DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]

A PROCESS FOR PREPARATION OF DEXMEDETOMIDINE HYDROCHLORIDE

PIRAMAL PHARMA LIMITED, a company incorporated under the Companies Act, 2013, of Ground Floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai 400070, State of Maharashtra, India

The following specification particularly describes the nature of this invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of dexmedetomidine hydrochloride of formula-1a.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

Dexmedetomidine is the (S)-enantiomer of medetomidine. It is sold under the trade name Precedex, is an anxiolytic, sedative, and pain medication.

Dexmedetomidine was first reported in US4910214. The patent discloses the preparation of dexmedetomidine by resolution of medetomidine using (+)-tartaric acid in presence of methanol. It is also disclosed in the patent that resolution can also be carried out using (-)-malic acid, (-)-mandelic acid or (+)-camphor-10-sulphonic acid. However, the patent does not disclose the yield and enantiomeric purity of dexmedetomidine.

Synthetic communication 26(8), 1585-1593 (1996) describes the preparation of dexmedetomidine where resolution of medetomidine was carried out by using (+)-tartaric acid in absolute ethanol. The suspension was heated to reflux until complete dissolution and stirred for 20 hours at room temperature before filtration of white solid. The solid was suspended by stirring for 18 hours in ethanol and filtered. The new solid was suspended by stirring for 66 hours in ethanol and filtered. The solid was dissolved in water and the solution was neutralized with 1N NaOH. The solution was extracted with ether, dried and evaporated under pressure. The residue was dissolved in hot ethanol and treated with (+) - tartaric acid and the resulting solution was stirred at room temperature overnight. The solid was filtered to get dexmedetomidine (+)-tartrate in greater than 99% enantiomeric excess and 21% overall. As the process requires 5 days to provide dexmedetomidine in very low overall yield it is industrially uneconomical. The process disclosed in Synthetic communication 26(8), 1585-1593 (1996) is represented in scheme-1.

Hence, there remains a need for providing efficient, safe, industrially feasible and economically viable process for manufacture of dexmedetomidine. Therefore, the inventors of the present invention have developed a process to manufacture dexmedetomidine.

SUMMARY OF THE INVENTION
The problem addressed by the present invention is that of providing a better improved, efficient, economic and an industrially viable process for preparation of dexmedetomidine hydrochloride of formula-1a.
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for describing the particular embodiments only, and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials described within but similar, equivalent to those described herein can be used in the practice, or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further, the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
Accordingly, the present invention relates to an improved process for the preparation of compound of dexmedetomidine hydrochloride of formula-1a,

comprising;
(a) reacting 1-trityl-1H-imidazole-4-carbaldehyde of formula-2 with Grignard reagent of compound of formula-3 which is formed in-situ in a solvent or mixture of solvents to give a compound of formula-4,

(b) oxidizing the compound of formula-4 with an oxidizing agent in presence of a catalyst and a base in a solvent to provide a compound of formula-5.

(c) reacting the compound of formula-5 with a Grignard reagent in a solvent, which on further treatment with an acid gives a compound of formula-6;

(d) reducing the compound of formula-6 to give a compound of formula-7, and optionally isolating the compound of formula-7;

(e) resolution of the compound of formula-7 with a chiral acid in a solvent or mixture of solvents to provide a corresponding chiral acid addition salt of a compound of formula-8, and optionally isolating compound of formula-8;

(f) treating the salt compound of formula-8 with a base followed by treatment with hydrochloric acid in a solvent to provide a dexmedetomidine hydrochloride compound of formula-1a.

According to another embodiment of the present invention, the process of step (d) can be carried out without isolating the intermediate compound 6 of step (c).
According to another embodiment of the present invention, the process of step (f) can be carried out without isolating the intermediate compound 8 of step (e).
The solvent used in steps (a) to step (f) is selected from an ether solvent selected from tetrahydrofuran (THF), cyclopentyl methyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane (DCM), 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ester solvent selected from ethyl acetate, methyl acetate and isopropyl acetate; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; demineralized water (DM); or a mixture thereof.
The oxidant used in step (b) is selected from the group consisting of sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium chlorite, hydrogen peroxide, tert-butyl hydroperoxide, trichloroisocyanuric acid, peracetic acid, performic acid, trichloroperacetic acid and trifluoroperacetic acid.
The catalyst used in step (b) is TEMPO based catalyst selected from the group consisting of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-acetoxy-TEMPO, 4-acetamino-TEMPO, 4-hydroxy-TEMPO, 4-benzoyloxy-TEMPO, 4-amino-TEMPO, N,N-dimethylamino-TEMPO, 4-oxo-TEMPO, poly [(6-[1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl], [(2,2,6,6-tetramyetho-4-Piperidyl)imino] hexamethylene[)2,2,6,6-tetramethyl-4-piperidnyl)imino]] or a combination thereof.
The base used in step (b) and step (f) is selected from triethylamine, trimethylamine, dimethyl amine, tert-butyl amine, ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert- butoxide.
The Grignard reagent used in step (c) is selected from methyl magnesium chloride or methyl magnesium bromide, preferably methyl magnesium chloride.
The acid catalyst used in step (c) is selected from sulfuric acid, hydrochloric acid (HCl), thionyl chloride, methane sulfonic acid and paratoluene sulfonic acid.
The reduction of compound of formula-6 in step (d) is carried out using reducing agent selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4, LiAlH4. The reduction of the compound can be carried out using reducing agent and suitably, in the presence of Lewis acid selected from AlCl3, LiCl, or BF3 etherate; or hydrogen gas or a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate. Preferably, the reducing agent is Pd/C and hydrogen gas.
The chiral acid for resolution used in step (e) is selected from S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-(-)malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)- (+)-camphor sulfonic acid (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)- bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaric acid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara-tolyl-L-tataricacid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine and D-lysine. Preferably, chiral acid for resolution used is L-(-)malic acid.

The complete synthetic scheme of preparation of dexmedetomidine hydrochloride of formula-1a according to the present invention can be represented as below:

According to another specific aspect of the present invention relates to an improved process for the preparation of dexmedetomidine hydrochloride of formula-1a,

comprising;
(a) reacting 1-trityl-1H-imidazole-4-carbaldehyde of formula-2 with Grignard reagent of compound of formula-3 which is formed in-situ in a mixture of dichloromethane (DCM) and Tetrahydrofuran (THF) to give the compound of formula-4,

(b) oxidizing the compound of formula-4 with sodium hypochlorite in presence of TEMPO and sodium bicarbonate in DCM to provide the compound of formula-5.

(c) reacting the compound of formula-5 with Methyl magnesium chloride solution in DCM which is on further treatment with concentrated HCl to give the compound of formula-6;

(d) reducing the compound of formula-6 by using Pd/C and a hydrogen gas to give the compound of formula-7, and optionally isolating the compound of formula-7;

(e) resolution of the compound of formula-7 with L-(-)malic acid in the mixture of acetone and ethanol to provide medetomidine malic acid salt of compound of formula-8, and optionally isolating compound of formula-8;

(f) treating medetomidine malic acid salt of compound of formula-8 with aqueous sodium hydroxide in DCM followed by treatment with hydrochloric acid in ethyl acetate to provide a dexmedetomidine hydrochloride compound of formula-1a.

According to another embodiment of the present invention, the process of step (d) can be carried out without isolating the intermediate compound 6 of step (c).
According to another embodiment of the present invention, the process of step (f) can be carried out without isolating the intermediate compound 8 of step (e).

The term “about,” as used herein, is intended to qualify the numerical values, which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

According to the invention, the overall yield of compound of formula-1a as obtained by using the process of the present invention is with purity of at least about 99.83% by HPLC.

Thus, the present invention offers below advantages over previous methods reported in the literature include:
(i) in spite of using two moisture-sensitive Grignard reagents the process offers a quite good overall yield;
(ii) use of low volume of THF in Grignard reaction which is a costly solvent by employing mixture solvents thereby increasing the economic viability of the process with desired yield;
(iii) use of cheaper reagent like conc. HCl and methyl magnesium chloride (MeMgCl) instead of trimethyl silane [(CH3)3SiH], trifluoroacetic acid (CF3CO2H) and methyl magnesium bromide (MeMgBr);
(iv) improvement of the yield by using L-(-)malic acid instead of L-(+)tartaric acid;
(v) use of oxidant viz. sodium hypochlorite instead of MnO2 helps to reduce effluent load.
(vi) use of Ethyl acetate HCl for preparing dexmedetomidine hydrochloride which does not require to distill out other solvent or stripping, which helps in reducing the effluent load of solvent.

Thereby, the practicability of the reaction is greatly enhanced at both the laboratory scale and the industrial scale. The present invention results into yield of at least about 49% with purity of at least 99.8 % by HPLC, thereby, making the process ef?cient, economic and industrially viable.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1
Synthesis of (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanol (4)
(Batch size-700 gm of compound of formula-2)
In a dry reactor, Magnesium turnings (1.83 eq), THF (0.5 Vol) and iodine (0.025%w/w) were charged and slowly 1-Bromo-2, 3-dimethyl benzene of formula-3 (1.83 eq.) and THF (2.0 Vol) were added and temperature was maintained at 50-70°C for 60 min. After completion of reaction, reaction mixture was cooled to 20-25°C and a solution of compound of formula-2 (1.0 eq) in DCM (4.0 Vol) was added and temperature was maintained at 25-35°C for 1hr. Reaction mass was cooled to 0-5°C and slowly DCM (2.0 Vol), DM water (3.0 Vol) and Conc HCl (1.1 Vol) were added, maintained for 15 min and upper organic layer was separated. Aqueous layer was extracted with DCM (1.0 Vol) and both DCM layers were combined and washed with water (2.0 Vol). In DCM layer, a solution of sodium hydroxide (1.3 eq) in DM water (1.1 Vol) was charged at 20-30 °C and pH NLT 9.0 was adjusted. Solvent was distilled out under reduced pressure up to 2.5 to 3.5 w/v below 35 °C temperature. After complete distillation, sidewall was flushed with DCM (0.3 Vol), cooled and maintained for 1-2 hr at 10-15°C. This was filtered and washed with DM water (3.0 Vol) followed by chilled THF (1.0 Vol) and DM water (1.0 Vol). The wet solid was dried under vacuum for 8-10 hr at 50-55°C to obtain (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanol of formula-4 with desired yield and quality.
Result:
Theoretical Yield (w/w) : 1.31
Practical Yield : 775 g out of 700 gm
Yield (%) : 84.5
Yield (w/w) : 1.107
HPLC purity : 99.64%

Example 2
Synthesis of (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanone (5)
[Batch size-300 gm of (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanol of formula- 4]
In a reactor, (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanol of formula-4 (1.0 eq) and DCM (5.0 Vol), TEMPO (0.5% w/w) and solution of potassium bromide (2.5%w/w) in DM water (0.1 Vol) at 25-35°C were charged and cooled to 5-10°C. Solution of sodium hypochlorite (1.5 eq), sodium bicarbonate (2.11 eq) in DM water (5.0 Vol) at 10-15 °C was prepared. Above solution was added into reaction mass at 5-15 °C and maintained for 1 hr. The reaction mixture was extracted with DCM (1.0 Vol) twice and the organic layer and aqueous layer were separated. Both organic layers were combined and washed with sodium chloride solution (2.0 Vol). DCM was recovered under reduced pressure below 30°C. MTBE (3.0 Vol) was charged, cooled and maintained for 1 hr. The reaction mixture was filtered and washed with MTBE (1.5 Vol). Wet solid obtained was dried under vacuum for 8-10 hr at 50-55°C to obtain (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanone of formula-5 with desired yield and quality.
Result:
Theoretical Yield (w/w) : 1.00
Practical Yield : 265 g out of 300 gm
Yield (%) : 88.3 %
Yield (w/w) : 0.88
HPLC purity : 99.01%

Example 3
Synthesis of 4-(1-(2,3-dimethylphenyl)vinyl)-1H-imidazole (6)
[Batch size-250 gm of (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanone of formula- 5]
In a reactor, a solution of (2,3-dimethylphenyl)(1-trityl-1H-imidazol-4-yl)methanone of formula- 5 (1.0 eq) and DCM (3.0 vol) was added into Methyl magnesium chloride solution (1.8 eq) at 25-35°C temperature and maintained for 1 hr. After completion of reaction, the reaction mixture was cooled to 10-15°C and slowly solution of DM water (3.0 Vol) and conc HCl (0.7 Vol) was added. Temperature was raised at 20-30°C and lower organic layer was separated. Aqueous layer was extracted with DCM (1.0 Vol). Both DCM layers were combined and solvent was recovered under reduced pressure below 40°C up to remaining volume ~2.5 vol. DM water was charged (3.0 Vol) and the reaction mass was heated at 70-80°C with continuous solvent recovery by simple distillation. Conc HCl was charged (2.0Vol), heated at 95-100 ° C and maintained for 3 hr. The reaction mixture was cooled to 25-30 °C, filtered, washed with DM water (2.0 Vol) and solid byproduct removed. A solution of Sodium hydroxide (10.56 eq) and DM water (1.5 Vol) was charged into the filtrate at 10-30 °C and maintained for 3-4 hr at 25-35°C. The reaction mixture was filtered and washed with DM water (2.0 Vol), followed by Toluene (1.5 Vol) and DM water (2.0 Vol). Wet solid obtained was dried under vacuum for 8-10 hr at 50-55°C to provide 4-(1-(2,3-dimethylphenyl)vinyl)-1H-imidazole of formula-6 with desired yield and quality.
Result:
Theoretical Yield (w/w) : 0.45
Practical Yield : 96.5 g out of 250 gm
Yield (%) : 86.16
Yield (w/w) : 0.386
HPLC purity : 99.25%

Example 4
Synthesis of Dexmedetomidine hydrochloride of formula-1a
(Batch size-90 gm of 4-(1-(2,3-dimethylphenyl)vinyl)-1H-imidazole of formula-6)
In a pressure reactor, 4-(1-(2,3-dimethylphenyl)vinyl)-1H-imidazole of formula-6 (1.0 eq), Methanol (5.0 Vol) and Palladium on carbon 5% wet (3% w/w) at 25-30°C were charged. Air from reaction was removed by using nitrogen gas and 2-3 kg hydrogen gas pressure at 25-30°C was applied, heated at 40-45°C and maintained for 3-5 hr. After completion of reaction, the reaction mixture was cooled to 25-30°C. Palladium on carbon was removed by filtration and washed with Methanol (2.0 Vol). The filtrate was subjected to carbon treatment (7.5% w/w) at 25-30°C and washed with Methanol (1.0 Vol). Solvent was recovered under reduced pressure below 40°C and stripped with Acetone (2.0 Vol). Acetone (5.5 Vol), Ethanol (0.35 Vol) and L(-) Malic acid (1.0 eq) was charged into reaction mass at 25-30°C and heated at 50-60°C, which was cooled to 25-30°C and maintained for 1-2 hr. The obtained solid was filtered and washed with Acetone (1.0 Vol) to obtain (~100 gm) of wet cake, which was purified with Ethanol (2.5 Vol). The obtained solid was heated at 50-60° C, cooled to 25-30° C, filtered and washed with ethanol (1.0 Vol). The obtained (~90 gm) wet cake was purified in Ethanol (2.5 Vol), heated at 50-60 °C, cooled to 25-30 ° C, filtered and washed with ethanol (1.0 Vol). The obtained (~85 gm) wet cake was again purified in Ethanol (2.5 Vol), heated at 50-60 °C, cooled to 25-30 ° C, filtered and washed with ethanol (1.0 Vol). The obtained (~80 gm) wet cake was again purified in Ethanol (2.5 Vol), heated at 50-60 ° C, cooled to 25-30 ° C, filtered and washed with ethanol (1.0 Vol). DCM (3.0 Vol) and wet cake was charged into a solution of DM water (3.0 Vol) and sodium hydroxide (1.5 eq) at 25-30°C. The obtained solution was stirred and lower organic layer was separated. Aqueous layer was extracted with DCM (1.0 Vol). Both DCM layers were combined and washed with DM water (1.0 Vol). The solution obtained was treated with activated carbon (7.5% w/w) at 25-30°C for 1 hr. Carbon was removed by filtration and washed with DCM (1.0 Vol). The solvent was distilled out under vacuum and stripped with Ethyl acetate (1.0 Vol) below 45°C. Ethyl acetate (2.0 Vol) and Ethyl acetate HCl Sol (1.38 W/W) was charged into obtained residue, which was cooled to 25-30°C and maintained for 1-2 hr. The wet solid was dried under vacuum for 8-10 hr at 50-55°C to obtain dexmedetomidine hydrochloride of formula-1a with desired yield and quality.
Result:
Theoretical Yield (w/w) : 0.597
Practical Yield : 26.5 g out of 90 g
Yield (%) : 49.3
Yield (w/w) : 0.294
HPLC purity : 99.83%
Chiral purity : 99.62%
,CLAIMS:We claim:
1. A process for preparation of dexmedetomidine hydrochloride of formula-1a,

Comprising the steps of;
(g) reacting 1-trityl-1H-imidazole-4-carbaldehyde of formula-2 with Grignard reagent of compound of formula-3 which is formed in-situ in a solvent or mixture of solvents to give a compound of formula-4,

(h) oxidizing the compound of formula-4 with an oxidizing agent in presence of a catalyst and a base in a solvent to provide a compound of formula-5.

(i) reacting the compound of formula-5 with a Grignard reagent in a solvent, which on further treatment with an acid gives a compound of formula-6;

(j) reducing the compound of formula-6 to give a compound of formula-7, and optionally isolating the compound of formula-7;

(k) resolving the compound of formula-7 with a chiral acid in a solvent or mixture of solvents to provide a corresponding chiral acid addition salt of a compound of formula-8, and optionally isolating compound of formula-8;

(l) treating the salt compound of formula-8 with a base followed by treatment with hydrochloric acid in a solvent to provide a dexmedetomidine hydrochloride compound of formula-1a.

wherein -
the process of step (d) can be carried out without isolating the intermediate compound 6 of step (c);
the process of step (f) can be carried out without isolating the intermediate compound 8 of step (e).
2. The process as claimed in claim 1, wherein the solvent in step (a), step (b), step (c), step (e) and step (f) is an ether solvent selected from tetrahydrofuran (THF), cyclopentyl methyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol (IPA), t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane (DCM), 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected from acetone or methyl isobutyl ketone (MIBK); an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; demineralized water (DM); or a mixture thereof.

3. The process as claimed in claim 1, wherein the oxidant used in step (b) is selected from the group consisting of sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium chlorite, hydrogen peroxide, tert-butyl hydroperoxide, trichloroisocyanuric acid, peracetic acid, performic acid, trichloroperacetic acid and trifluoroperacetic acid.

4. The process as claimed in claim 1, wherein the catalyst used in step (b) is a TEMPO based catalyst selected from the group consisting of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 4-methoxy-TEMPO, 4-ethoxy-TEMPO, 4-acetoxy-TEMPO, 4-acetamino-TEMPO, 4-hydroxy-TEMPO, 4-benzoyloxy-TEMPO, 4-amino-TEMPO, N,N-dimethylamino-TEMPO, 4-oxo-TEMPO; or a combination thereof.

5. The process as claimed in claim 1, wherein the base used in step (b) and step (f) is selected from the group consisting of triethylamine, trimethylamine, dimethyl amine, tert-butyl amine, ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert- butoxide.

6. The process as claimed in claim 1, wherein the Grignard reagent used in step (c) is selected from methyl magnesium chloride or methyl magnesium bromide, preferably methyl magnesium chloride.

7. The process as claimed in claim 1, wherein the acid catalyst used in step (c) is selected from the group consisting of sulfuric acid, hydrochloric acid (HCl), thionyl chloride, methane sulfonic acid and para toluene sulfonic acid.

8. The process as claimed in claim 1, wherein the reducing agent used in step (d) is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol/trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4, LiAlH4; or hydrogen gas or a hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid or hydrazinium monoformate.

9. The process as claimed in claim 1, wherein the chiral acid used for resolving compound of formula-7 in step (e) is selected from the group consisting of S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-(-)malic acid, D-malic acid, D-maleic acid, (-)-naproxen, (+)-naproxen, (1R)-(-)-camphor sulfonic acid, (1S)- (+)-camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)- bromocamphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L- tartaric acid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D-tartaric acid, (-)-dipara-tolyl-L-tataricacid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine and D-lysine.

10. A process for the preparation of dexmedetomidine hydrochloride of formula-1a, having a purity of about 99.8% or more by area percentage of HPLC, comprising the steps of:

(g) reacting 1-trityl-1H-imidazole-4-carbaldehyde of formula-2 with Grignard reagent of compound of formula-3 which is formed in-situ in a mixture of dichloromethane (DCM) and Tetrahydrofuran (THF) to give the compound of formula-4,

(h) oxidizing the compound of formula-4 with sodium hypochlorite in presence of TEMPO and sodium bicarbonate in DCM to provide the compound of formula-5.

(i) reacting the compound of formula-5 with Methyl magnesium chloride solution in DCM, which on further treatment with concentrated HCl to give the compound of formula-6;

(j) reducing the compound of formula-6 by using Pd/C and a hydrogen gas to give the compound of formula-7, and optionally isolating the compound of formula-7;

(k) resolving the compound of formula-7 with L-(-)malic acid in the mixture of acetone and ethanol to provide medetomidine malic acid salt of compound of formula-8, and optionally isolating compound of formula-8;

(l) treating medetomidine malic acid salt of compound of formula-8 with aqueous sodium hydroxide in DCM followed by treatment with hydrochloric acid in ethyl acetate to provide a dexmedetomidine hydrochloride compound of formula-1a.

wherein -
the process of step (d) can be carried out without isolating the intermediate compound 6 of step (c);
the process of step (f) can be carried out without isolating the intermediate compound 8 of step (e).