all the raw materials employed in the process are readily available and cheap. The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example 1

Preparation of 3-(N-Methyl-N-pentylamino) propionitrile

Into a 3L, three-necked RB flask were charged 1.5L of DMF, 300g of 3 -N- methylaminopropionitrile, and 30Og of potassium carbonate at RT. Pentyl bromide (60Og) was slowly added to the reaction mass keeping the internal temperature below 40°C. After the addition reaction was maintained at same temperature for 9-1 Ohr. Sample was taken out from the reaction mass and checked for the presence of 3-(N- methylamino)propionitrile by GC. Reaction was found to be over by GC.

Into a 2OL flask water (12L) was taken and quenched the reaction mass into the water below 25°C. The reaction mass was stirred for lhr and separated the organic layer. The aqueous layer was extracted with 700ml of toluene. Combined the toluene layer with organic layer and washed with 2 x 1.5L of water. Toluene was distilled off from the organic layer below 70°C. The residue containing more than 85% of required product was fractionally distilled at 140⁰C under vaccum to get the title compound (29Og) as colorless liquid. GC purity of this compound showed more than 99%. IR (neat): 2955, 2932, 2860, 2799, 2249, 1464, 1426, 1378,1334, 1254, 1195, 1158, 1134, 1098, 1051, 935, 830, 772, and 729cm^"1. ¹H-NMR (300MHz, CDCl₃): 2.72 (t, J = 7.0Hz, 2H, - CH₂CH₂CN); 2.47 (t, J = 6.6Hz, 2H, -CH₂CN); 2.38 (t, J = 6.9Hz, 2H, -NCH₂); 2.27 (s, 3H₅ NCH₃); 1.24-1.69 (m, 6H, -CH₂CH₂CH₂-); 0.89-0.93 (m, 3H, -CH₃).

Example 2

Preparation of 3-(N-Methyl-N-pentylamino) propionic acid hydrochloride

Into a IL three-necked RB flask was charged lOOg of 3-(N-Methyl-N-pentyl-amino) propionitrile and 144g of hydrochloric acid. The reaction mass was heated to reflux temperature and maintained for four hours. Water and excess hydrochloric acid were distilled of from the reaction mass under vaccum. Traces of water was removed from the reaction mass by adding toluene and distilled of toluene under vaccum. Acetone (100ml) was added to the reaction mass and distilled under vaccum. Th residue was dissolved in acetone (1200ml) and filtered to remove inorganic salts. Acetone (7800ml) was partially removed from the filtrate by distillation under vaccum. The residue was cooled to 25°C and maintained for Ih. The reaction mass was filtered and dried to get 12Og of the title compound as white crystalline solid. Melting point of the solid is 106°C. IR (KBr): 3500, 3200, 2957, 2870, 2710, 2646, 1725, 1470, 1434, 1406, 1366, 1297, 1196, 1151, 1095, 1047, 1016, 965, 855, 807, and 654cm^"1. ¹H-NMR (300MHz, D₂O): 3.49-3.64 (m, 2H, -NCH₂-); 3.23-3.46 (m, 2H, -NCH₂-); 2.99-3.05 (m, 5H, -NCH₃ and CH₂COOH); 1.82-1.90 (m, 2H), 1.46 (br. s, 4H); 1.01 (br. s, 3H).

Example 3

Preparation of ibandronate monosodium:

Into a 250ml three-necked RB flask are charged 5.Og of 3-(N-Methyl-N-pentylamino)- propionic acid hydrochloride, 20ml of chlorobenzene, and 6.9g of phosphoric acid. The reaction mass was heated to 60°C and added slowly 9.9g of phosphorus trichloride. Temperature of the reaction mass was allowed to reach 110⁰C. After the reaction was maintained at same temperature for Hh hydrochloric acid (60ml, 6N) was added to the reaction mass and heated to reflux temperature. The reaction was maintained at reflux for 7h and cooled to 30⁰C. Chlorobenzene layer was separated and the aqueous layer treated with Ig activated carbon. Reaction mass was filtered and the pH of filtrate adjusted to 4.2-4.3 with sodium hydroxide. The reaction mass was diluted with methanol and the resulting precipitate isolated by filtration. The wet material was dried to yield 3.Og of ibandronate monosodium as white solid.

Example 4

Preparation of Ibandronate sodium i) Preparation of 3-(N-Methyl-N-pentylamino)propionic acid hydrochloride

Into a glass lined reactor was charged 144 kg of hydrochloric acid and 100 kg of 3-(N- methyl-N-pentylamino)proρionitrile at 30⁰C under stirring. Slowly heated the reaction mass to reflux temperature and maintained at reflux temperature (105-120⁰C) for 3h. After the reflux maintenance distilled off water from the reaction mass under vaccum. Final traces of water was removed from the reaction mass using 2 x IOOL of toluene. Acetone (IOOL) was charged into the reaction mass and distilled under vaccum. Acetone (1500 L) was charged into the reactor and heated the reaction mass to reflux temperature. The reaction mass was maintained at reflux for 2h and removed the inorganic salts by filtration. The filtrate was transferred into a glass-lined reactor and distilled of acetone partially. The reaction mass was cooled to 5°C, maintained for 3h and filtered the solid under vaccum. Finally washed the wet solid with 5OL of chilled acetone. The wet material was dried in a tray drier at 50-55°C to get 120kg of the title compound as white crystalline solid. ii) Preparation of Ibandronaate monosodium

Into a glass-lined reactor was charged 50kg of 3-(N-methyl-N-pentylamino)propionic acid hydrochloride and 49kg of phosphorous acid. The temperature of the reaction mass was raised to 75°C under stirring. Phosphorus trichloride (132kg) was added into the reaction mass in 3h period maintaining the mass temperature at reflux. After the addition the reaction mass was maintained at reflux temperature for 5h. The reaction mass was cooled to 30°C. Water (180L) was added into the reaction mass and heated the reaction mass to reflux temperature. The reaction mass was maintained at reflux temperature for 7 hours. The reaction mass was cooled to 65°C and added 5kg of activated carbon to the reaction mass. The reaction mass was filtered using leaf filter and washed the reactor and leaf filter with 50L of water. The filtrate was collected into a reactor and adjusted the mass pH of reaction mass to 4.20-4.30 by slowly adding aqueous sodium hydroxide solution. The reaction mass was diluted with methanol equal to the volume of reaction mass at 55°C. The reaction mass was slowly cooled to 25°C and maintained for 2h. The reaction mass was filtered and washed the wet material with methanol. The wet material was dried at 65°C ^• to get 70kg of technical grade ibandronate monosodium as white crystalline solid. iii) Recrystallization of ibandronate monosodium: Into a glass-lined reactor charged 400L of water and 50kg of technical grade ibandronate monosodium obtained above. Reaction mass was heated to reflux temperature and distilled of about 200L of water. The reaction mass was cooled to 50 °C and added 2kg of activated carbon. The reaction mass was filtered and the filtrate taken into another reactor. Acetone (400L) was added to the reaction mass at 50°C and slowly cooled to 25⁰C. After maintaining at 25°C for 2h reaction mass was filtered and the wet cake washed with 50L of acetone and dried the product at 5O⁰C to get 45kg of pharma grade ibandronate monosodium as a monohydrate.

Advantages of present invention:

1. 3-(Pentylmethylamino)propionic acid hydrochloride of formula-X, a key intermediate used in the process for ibandronic acid and its monosodium salt is produced at a much cheaper process and in improved yield. This led to the synthesis of ibandronic acid and its monosodium salt in higher yield.

2. Overall yield of ibandronic acid and its monosodium salt is more than 85% from 3- (pentylmethylamino) propionic acid hydrochloride of formula-X.

3. Process of present invention uses simple and readily available raw materials such as acrylonitrile, methylamine, and pentyl bromide.

4. Process for preparation of ibandronic acid and its monosodium salt is suitable for commercial scale and studied up to 50 kg ibandronate monosodium per batch.

Claims

We Claims:

1. Present invention provides an improved process for the preparation of ibandronic acid of the formula-I and its monosodium of formula-la,

I X = H Ia X = Na

which comprises:

(i) Reaction of 3-methylaminopropionitrile of formula-XIII with n-pentyl halide in the presence of a base to get the compound of formula-II.

(iii) Reaction of the acid compound of formula-X with phosphorous trihalide in the presence of phosphoric acid or phosphorous acid to get aqueous solution of ibandronic acid of formula-I.

(iv) Reaction of aqueous ibandronic acid of formula-I with sodium hydroxide followed by dilution with a water miscible organic solvent to get the ibandronate monosodium of formula-la.

(v) Recrystallization of the ibandronate monosodium from aqueous organic solvents.

(vi) Neutralization of ibandronate monosodium with' an acid to get ibandronic acid.

2. A process according to claim 1 wherein the pentyl halide used in step (i) is pentyl chloride or bromide, preferably pentyl bromide.

3. A process according to claim 1 and 2 wherein the base used in step (i) is selected from organic base such as trialkylamines, pyridine or alkylated pyridine, etc or inorganic base such as alkali or alkaline earth metal bicarbonate, carbonate or hydroxide such as sodium, calcium or potassium, preferably potassium carbonate.

4. A process according to claim 1 to 3 wherein the base used in step (ii) is selected from alkali or alkaline earth metal bicarbonate, carbonate or hydroxide such as sodium, calcium or potassium, preferably sodium or potassium hydroxide.

5. A process according to claim 1 to 4 wherein the acid used in step (ii) is selected from hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, etc, preferably hydrochloric acid.

6. A process according to claim 1 to 4 wherein the water miscible organic solvent used in step (iv) and (v) is selected from alcohols like methanol, ethanol, isopropanol, n-butanol, t-butanol; ketones like, acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles like acetonitrile; ethers like tetrahydrofuran, 1,4-dioxane; amides like N, N- dimethylformamide, preferably methanol or acetone.

7. A process according claims 1-6 wherein the organic solvent used in step (vi) is selected from alcohols like methanol, ethanol, isopropanol, n-butanol, t-butanol; ketones like, acetone, methyl ethyl ketone, methyl isobutyl ketone; nitriles like acetonitrile; ethers like tetrahydrofuran, 1,4-dioxane; amides like N, N-dimethylformamide, preferably acetone, acetonitrile, tetrahydrofuran.

8. A process according to claims 1-7 wherein the acid used in step (vi) is selected from hydrogen chloride gas, hydrogen bromide gas, aqueous hydrochloric acid, alcoholic hydrogen chloride, preferably hydrogen chloride gas.

9. A process according to claim 8 wherein the alcoholic solvent used is selected from methanol, ethanol, isopropanol, 2-butanol, n-butanol, preferably methanol or isopropanol.