DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(SECTION 10)

AN IMPROVED PROCESS FOR THE PREPARATION OF
N-ALKYLPENTYLAMINE

We, Tyche Industries Limited,
a company incorporated under the companies act, 1956 having address at
C-21/A, Road No.9, Film Nagar, Jubilee Hills, Hyderabad – 500096, India

The following specification particularly describes and ascertains the nature of the invention and the manner in which it is to be performed:
Field of the invention
The present invention relates to an improved process for the preparation of N-alkylpentylamine, which is an intermediate useful in the preparation of medicaments. More particularly, the present invention relates to an improved the preparation of N-methylpentylamine, which is used as a starting material in the preparation of ibandronic acid or its pharmaceutically acceptable salt.

Background of the invention
Ibandronate sodium is a potent bisphosphonate drug used in the prevention and treatment of osteoporosis and is marketed under the trade name of Boniva in United States and Bonviva in UK. The chemical name for ibandronate sodium is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acid, monosodium salt, monohydrate of formula (I).

Considering the importance of ibandronate sodium several literature references provided processes for the preparation of ibandronate. Most of them, as discussed herein, involve the use of N-methylpentylamine as an intermediate. However, the process reported in most of these references is different.
US 4,927,814 claims ibandronic acid and its pharmaceutical acceptable salt. The patent also discloses a process for the synthesis of ibandronic acid by reacting benzaldehyde with N-pentylamine to obtain schiff base followed by reduction and methylation to obtain N-benzyl-N-methylpentylamine as oil, which on reduction gives N-methylpentylamine. N-methylpentyl amine is reacted with methyl acrylate and subsequent hydrolysis of resulting compound yields 3-(N-methyl-N-pentylamino propionic acid). This compound was converted to ibandronic acid by reaction with phosphorous acid and phosphorous trichloride. The reaction is shown in scheme I given below :

Scheme – I
US 7,214,818 discloses a process which involves condensation of N-pentylamine with benzaldehyde to produce N-benzylidene pentylamine, transforming the ensuing compound into N-methyl-N-pentylamine using a methylating agent followed by reaction with methyl acrylate to form N-methyl-N-pentyl-ß-alanine methyl ester, which on reaction with phosphoryl chloride and phosphorus acid yields ibandronate sodium monohydrate. The reaction is shown in scheme II given below :

Scheme – II
US 8,178,712 discloses a process for the preparation of Ibandronate sodium in which N-methylpentylamine is obtained by the reaction of N-benzyl methylamine with 1-bromopentane followed by debenzylation. N-methylpentylamine is converted to ibandronate sodium using 3-halopropionate followed by bisphosphonation. The reaction is shown in scheme III given below :

Scheme – III

Tetrahedron, Vol.41, 1985, 4261-4277 discloses a process in which N-methylpentylamine is prepared by reacting 1-bromopentane with monomethylamine in the presence of sodium carbonate. However the reported process suffers in terms of yield. The reaction is shown in scheme V given below :

Scheme – IV

Indian J. Chem., Sec B, September 2010 Pages 1257-1260 discloses a process in N-methylpentylamine is prepared from benzoylchloride.

WO 2008/014510 discloses a process for the preparation of ibandronic acid starting from valeric acid. According to this patent publication, N-methylpentyl amine is prepared by condensing valeric acid with methylamine to obtain N-methylpentanamide followed by reduction.
All the above reported processes for the preparation of N-methylpentylamine has one or more of the following drawbacks
a) involves multiple steps like benzylation, debenzylation, etc which effects overall yield and
b) requires the use of hazardous Pd/C and other reducing agents.
Considering the importance of Ibandronate sodium, there is need for a simple, economical and industrially viable process for the synthesis of N-methylpentylamine. With a view to find a simple process the present applicant diligently worked and identified a robust and economical process for the preparation of N-(alkyl)methylpentylamine.

Objectives of the invention
The main objective of the present invention is to provide an improved process for the preparation of N-methylpentylamine with high purity and yield.
Still another objective of the present invention is to provide a process for the preparation of Ibandronate using N-methylpentylamine of present invention.

Summary of the invention
Accordingly, the present invention provides an improved process for the preparation of N-methylpentylamine which comprises reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent, wherein the reaction is carried out in the absence of base.
Another embodiment of the present invention is to provide a process for the preparation of Ibandronate or its salt which comprises:
i) reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent, wherein the reaction is carried out in the absence of base and
ii) converting the N-methylpentylamine into Ibandronate or its salt.

Detailed description of the invention
In another embodiment of the present invention the reaction of halopentane with methylamine is carried out in the presence of solvent selected from, but not limited to, methanol, ethanol, iso-propanol, n-propanol, toluene, xylene, acetonitrile, tetrahydrofuran, heptanes, hexane, 1,4-dioxane etc or mixtures thereof.
In yet another embodiment, the reaction of halopentane with methylamine is carried out at a temperature in the range of 5 – 100?C.
In a preferred embodiment, the present invention provides an improved process for the preparation of N-methylpentylamine which comprises reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent selected from methanol, ethanol, iso-propanol, n-propanol, toluene, xylene, acetonitrile, tetrahydrofuran, heptanes, hexane, 1,4-dioxane etc or mixtures thereof, wherein the reaction is carried out in the absence of base.
In a preferred embodiment, the present invention provides an improved process for the preparation of Ibandronate sodium of formula (I) which comprises
i) reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent selected from methanol, ethanol, iso-propanol, n-propanol, toluene, xylene, acetonitrile, tetrahydrofuran, heptanes, hexane, 1,4-dioxane etc or mixtures thereof, wherein the reaction is carried out in the absence of base and
ii) converting the N-methylpentylamine into Ibandronate sodium.

Applicant found that the use of base, as provided in the prior art, in the said condensation yields N-methylpentylamine with poor yield & low quality. Surprisingly the condensation in the absence of base proceed smoothly and yields N-methylpentylamine in good yield and quality.
In another embodiment of the present invention the N-methylpentylamine obtained according to the present invention is converted to Ibandronate sodium by following the processes known in the art or by following the general process described below or by following the process described in the examples.
In still another embodiment of the present invention the N-methylpentylamine is converted to 3-(N-methyl-N-pentylamino)propionic acid using methyl acrylate or acrylonitrile or methyl-3-halopropionate followed by hydrolysis of resulting compound. Bisphosphonation of 3-(N-methyl-N-pen1ylamino)propionic acid using phosphorous acid and a halophosporous compound yields ibandronate sodium. Suitable halophosporous compound include phosphorous trichloride (PCl3), phosphorous pentachloride (PCl5), phosphorous tribromide (PBr3), phosphorous pentabromide(PBr5), Phosphorous oxybromide (POBr3), phosphorous oxychloride (POCl3) and the like or mixtures thereof. The bisphophoryaltion reaction may also include co-diluent such as ortho-phosphoric acid, or a silicone fluid.
In another embodiment, the Ibandronate sodium of the present invention may be in the form of amorphous or crystalline nature.
In yet another embodiment of the present invention the bisphosphonation reaction generally takes place at a temperature of from 45 °C to 125 °C and optionally in the presence or absence of solvent in selected from water, toluene, chlorobenzene, xylene, methane sulphonic acid, benzene sulphonic acid, ethylene dichloride and the like.
The present invention is exemplified by the following examples, which is provided for illustration only and should not be construed to limit the scope of the invention.
Example 1
Preparation of N-methylpentan-1-amine (N-methylpentyl amine)
To a solution of methylamine in methanol (1250 ml, 30%), 1-bromopentane (250 g) was added dropwise at 10-15 ?C for 6-8 hr . The resultant mass was stirred at 22 – 25 ?C for 8 hr. After completion of reaction the methanol was concentrated under normal conditions and charged 250 ml of 25% aq. sodium hydroxide solution. The reaction mass was stirred at room temperature for 30 min and layers were separated. The title compound was obtained, by fractional distillation of organic layer. Wt : 100 g; Purity : >98% by GC.

Example 2 :
Preparation of Ibandronate Sodium
Step 1 : Methyl 3-(N-methyl-N-pentylamino)propanoate
To a solution of methyl acrylate (102.0 g, 1.176 m) in methanol (300 ml) N-methylpentylamine (100 g, 1.030 mol) in methanol (100ml), prepared according to example 1, was added slowly at 15-20 ?C for 6-8 hr and the resultant mass stirred at 20-25 ?C for 4 hr.. After completion of reaction, the methanol was distilled under normal pressure to obtain the title compound. Wt: 124.0 g

Step 2: 3-(N-methyl-N-pentylamino)-propanoic acid hydrochloride
To Step-2 material (124.00 g), DM water (250 ml) was added and refluxed at 95-98 ?C for 4 hr.. After hydrolysis, approximately 50% of water was distilled at 50-55 ?C. To the resultant mass was added dil HCl (240 ml) and stirred at RT for 30 min. The water was completely distilled under vacuum and 375 ml of acetone was added to the recidue and stirred at RT for 1-2 hr. The solid obtained was filtered and washed with acetone to obtain title compound. Wt. 108 g.

Step 3 : Ibandronate Sodium
To 3-(N-methyl-N-pentylamino)-propanoic acid hydrochloride obtained in step 2 (150 g, 0.705 m) , phosphorus acid (88.8 gm, 1.08 m) was added and heated to 60-65 ?C followed by phosphorus trichloride (285 gm, 207 m) was added slowly at 60-65 ?C for 2-3 hr. The reaction mass was heated to 70-75 ?C and stirred for 20 hr. After completion of reaction, the mass was cooled to 50-55 ?C and excess phosphorus trichloride was distilled under vacuum. To the reaction mass , 1000 ml of 6N HCl was added at 20 ?C. The reaction mixture was heated to 90-95 ?C and maintained for 8 hr at same temperature. The pH of the reaction mass was adjusted to 4.35 to 4.40 with aq sodium hydroxide and the mass was subjected to carbon treatment at 50-55 ?C. Filter the reaction mass and washed with hot DM water (150 ml). The filtrate was heated to 50-55 ?C and added methanol (450 ml) for 1 hr. The reaction mass was maintained at 50-55 ?C for 30 min. Cool to RT and stir for 4 to 6 hrs. Filter the reaction mass and wash with 100 ml methanol. Dried at 90-95 ?C for 4 hr to yield Ibandronate sodium
Dry weight: 254 gm.

Step 4 : Preparation of Crystalline Ibandronate sodium
To the above dry compound (254 gr), DM Water was added (1056 ml), stirred for 30 min . Methanol (660 ml) was added to the reaction mass. The reaction mass was stirred at RT for 3 hr and filtered and washed with methanol (150 ml) to yield wet cake. To this wet cake, DM water (1056 ml) was added and heated to 50- 55 ?C and stirred for 30 min at 50 – 55 ?C. Charged activate carbon (15 gm) at 50-55 ?and stirred for 30 min at same temperature. Filtered the hot reaction mass on hyflobed and wash the bed with 150 ml hot water. The reaction mass was cooled to RT and slowly added methanol (960 ml) for 15 min and stirred at RT for 4 hr. Filtered the reaction mass and washed with methanol (150 ml). Wet : 310 gm;Dried at 90-95 ?C for 4 hr.
Dry weight : 185 gm.
To the above dry compound ( 185 gr), DM Water (546 ml) was added . Heated to 45-50 ?C and checked pH (Range 4.35 to 4.40) and adjusted to CS lye (3 gr). Heated to 90 ?C and maintained at 90 – 95 ?C for 45 min. Distilled out water and cooled to RT. Maintained the reaction mass at RT for 5 hr. Filtered the reaction mass and washed with 10 ml of water to obtain crystalline Ibandronate sodium. Dried at RT for 12 hr,
Dry weight : 104 gm. MC : 4.51 %.
,CLAIMS:We Claim:

1. An improved process for the preparation of N-methylpentylamine which comprises reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent, wherein the reaction is carried out in the absence of base.

2. The process as claimed in claim 1 wherein the solvent is selected from methanol, ethanol, iso-propanol, n-propanol, toluene, xylene, acetonitrile, tetrahydrofuran, heptanes, hexane, 1,4-dioxane etc or mixtures thereof.

3. The process as claimed in claim 1 wherein the reaction of halopentane with methylamine is carried out at a temperature in the range of 5 – 100?C.

4. An improved process for the preparation of N-methylpentylamine which comprises reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent selected from methanol, ethanol, iso-propanol, n-propanol, toluene, xylene, acetonitrile, tetrahydrofuran, heptanes, hexane, 1,4-dioxane etc or mixtures thereof, wherein the reaction is carried out in the absence of base.

5. The process as claimed in claim 1 or 4 wherein N-methylpentylamine is converted to Ibandronate.

6. An improved process for the preparation of Ibandronate or its salt which comprises:
i) reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent, wherein the reaction is carried out in the absence of base and
ii) converting the N-methylpentylamine into Ibandronate or its salt.

7. An improved process for the preparation of Ibandronate or its salt which comprises:
i) reacting 1-halopentane of formula (II)

wherein X represents halogen atom with methylamine using a solvent selected from methanol, ethanol, iso-propanol, n-propanol, toluene, xylene, acetonitrile, tetrahydrofuran, heptanes, hexane, 1,4-dioxane etc or mixtures thereof, wherein the reaction is carried out in the absence of base and
ii) converting the N-methylpentylamine into Ibandronate or its salt.

Date this Sixteenth (16th) day of May 2014

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883