A process for the preparation of (2s,3s)-2-benzhydryl- n-(5-TERT-butyl-2-methoxybenzyl) quinuclidin-3-amine and pharmaceutically acceptable salts thereof

Abstract

The present invention relates to a process for the preparation of (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine represented by the following structural formula-1a and its pharmaceutically acceptable salts thereof. Further, the present invention provides 2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine salts with purity greater than 99.0% by High-performance liquid chromatography (HPLC). It further relates to a process for the preparation of (S)-2-benzhydrylquinuclidin-3-one (6) with purity greater than 99.0% by High-performance liquid chromatography (HPLC).

Description

[0001] "A PROCESS FOR THE PREPARATION OF (2S,3S)-2-BENZHYDRYL- N-(5-TERT-BUTYL-2-METHOXYBENZYL) QUINUCLIDIN-3-AMINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF"

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for the preparation of (2S,3S)-2- benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine represented by the following structural formula- la and its pharmaceutically acceptable salts thereof. Further, the present invention provides 2S,3S)-2-benzhydryl-N-(5-tert- butyl-2-methoxybenzyl) quinuclidin-3-amine salts with purity greater than 99.0% by High-performance liquid chromatography (HPLC). It further relates to a process for the preparation of (S)-2-benzhydrylquinuclidin-3- one (6) with purity greater than 99.0% by High-performance liquid chromatography (HPLC).

[0004] BACKGROUND OF THE INVENTION (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine is known as Maropitant. It is a neurokinin (NK1) receptor antagonist that blocks the pharmacological action of substance P in the central nervous system (CNS). The empirical formula is C32H40N2O; has the molecular weight 468.685 g-mol-1and the structure is as follows:

[0005]

[0006] The synthesis of Maropitant was reported in many patents and non-patent literature.

[0007] The contents of which are hereby incorporated as reference in their entirety. US6222038B 1 discloses (2S, 3S)-N-(5-tert-butyl-2-methoxyphenyl) methyl-2- diphenylmethyl- 1 -azabicyclo [2.2.2] octan-3-amine, Maropitant free base and its methane sulfonic acid salt specifically as described in scheme- 1. The process comprises of deprotecting 2-metoxybenxyl with hydrogenation using 20% palladium (II) hydroxide as catalyst to a compound of formula I.B. Nucleophilic substitution of the bromide with amine I.B provided Maropitant.

[0008] Scheme- 1

[0009] W02005075473A1 discloses a process for preparation of process for the preparation of (2S ,3 S )-2-benzhydryl-N-(5-tent-butyl-2-methoxybenzyl) quinuclidin-3-amine (I) and its pharmaceutically acceptable monohydrate citrate salt (la). The process comprising the steps of deprotecting compound of Formula (Via) to provide a compound of formula (Vlld); then reacting the compound of formula (VII) with a compound of formula (VIII), a reductive amination has been carried out to provide camphor sulfonate salt compound of Formula (lb). Then removing the camphor sulfonate salt from the compound of Formula (lb) to provide

[0010] Maropitant compound of formula (I), then treated with citric acid to form (2S,3S)-

[0011] -2-benzhydryl-N-(5-tent-butyl-2-methoxybenzyl) quinuclidin-3-amine monohydrate citrate salt (la) as represented in below Scheme 2.

[0012] Scheme-2

[0013] As can be seen from the above, the disadvantages of the prior art process for the preparation of (2S ,3 S )-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine or its salts is usage of expensive solvents, reaction conditions and requiring further purification process, which leads to decreases the yield of the final product which are not industrially viable for scale-up production at plant level.

[0014] Thus, there is a need to develop a simple cost effective, robust and industrially viable process for the preparation of (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2- methoxybenzyl) quinuclidin-3-amine or it’s slats having purity greater than 99.0% by High-performance liquid chromatography (HPLC).

[0015] OBJECTIVE OF THE INVENTION

[0016] The main objective of the present invention is to provide an easy, inexpensive, and industrially feasible process for the preparation of Maropitant (la) and its pharmaceutically acceptable salts thereof (1). In another objective, the present invention is to provide a reductive amination, to furnish desired isomer predominantly. The present invention provides an efficient method for the removal of undesired isomer at intermediate stage i.e (S)-2- benzhydrylquinuclidin-3-one (6).

[0017] In yet another objective, the present invention is to provide Maropitant (la) and its pharmaceutically acceptable salts with enantiomer excess of at least 99% and purity greater than 99.0% by High-performance liquid chromatography (HPLC).

[0018] SUMMARY OF THE INVENTION

[0019] Accordingly, in one aspect of the present invention is to provide a process for the preparation of Maropitant and its pharmaceutically acceptable salts is having purity greater than 99.0% by HPLC, which comprises the following steps; a) reacting (S)-2-benzhydrylquinuclidin-3-one (6) with benzylamine (5) in the presence of titanium isopropoxide and reducing agent in solvent to provide (2S ,3 S )-2-benzhydryl-N -benzylquinuclidin-3 -amine (4) ; b) hydrogenating the compound of formula (4) in presence of hydrogenating agent in a solvent to provide (2S,3S)-2-benzhydrylquinuclidin-3-amine (3) optionally in-situ; c) reductive amination of the compound of formula (3) with 5-tert-butyl-2- methoxybenzaldehyde (2) to provide Maropitant (la); d) converting Maropitant (la) to its pharmaceutically acceptable salt(s) (1); and e) optionally, purifying crude Maropitant (la) and its pharmaceutically acceptable salts (1) to get pure Maropitant (la) and its pharmaceutically acceptable salts (1).

[0020] In another aspect, the present invention provides a process for the preparation of Maropitant (la) and it’s pharmaceutically acceptable salts (1) using an inexpensive hydride reducing agent like sodium borohydride instead of expensive Palladium / carbon catalyst and highly volatile and flammable hydrogen for reduction of imine intermediate.

[0021] In another aspect, the compounds of formula (3) of step b) and Maropitant (la) of step d) can be prepared optionally in-situ and proceeds to next steps without further purification.

[0022] In another aspect, the present invention provides a process for the purification of Maropitant (la) and its pharmaceutically acceptable salts (1), which comprises: i. dissolving Maropitant (la) and its pharmaceutically acceptable salts (1) in a suitable solvent; ii. heating the reaction mixture at a suitable temperature; iii. cooling the reaction mixture to a suitable temperature; and iv. isolating pure Maropitant (la) and its pharmaceutically acceptable salts (1).

[0023] In further aspect, the present invention provides Maropitant (la) and its pharmaceutically acceptable salts (1) obtained after purification is having purity greater than 99.0%, preferably greater than 99.5%, and more preferably greater than 99.9%, as determined by High-Performance Liquid Chromatography (HPLC).

[0024] In another aspect, the present invention provides a process for the preparation of intermediate (S)-2-benzhydrylquinuclidin-3-one (6) as shown in scheme-4, which comprises:

[0025] 1. reacting (Z)-2-benzylidenequinuclidin-3-one (10) with phenyl magnesium chloride in the presence of a catalyst in a solvent to provide 2- benzhydrylquinuclidin-3-one (9);

[0026] 2. reacting 2-benzhydrylquinuclidin-3-one (9) with an optically active 2,3- dihydroxy succinic acid (8) in a solvent to provide (S)-2- benzhydrylquinuclidin-3-one 2,3-dihydroxysuccinate (7);

[0027] 3. converting (S)-2-benzhydrylquinuclidin-3-one 2,3-dihydroxysuccinate (7) to (S)-2-benzhydrylquinuclidin-3-one (6) in the presence of base and a solvent. In another aspect, the present invention provides (S)-2-benzhydrylquinuclidin-3- one (6) with purity at least 95% by HPLC

[0028] BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1: X-Ray powder diffraction pattern (XRPD) of amorphous Form of Maropitant citrate (1).

[0030] DETAILED DESCRIPTION OF THE INVENTION

[0031] The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydro furan, 1,4-dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and water and / or mixtures thereof.

[0032] The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine (DIPEA), di isobutyl amine, trimethylamine, triethylamine, tri isopropyl amine, tributylamine, tert-butyl amine, pyridine, piperidine, 4- dimethylamino pyridine (DMAP) or mixtures thereof.

[0033] As used herein, the term “reducing agent” is selected from but not limited to lithium borohydride, sodium borohydride, potassium borohydride, sodium triacetoxy borohydride (NaBH(OAc)3), and sodium cyanoborohydride (NaBHsCN).

[0034] As used herein, the term :hydrogenating agent: is selected from but not limited to Pd / C, Pd(OH)2 / C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh / C, Ru, sodium borohydride, Na-liquid ammonia, Raney-Ni, Zn- acetic acid, tri(Ci-C6)alkyl silanes, tri(Ci-C6) alkyl silyl halides and the like.

[0035] The term “pharmaceutically acceptable salts” as referred herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2- sulfonic, and other acids, preferably citric acid.

[0036] In another embodiment, Maropitant and its pharmaceutically acceptable salt forms different hydrates viz-a-viz., monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrates, heptahydrate, preferably monohydrate.

[0037] The main embodiment of the present invention provides a process for the preparation of Maropitant, and its pharmaceutically acceptable salts is having purity greater than 99.0% by High-performance liquid chromatography (HPLC) as illustrated in scheme-3:

[0038] In another embodiment, the steps involved in the preparation of Maropitant (la), and its pharmaceutically acceptable salts (1) as shown in scheme-3 are as follows:

[0039] The step a) of the foregoing process involves reacting (S)-2-benzhydrylquinuclidin- 3 -one (6) with benzylamine (5) in the presence of titanium isopropoxide and reducing agent in a solvent, followed by purification in a solvent under appropriate reaction condition to obtain (2S,3S)-2-benzhydryl-N-benzylquinuclidin-3-amine (4). The reducing agent used in step a) is selected from the list as defined above, preferably sodium borohydride. The solvent used in step a) is selected from the list as defined above, preferably tetrahydrofuran. The solvent used for purification in step a) is selected from the list as defined above, preferably methanol. The step a) reaction is carried out at a suitable temperature of about 25 °C to about 35 °C for a sufficient period till completion of the reaction.

[0040] The step b) of the foregoing process involves hydrogenating the compound of formula (4) with hydrogenating agent in a solvent under appropriate reaction conditions to obtain (2S,3S)-2-benzhydrylquinuclidin-3-amine (3) optionally in- situ. The hydrogenating agent used in step b) is selected from the list as defined above, preferably palladium in carbon. The solvent used in step b) is selected from the list as defined above, preferably isopropyl alcohol. The step b) reaction is carried out at a suitable temperature of about 80°C to about 90°C for a sufficient period till completion of the reaction.

[0041] The step c) of the foregoing process involves reacting the compound of formula (3) with 5-tert-butyl-2-methoxybenzaldehyde (2) in a solvent under appropriate reaction conditions to obtain Maropitant (la). The solvent used in step c) is selected from the list as defined above, preferably isopropyl alcohol. The step c) reaction is carried out at a suitable temperature of about 80°C to about 90°C for a sufficient period till completion of the reaction.

[0042] The step d) of the foregoing process involves converting the Maropitant (la) to its pharmaceutically acceptable salts (1) using an acid in a solvent under appropriate reaction conditions. The acid used in step d) is selected from the list as defined above, preferably citric acid solution. The solvent used in step d) is selected from the list as defined above, preferably acetone. The step d) reaction is carried out at a suitable temperature of about 35 °C to about 50°C for a sufficient period till completion of the reaction.

[0043] The step e) of the foregoing process involves optionally purifying crude Maropitant citrate in a solvent under appropriate reaction conditions to obtain pure Maropitant citrate. The solvent used in step e) is selected from the list as defined above, preferably methyl tert-butyl ether. The step e) reaction is carried out at a suitable temperature of about 25 °C to about 35 °C for a sufficient period till completion of the reaction.

[0044] In another aspect, the compounds of formula (4) and Maropitant (la) can be prepared in-situ and proceeds to next steps without further purification. In another embodiment, the present invention provides Maropitant citrate (1) obtained after purification is having water content of less than 10% (w / w) and more preferably less than 4%(w / w), still more preferably less than 3.0% (w / w).

[0045] In another embodiment, Maropitant citrate (1) obtained after purification exists in amorphous form. Preferably Maropitant citrate (1) exists as monohydrate form.

[0046] In another embodiment, the present invention provides amorphous form of Maropitant citrate characterized by an which is characterized by X-ray diffractogram as shown in figure 1.

[0047] In another embodiment, the present invention provides amorphous form of Maropitant citrate monohydrate having purity greater than 99.0%, preferably greater than 99.5%, and more preferably greater than 99.9%, as determined by High-Performance Liquid Chromatography (HPLC).

[0048] In another embodiment, Maropitant citrate (1) produced in the above method is having total impurities less than 1.0% (w / w) by HPLC; preferably less than 0.5 % (w / w) by HPLC; more preferably less than 0.2%.

[0049] In another embodiment, Maropitant citrate (1) produced in the above method has a particle size distribution of D90 less than 200 pm, preferably less than 150 pm and more preferably less than 100 pm.

[0050] In another embodiment, the present invention involves purifying crude Maropitant citrate in a solvent under appropriate reaction conditions to obtain pure Maropitant citrate. The solvent used is selected from the list as defined above, preferably methyl tert-butyl ether. The reaction is carried out at a suitable temperature of about 25°C to about 35°C for a sufficient period till completion of the reaction. In another embodiment, the present invention provides a process for the preparation of (S)-2-benzhydrylquinuclidin-3-one (6) as illustrated in Scheme-4:

[0051] Scheme-4

[0052] In another embodiment, the steps involved in the preparation of (S)-2- benzhydrylquinuclidin-3-one (6) as shown in Scheme-4 are as follows:

[0053] The step 1) of the foregoing process proceeds with reacting compound of formula (10) with phenyl magnesium chloride in the presence of a catalyst in a solvent under suitable conditions to obtain 2-benzhydrylquinuclidin-3-one (9). The catalyst used in step 1) is selected from the list as defined above, preferably copper iodide. The solvent used in step 1) is selected from the list as defined above, preferably ethyl acetate. The step 1) reaction is carried out at a suitable temperature of about 80°C to about 85°C for a sufficient period till completion of the reaction.

[0054] The step 2) of the foregoing process proceeds with resolution of compound of formula (9) with an acid in a solvent under appropriate reaction conditions to obtain (S)-2-benzhydrylquinuclidin-3-one 2,3-dihydroxysuccinate (7). The acid used in step 2) is selected from the list as defined above, preferably L (+)-Tartaric acid. The solvent used in step 2) is selected from the list as defined above, preferably ethanol. The step 2) reaction is carried out at temperature of about 80°C to about 90°C for a sufficient period till completion of the reaction.

[0055] The step 3) of the foregoing process proceeds with reacting compound of formula (7) in the presence of base in a solvent to obtain (S)-2-benzhydrylquinuclidin-3-one (6). The base used in step 3) is selected from the list as defined above, preferably sodium bicarbonate. The solvent used in step 3) is selected from the list as defined above, preferably Toluene. The step 3) reaction is carried out at temperature of about 20°C to about 30°C for a sufficient period till completion of the reaction.

[0056] Resolution of quiniclidine (9) with optically active dicarboxylic acid, preferably with L-tartaric acid provided desired isomer (6) with greater than 99% ee. When D- tartartic acid was used enantiomer of (6) was obtained with greater than 99% ee.

[0057] In another embodiment, the present invention provides a process for the preparation of (Z) -2 -benzylidene quinuclidin-3-one (10) as illustrated in Scheme-5:

[0058] Scheme-5

[0059] In an embodiment, the present invention proceeds with condensing Quinuclidinone hydrochloride (12) with benzaldehyde (11) in the presence of base in a solvent to obtain (Z)-2-benzylidene quinuclidin-3-one (10). The base is selected from the list as defined above, preferably sodium hydroxide. The solvent is selected from the list as defined above, preferably methanol. The reaction temperature is carried out at a suitable temperature of about 50°C to about 55°C for a sufficient period till completion of the reaction.

[0060] The following examples further illustrate the present invention but should not be construed in any way as to limit its scope. EXAMPLES

[0061] Example 1: Preparation of ((2S,3S)-2-Benzhydryl-n-benzyl quinuclidin-3- amine (4)

[0062] 100 g of ((S)-2-benzhydryl quinuclidine-3-one (6) was dissolved in 8 Volumes of Tetrahydrofuran at 25-30°C. To this reaction mass 20 g of 4 A0molecular sieves were added and stirred. 55 g of benzyl amine was added to the reaction mass at 25- 30°C. The reaction mass was cooled to 0-5°C, then, 195 g of Titanium isopropoxide in 200 ml of Tetrahydrofuran was added and stirred for 10-15 minutes. The reaction mass temperature was raised to 25-30°C and stirred for 5-6 hours. The reaction mass was cooled to 0-5°C. 300 ml of ethanol was added and stirred. 19 g of Sodium borohydride was added to the reaction mass at lot wise and stirred for 10-12 hrs at 25-30°C. After completion of the reaction, the reaction mass was cooled to 0-5°C, then 500 mL of water was slowly added. The reaction mass temperature was raised to 25-30°C and stirred. Distilled off the solvent completely under vacuum at below 50°C. 500 ml of Toluene was added to the reaction mass and stirred. 10 g of Hy- flow was added to the reaction mass and stirred. Both the layers were separated. The organic layer was distilled off under vacuum at below 60°C. 100 ml of methanol was added and distilled off under vacuum. 1200 ml of methanol was added to the crude at 25-30°C. The reaction mass temperature was raised to 65±5°C and stirred for 1 hr. The reaction mass was cooled to 25-30°C and washed with methanol. The obtained material was dried under vacuum to get the title compound. Yield: 35 g. Purity by HPLC, not less than 99% and Diastereomer impurity not less than 1%) Chiral HPLC purity, not less than 99%, R isomer not less than 0.5%.

[0063] Example 2: Preparation of (2S,3S)-2-benzhydryl-n-(5-(tert-butyl)-2- methoxybenzyl) quinuclidin-3-amine (la)

[0064] 60 g of ((2S,3S)-2-Benzhydryl-n-benzyl quinuclidin-3-amine (4) was dissolved in 1200 ml of isopropyl alcohol at room temperature. To this 12 g of 5% Pd / C was added and stirred. The reaction mass temperature was raised to 85±5°C and stirred under hydrogen pressure for 10-12 hours. After completion of the reaction, the reaction mass was cooled to 25-30 °C, then 35 g of 5-(tert-butyl)-2- methoxybenzaldehyde (2) & 30 ml of isopropyl alcohol were added and stirred. The reaction mass temperature was raised to 85±5°C and stirred under hydrogen pressure for 6-7 hours. After completion of reaction, the reaction mass was cooled to room temperature. 600 ml of Dichloromethane was added to the reaction mass and stirred. Filtered the slurry mass and washed with dichloromethane. The reaction mass was quenched with 4N hydrochloric acid and separated organic and aqueous layers. The organic layer was distilled off under vacuum and 240 ml of isopropyl alcohol was added to the crude and heated for 1-2 hrs at 80-85°C. The reaction mixture was cooled to 10-15°C and filtered the solid under vacuum. The obtained solid was dried under vacuum to get the title compound. Yield: 82%

[0065] Example 3: Preparation of (2S,3S)-2-benzhydryl-N-(5-(tert-butyl)-2- methoxybenzyl) quinuclidin-3-amine 2-hydroxypropane-l,2,3-tricarboxylate hydrate (1)

[0066] 75 g of (2S,3S)-2-benzhydryl-n-(5-(tert-butyl)-2-methoxybenzyl) quinuclidin-3- amine (la) was dissolved in 600 ml acetone at room temperature and stirred. 34 g of citric acid was added to the reaction mixture at 25-30°C. The reaction mixture was heated for 1 hr at 40-45°C, then cooled to 30+5°. 750 ml of methyl tert-butyl ether was slowly added to the reaction mixture at 30-35°C. The reaction mass was cooled to 25±5°C and stirred for 20-24 hrs. Filter the solid and dry under vacuum to get the title compound. Yield: 86.5%. (IPC-01: Purity by HPLC, FP not less than 99.5% and Total impurities not less than 0.5%) (IPC-02: Chiral HPLC purity, FP not less than 99.9%, R isomer not less than 0.15%).

[0067] Example 4: Preparation of 2-benzhydrylquinuclidin-3-one (9)

[0068] A mixture of phenyl magnesium chloride (2000 mL) and tetrahydrofuran (1060 mL) was taken in flask and cooled to 0-5°C. Copper iodide (I) (94.7 g) was added to the reaction mass at 0-5°C. (Z)-2-benzylidenequinuclidin-3-one (10) (212.0 g) was added to the reaction mixture for 2-3 hrs. The reaction mixture was stirred for 1-2 hrs at 0-5°C. after completion of reaction, the reaction mass was quenched with ammonium chloride solution and raised temperature to 25-30°C. The reaction mixture was filtered and washed with 420 ml of ethyl acetate. Organic and aqueous layers were separated and extracted aqueous layer with ethyl acetate. The total organic layer was washed with water and sodium chloride solutions. The obtained organic layer was distilled off under vacuum and isopropyl alcohol was added to the crude (9) and distilled off under vacuum at below 50°C. 1000 ml of Isopropyl alcohol was added to the crude and heated for 1-2 hrs at 80-85°C. The reaction mixture was cooled to 10-15°C. The solid was filtered and washed with 100 ml of Isopropyl alcohol. Dry the solid under vacuum at below 70°C to get the title compound. Yield: 80%

[0069] Example 5: Preparation of (S)-2-benzhydrylquinuclidin-3-one 2,3- dihydroxysuccinate (7)

[0070] 220 g of 2-benzhydrylquinuclidin-3-one (9) was added to 1900 ml of ethanol and stirred for 5-10 minutes at 25-30°C. 113 g of L (+)-Tartaric acid was added to the reaction mixture. 110 ml of methanol, 44 ml of acetic acid and 110 ml of Isopropyl alcohol were added to the reaction mixture. The reaction mixture was stirred for 5- 10 hrs at 25-30°C. The reaction temperature was raised to 80-85°C and stirred for 12 hrs. After completion of the reaction, the reaction mass was stirred for 2-3 hrs at 25-30°C. The obtained reaction mass filtered and washed with ethanol. The obtained solid was dried under vacuum at below 75°C to get the title compound. Yield: 87%

[0071] Example 6: Preparation of (S)-2-benzhydrylquinuclidin-3-one (6)

[0072] 4000 ml of Toluene and 400 g of (S)-2-benzhydrylquinuclidin-3-one 2,3- dihydroxy succinate (7) (400 g) into RB flask. The reaction mixture was cooled to 5-10°C. The pH of the reaction mixture was adjusted with aqueous sodium bicarbonate solution to 8.0 and 8.5. The reaction mixture was stirred for 15-20 minutes at 20-25°C and layers separated. The organic layer was washed with 800 ml of water and distilled off the solvent to 2 volumes. To the reaction crude, 2.4 litres of hexane was added and stirred for 2-3 hrs at 25+5 °C Filter the slurry mass and suck dried under vacuum. The obtained solid was dried under vacuum to get the title compound. Yield: 95%. Purity: > 99%(w / w); %, R isomer content less than 0.15%). Example 7: Preparation of (Z)-2-Benzylidenequinuclidin-3- One (10)

[0073] 150 g of quinuclidinone hydrochloride (12) was added to 450 ml of methanol. The reaction mixture was cooled to 10-15°C, and 50% aqueous solution of sodium hydroxide was added the reaction mixture.109 g of benzaldehyde in 90 ml of methanol solution was added to the reaction mixture at 10-15°C. The reaction mass was stirred for 10-15 minutes at 10-15°C. Further the reaction mass was stirred for 2-3 hrs at 50-55°C.After completion of reaction, 300 ml of water was added to the reaction mass at 50-55°C. The reaction mixture was cooled to 20-25°C and filtered the solid under vacuum. The obtained solid was washed with mixture of methanol and water. The obtained solid was dried under vacuum to get the title compound.

[0074] Yield: 98.5%

Claims

We claim:

1. A process for the preparation of Maropitant citrate of formula (1),wherein the process comprising the following steps: a) reducing (S)-2-benzhydrylquinuclidin-3-one of formula (6) with benzylamine of formula (5)in the presence of Titanium isopropoxide and reducing agent to obtain (2S,3S)-2-benzhydryl-N-benzylquinuclidin-3-amine of formula (4);b) hydrogenating the compound of formula (4) with suitable hydrogenating agent to obtain (2S,3S)-2-benzhydrylquinuclidin-3-amine of formula (3)c) reacting the compound of formula (3) with 5-tert-butyl-2-methoxy benzaldehyde of formula (2)to obtain Maropitant of formula (la); andd) reacting Maropitant of formula (la) with citric acid solution to obtain crude Maropitant citrate of formula (1). e) purifying crude Maropitant citrate of formula (1) to obtain Maropitant citrate of formula (1).

2. The process as claimed in claim 1, wherein the reducing agent used in step a) is selected from lithium aluminium hydride (LiAlEU), sodium aluminium hydride (NaAlEU), potassium borohydride (KBH4), sodium triacetoxy borohydride (NaBH(OAc)s), sodium cyanoborohydride (NaBHsCN) and sodium borohydride (NaBtB).

3. The process as claimed in claim 1, wherein the hydrogenating agent used in step b) is selected from, Pd / C, Pd(OH)2 / C (Pearlman’s catalyst), palladium acetate, platinum oxide, platinum black, Rh / C, Ru, sodium borohydride, Na-liquid ammonia, Raney-Ni, Zn-acetic acid, tri(Ci-C6)alkylsilanes, tri(Ci-C6) alkylsilyl halides and the like.

4. The process as claimed in claim 1, wherein the reaction in each step is carried out in a solvent selected from alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, 1,4-di oxane and the like; “chloro solvents” such as dichloromethane, ethylenedichloride, carbon tetrachloride, chloroform and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; and water and / or mixtures thereof.

5. A process for purification of Maropitant citrate of formula (1) with purity greater than 99%, which comprises the steps of: i. dissolving Maropitant citrate of formula (1) in suitable solvent; and ii. heating the reaction mixture at a suitable temperature; iii. cooling the reaction mixture to a suitable temperature; and iv. isolating Maropitant citrate monohydrate of formula (1).

6. The process as claimed in claim 5, wherein the solvent used in step (i) is selected from alcoholic solvents such as alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, 1,4-dioxane and the like and / or mixture thereof.

7. The process as claimed in claim 5, wherein Maropitant citrate of formula (1) obtained is in amorphous form and contains less than 3.0% (w / w) of moisture content.

8. The process as claimed in claim 1, wherein (S)-2-benzhydrylquinuclidin-3-one of formula (6) is prepared by a process comprising the following steps: a) reacting (Z)-2-benzylidenequinuclidin-3-one of formula (10)with phenyl magnesium chloride and copper iodide to obtain a compound of 2-benzhydrylquinuclidin-3-one of formula (9);b) reacting the compound of formula (9) with 2,3-dihydroxysuccinic acid in the presence of acetic acid to obtain (S)-2-benzhydrylquinuclidin-3-one 2,3- dihydroxy succinate of formula (7); andc) reacting the compound of formula (7) with a base to obtain (S)-2- benzhydrylquinuclidin-3-one of formula (6).

8. The process as claimed in claim 7, wherein the base is selected from “alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like.

9. The process as claimed in claim 7, wherein the solvent is selected from alcoholic solvents such as alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, 1,4-dioxane and the like and / or mixture thereof.

10. The process as claimed in claim 7, wherein (Z)-2-benzylidene quinuclidin-3- one (10), is prepared by reacting to a compound of Quinuclidinone hydrochloride of formula (12)with benzaldehyde of formula (11)

Images