DESC:RELATED PATENT APPLICATION
This application claims the priority to and benefit of Indian Provisional Patent Application No. 202141016882 filed on April 10, 2021; the disclosure of which are incorporated herein by reference.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Rupatadine fumarate (1). It further discloses the process for the purification of Rupatadine fumarate (1) having a purity greater than 99.0% (w/w) and preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

BACKGROUND OF THE INVENTION
Rupatadine fumarate is a dual histamine H1 receptor and platelet activating factor receptor antagonist chemically known as 8-chloro-11-[1-[(5-methyl-3-pyridinyl )methyl]piperidin-4-ylidene]-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine fumarate(1:1). Currently marked in the Europe under the trade name Rupafin as 10 mg oral tablet. Rupafin is indicated for the treatment of allergic rhinitis and urticaria in adults and teenagers.

The synthesis of Rupatadine fumarate (1) has been reported in few patents the contents of which are hereby incorporated as reference in their entirety.

2102/MUM/2006 application discloses process for the preparation of Rupatadine by esterification of 5- methyl nicotinic acid, which on treatment with lithium aluminium hydride and thionyl chloride formed 5-methyl-3-(chloromethyl)-pyridine. 5-methyl-3-(chloromethyl)-pyridine was condensed with Desloratadine under basic conditions for 16 hours and further treated with fumaric acid to form Rupatadine fumarate. The main disadvantage of this process is long working hours.

US 5476856 and US5407941 patents discloses preparation of Rupatadine by bromination of 3,5 lutidine in carbon tetrachloride using N-Bromosuccinimide or NBS and reacting the product formed with Desloratadine using 4-(dimethylamino) pyridine for 18 hours. And extractive workup chromatographic purification to yield Rupatadine in 40 % yield.

Alternatively, preparation of Rupatadine hemipenta fumarate was disclosed by the scheme given below.

The main disadvantage of this process is long working hours, which makes the process tedious and not vial for industrial level. The low yield Rupatadine makes the process commercially unviable. Further the above process does not disclose preparation of Rupatadine fumarate (1).

WO2006114676 application discloses Rupatadine preparation involving N-alkylation of Desloratadine with 5-methyl-3-(chloromethyl)-pyridine using biphasic solvent a phase transfer catalyst. Use of phase transfer catalyst is costly and difficult to handle in large amounts during scale up in industry.

Hence, there is a need for providing a process for the preparation of Rupatadine fumarate (1) which is commercially viable and economical. Therefore, the present inventors report an improved process for the preparation of Rupatadine fumarate (1) in good yields with high purity.

OBJECTIVE OF THE INVENTION
Accordingly, one objective of the present invention is to provide an improved process for the preparation of Rupatadine fumarate (1).

Another objective of the present invention is to provide a process for purification of Rupatadine(1a) and conversion to Rupatadine fumarate (1).

Another objective of the present invention is to provide Rupatadine fumarate (1) with purity greater than 99.0%(w/w) and preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

SUMMARY OF THE INVENTION
Accordingly, in one embodiment the present invention provides an improved process for the preparation of Rupatadine fumarate (1).

In another embodiment, the steps involved in the preparation of Rupatadine fumarate (1) as shown in scheme 1 are as follows:
a) De esterification of Loratadine (4) to form Desloratadine (3);
b) reacting Desloratadine (3) with 3-(chloromethyl)-5-methylpyridine hydrochloride (2) to form Rupatadine (1a); and
c) reacting Rupatadine(1a) with fumaric acid to form Rupatadine fumarate (1).

In another embodiment the present invention provides process for the purification of Rupatadine fumarate (1) with purity greater than 99.0%(w/w) , preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

BRIEF DESCRIPTION OF DRAWINGS
Figure 1: illustrates the X-Ray powder diffraction pattern (XRPD) of Rupatadine Fumarate (1).
Figure 2: Differential scanning calorimetry (DSC) endotherm of Rupatadine Fumarate (1).
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of Rupatadine fumarate (1) with purity greater than 99.0% and preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC) as illustrated in scheme 1 below:

Scheme-1

In another embodiment, step a) involves de esterification of Loratadine (4) to form Desloratadine (3). Loratadine (4) was treated with a suitable base and heated to a temperature of 70-100 oC, preferably 85-90 oC. Desloratadine (3) was then isolated from a suitable mixture of solvents.

Step b) proceeds with reacting Desloratadine (3) with 3-(chloromethyl)-5-methylpyridine hydrochloride (2) to form Rupatadine free base (1a). Desloratadine (3) was added to a suitable solvent and base and heated to a temperature of 60-90 oC, preferably 70-75 oC. 3-(chloromethyl)-5-methylpyridine hydrochloride (2) was then added to the reaction mass to yield Rupatadine free base (1a).

Step c) involves reacting Rupatadine(1a) with fumaric acid to form Rupatadine fumarate (1). Fumaric acid was dissolved in a suitable solvent and added to Rupatadine free base (1a) dissolved in a suitable solvent at a temperature of 50-100oC, preferably 60-70oC. The reaction mass was cooled to 0-5 oC and the solid formed was isolated from a mixture of solvents to yield Rupatadine fumarate (1).

In another embodiment, the Rupatadine fumarate (1) so obtained is having purity greater than 99.0% (w/w) and preferably greater than 99.5% (w/w) by High-performance liquid chromatography (HPLC).

The suitable solvent used herein can be selected from the group comprising water, methanol, ethanol, propanol, isopropanol, and the like and aprotic solvents selected from a group comprising of acetone, dichloromethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, heptane, toluene, tetrahydrofuran, methyl tertiary-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, and mixtures thereof. Preferably, water, methanol, dichloromethane, acetonitrile, methyl tertiary butyl ether and ethyl acetate were used.

In some embodiment, the bases used may be selected from a group comprising of organic or inorganic bases. The inorganic base used herein may be selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, caesium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tertiary butoxide, potassium ethoxide, sodium methoxide, lithium tertiary butoxide, or the like. The suitable organic bases used in the present invention may be selected from the group comprising of triethyl amine, trimethyl amine, diisopropylethylamine, diethyl amine, isopropyl amine, N-butyl lithium, imidazole, morpholine, N-methyl morpholine, pyridine, ammonia, or the like. Preferably, sodium hydroxide, sodium carbonate, trimethyl amine were used in the present invention.

In another embodiment, 3-(chloromethyl)-5-methylpyridine hydrochloride (2) used may be prepared as disclosed in scheme-2 below.

Scheme-2

In some embodiment, 3,5-dimethylpyridine (6) was added to a suitable solvent and heated to a temperature of 30-50 ?, in presence of a suitable oxidizing agent, preferably potassium permanganate and acid, preferably hydrochloric acid. The reaction mass was then treated with sodium hydroxide solution to yield 5-methylnicotinic acid (5). 5-methylnicotinic acid (5) was treated with thionyl chloride, followed by treatment with sodium borohydride and acid-base treatment to yield (5-methylpyridin-3-yl) methanol (2a). Intermediate (2a) was further treated with thionyl chloride and heated. The reaction mass was cooled and the solid obtained was washed with isopropanol to yield 3-(chloromethyl)-5-methylpyridine hydrochloride (2).

In another embodiment, Loratadine (4) used may be prepared as disclosed in scheme-3 below.

Scheme-3
In some embodiment, methyl Loratadine (7) was esterified in presence of suitable esterifying agents preferably triethyl amine and ethyl chloroformate. Suitable solvent preferably toluene and acid, preferably hydrochloric acid. The reaction mass was then treated with di-isopropyl ethylamine to yield Loratadine (4)

In some embodiment, Rupatadine fumarate (1) so obtained is having loss on drying less than 0.5% (w/w).

In some embodiment, Rupatadine fumarate (1) so obtained is having sulfated ash less than 0.10 % (w/w).

In some embodiment, Rupatadine fumarate (1) so obtained is having purity greater than 99.0% (w/w) and total impurities less than 1.0% (w/w).

In some embodiment, Rupatadine fumarate (1) so obtained is having the below impurities less than 1.0% (w/w), preferably less than 0.5% (w/w).

Impurity A
Impurity B
In another embodiment, the present invention provides the Rupatadine fumarate (1) obtained is having the Differential scanning calorimetry (DSC) endotherm at 203.45 °C as shown in figure 2.

In some embodiment, Rupatadine fumarate (1) so obtained is having XRD pattern as shown in figure 1 and two theta (2?) ± 0.2° values as in table 1.

Table 1:
Two theta (2T) values Relative Intensity (%)
8.15 42.9
11.16 14.7
11.85 63.2
12.68 43.9
13.78 85.4
15.12 14.9
15.70 22.7
16.35 29.1
16.81 89.9
17.22 21.2
18.23 15.4
19.75 100
20.39 37.1
21.48 16.9
22.34 41.8
23.18 39.2
23.80 40.3
24.51 74.6
25.03 15.9
25.52 21.9
26.01 18.7
26.98 22.2
27.70 15.2
28.68 13.0
29.01 17.3
30.74 7.60
32.84 7.10
34.74 13.3
36.42 10.0
37.84 12.5
39.33 7.70

The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
Example-1: Preparation of Desloratadine (3)
100g of Loratadine (4) was added to methanolic solution of sodium hydroxide at 20-25oC.The reaction mass was heated to 85-90oC. On completion of reaction, the reaction mas was cooled, and solvent distilled off. The concentrate was cooled to 15-20oC and 1500mL of water and 1500mL of dichloromethane were added and layers separated. 500 mL of water to combined organic layer, stirred and the aqueous layer was collected, and pH was adjusted to 7-8. The organic layer was separated, and solvent distilled off. 200mL of acetonitrile was added to the concentrate and cooled to 0-5oC. The obtained solid was washed with acetonitrile and dried to yield Desloratadine (3). Yield: 95% (w/w); Purity: 99.0% (w/w).

Example-2: Preparation of Rupatadine(1a)
100g of Desloratadine (3) was added to 700 mL of acetonitrile at 25-30°C. 75 g of sodium carbonate to reaction mass and heated to 70-75oC. A solution of 60g of 3-(chloromethyl)-5-methylpyridine hydrochloride (2) in water was added to the above reaction mass and stirred. On completion of reaction, the reaction mass was cooled to 45-50 oC and the solvent was distilled off. A mixture of water and methyl tertiary butyl ether was then added to the concentrate and stirred. The layers were separated, and methyl tertiary butyl ether was added lot wise to aqueous layer and separated. Further the water was added to the organic layer and layers separated. Different volumes of potassium dihydrogen phosphate aqueous solution were added to the organic layer and stirred for 20 min at 25-30oC. The organic layer was separated and treated with 10 g of neutral activated charcoal and heated to 45-50oC. The reaction mass was filtered and washed with methyl tertiary butyl ether. The reaction mass was again heated, and solvent distilled off to yield Rupatadine free base (1a). Yield: 85% (w/w); Purity: 99.75% (w/w).

Example-3: Preparation of Rupatadine fumarate (1)
Rupatadine free base (1a) was added to 50 mL of methanol and distilled the solvent under vacuum. 450 mL of ethyl acetate was then added to the concentrate and a solution containing 35g of fumaric acid dissolved in 450 ml of methanol was added to the reaction mass over a period of 15-20 min at 60-70oC. The reaction mass was cooled to 0-5oC, filtered, and washed with 100ml mixture of chilled methanol/ethyl acetate (1:1) solution and dried under vacuum to yield Rupatadine fumarate (1). Yield: 75% (w/w); Purity: 99.95% (w/w).

Example-4: Alternative process for the preparation of Rupatadine fumarate (1)
Fumaric acid was dissolved in ethanol and added to the Rupatadine free base (1a) and the reaction mass left for 24 hr to get crystalline Rupatadine fumarate (1). The compound obtained was recrystallized from ethanol to obtain pure Rupatadine fumarate (1). Yield:70%(w/w); Purity: 99.90% (w/w).

Example-5: Preparation of 5-methylnicotinic acid (5)
100g of 3,5-dimethylpyridine (6) was added to 4500mL of water and heated to 40-45oC.70 g of potassium permanganate was then added to the reaction mass and stirred. On completion of reaction, the reaction mixture was filtered. 200 mL of dichloromethane was added to the filtrate and stirred for 20-30 min at 25-30oC. The aqueous layer was separated and concentrated by distillation. The concentrate was cooled to 0-10oC. The pH of the concentrate was adjusted to 1.5 using concentrated hydrochloric acid and stirred. The reaction mass was then filtered and 50 % aq. sodium hydroxide solution was added at 2-10oC and stirred. The solid formed was filtered and dried under vacuum to yield 5-methylnicotinic acid (5). Yield: 35% (w/w).

Example-6: Preparation of 3-(chloromethyl)-5-methylpyridine hydrochloride (2)
100 g 5-methylnicotinic acid (5) was added to 500mL of methanol and cooled to 2-10 oC.100mL of thionyl chloride was added to the reaction and heated to 60-65oC.On completion of reaction, the reaction mass was cooled to 20-25oC. The pH was adjusted to 7.0 to 8.0 using 30 % aqueous sodium carbonate solution. 500 mL of dichloromethane to reaction mass and stirred. The organic layer was collected and distilled off. 500 mL of methanol was added to the concentrate and the solvent distilled under reduced pressure at 40-45oC.The reaction mass was cooled to 0-10oC and 55 g of sodium borohydride added to the reaction mass. The temperature of the reaction mass was raised to 20-25oC. On completion of reaction, the reaction mass was heated to 45-50oC and methanol distilled off. The reaction mass was cooled to 0-10oC and 500mL of water and 250 mL of concentrated hydrochloric acid were added to adjust the pH of the reaction mass between 1-2.
200 mL of dichloromethane was added to the reaction mass and layers separated. The aqueous layer was collected m cooled to 2-10oC and pH adjusted to 11-12 using 50 % aq. sodium hydroxide solution at 2-15oC to remove the dialcohol impurity. On completion of reaction, the organic layer was evaporated to yield the concentrate. The concentrate was cooled 10-15oC and 500mL of dichloromethane and 60 mL of thionyl chloride were added and heated to 40-45oC. On completion of reaction, solvent was distilled under vacuum and 350 mL of isopropanol was added to the concentrate. The reaction mass was heated to 55-60oC, stirred, and cooled to 20-25oC. The reaction mass was filtered and dried under vacuum below 50oC to yield 3-(chloromethyl)-5-methylpyridine hydrochloride (2). Yield: 65%(w/w); Purity: 99.90% (w/w).

Example-7: Preparation of Loratadine (4)
190g of methyl Loratadine (7) was added to 35g triethyl amine in toluene under nitrogen atmosphere. 35g ethyl chloroformate was then added to the reaction mass at 50-60? and stirred for 2 hr at 70-80?. The reaction mass was cooled. The organic layer was washed with water and liquid ammonia added to the aqueous layer. The organic layer was collected and acidified using hydrochloric acid and water. The organic layer was further treated with sodium hydroxide to attain a pH of 7.0 – 8.0 and washed with water and Ethylenediaminetetraacetic acid (EDTA). The organic layer was distilled off and the concentrate was treated with Di-Isopropyl Ether (DIPE) and activated carbon and filtered through micron filter. The reaction mixture was cooled to 25-30oC, centrifuged, and washed with di-Isopropyl ether and dried to yield Loratadine (4). Yield: 90%(w/w); Purity: 99.90% (w/w).

Example-8: Alternate process for the preparation of Loratadine (4)
200g of methyl Loratadine (7) was added to 38g triethyl amine in toluene under nitrogen atmosphere. 38g ethyl chloroformate was then added to the reaction mass at 50-60? and stirred for 2hrs at 70-80?. The solvent was distilled off and the concentrate was treated with di-isopropyl ether and carbon and filtered. The filtrate was cooled to 25-30oC and washed with water then the residue was purified with di isopropyl ether to obtain Loratadine (4). Yield:80%(w/w); Purity: 99.85% (w/w).
,CLAIMS:1. An improved process for the preparation of Rupatadine fumarate (1),

comprising the steps of:
a) De esterification of Loratadine (4)

with a suitable base to form Desloratadine (3);

b) reacting Desloratadine (3) with 3-(chloromethyl)-5-methylpyridine hydrochloride (2)

in the presence of a base in a suitable solvent to form Rupatadine (1a);

c) reacting Rupatadine(1a) with fumaric acid in a suitable solvent to form Rupatadine fumarate (1); and
d) purifying Rupatadine fumarate (1) in a suitable solvent.

2. The process as claimed in claim 1, wherein the compound of formula 4

is prepared by the process comprising the step of:
a) esterifying compound of formula 7

with ethyl chloroformate in the presence of a suitable base in a suitable solvent to obtain crude compound of formula 4; and
b) purifying crude compound of formula 4 with di isopropyl ether to obtain pure compound of formula 4.

3. The process as claimed in claim 1, wherein the compound of formula 2

is prepared by the process comprising the step of:
a) oxidizing 3,5-dimethylpyridine (6)

with potassium permanganate in water to obtain 5-methylnicotinic acid (5);

b) chlorinating 5-methylnicotinic acid (5) with chlorinating agent in methanol, followed by treating with methanol to obtain methyl 5-methylnicotinate (2b) in situ.

c) reducing methyl 5-methylnicotinate (2b) with suitable reducing agent to obtain (5-methylpyridin-3-yl) methanol (2a) in situ; and
d)
d) chlorinating (5-methylpyridin-3-yl) methanol (2a) with chlorinating agent in a suitable solvent to obtain 3-(chloromethyl)-5-methylpyridine hydrochloride (2).

4. The process as claimed in claim 3, wherein the chlorinating agent is selected from oxalyl chloride, thionyl chloride, phosphorous oxy chloride, phosphorous trichloride, or phosphorus pentachloride.

5. The process as claimed in claim 1, 2 and 3, wherein said suitable solvent is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, and the like and aprotic solvents selected from a group comprising of acetone, dichloromethane, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexane, heptane, toluene, tetrahydrofuran, methyl tertiary-butyl ether, 1,4-dioxane, ethyl acetate, isopropyl acetate, acetonitrile, chloroform, and mixtures thereof.

6. The process as claimed in claim 1 and 2, wherein said base refers to an inorganic base or an organic base, wherein the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, caesium hydroxide, sodium carbonate, potassium carbonate, magnesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tertiary butoxide, potassium ethoxide, sodium methoxide, lithium tertiary butoxide, or the like, and the organic base is selected from the group consisting of triethyl amine, trimethyl amine, diisopropylethylamine, diethyl amine, isopropyl amine, N-butyl lithium, imidazole, morpholine, N-methyl morpholine, pyridine, ammonia, or the like.

7. The process as claimed in claim 1, wherein said Rupatadine fumarate (1) obtained is having less than 1.0% of one or more impurities selected from impurity A and impurity B.

Impurity A
Impurity B