Description:FIELD OF THE INVENTION:
The present invention relates to deuterated S (-) metoprolol succinate compounds of formulae 1, 2 and 3, a process for its preparation.

BACKGROUND OF THE INVENTION:
Deuteration, the process of substituting hydrogen atoms with deuterium, presents a promising avenue for enhancing the metabolic profile of pharmaceutical compounds while preserving their biological potency and efficacy.
Deuterium, a stable and nonradioactive isotope of hydrogen, possesses a unique property owing to its increased mass, which strengthens the bond between carbon and deuterium compared to that of hydrogen and carbon. This alteration slows down cytochrome P450 mediated metabolism, resulting in reduced metabolic reaction rates. Consequently, deuterated molecules exhibit improved ADME (absorption, distribution, metabolism, and excretion) properties, leading to enhanced potency, efficacy, safety, and tolerability.
Importantly, the replacement of hydrogen with deuterium does not significantly alter other physical characteristics, ensuring minimal biological impact on the molecule. Thus, deuteration has emerged as an ever-greening strategy in pharmaceutical development for optimizing drug performance without compromising safety or efficacy.

Carbon-Hydrogen bond breaking is the rate-determining step in the biotransformation of a drug, the deuterated drug is likely to show improved pharmacokinetic characteristics, such as longer half-life, which considerably reduces the frequency of dosing. If a toxic metabolite or reactive intermediate is formed when the Carbon-Hydrogen bond is broken, then deuteration of the drug may delay or reduce the unwanted side effects of the drugs.
Recently, several deuterated drugs like deuterium enriched analogue of lenalidomide (Revlimid) have advanced to the clinical trial stage while deuterated tetrabenazine has received FDA approval via the 505(b)(2) pathway. Other deuterated forms of drugs like d6-dextrometorphane, ruxolitinib, venlafaxine and its desmethyl derivative, pioglitazone, apremilast and ivacaftor are in various stages of clinical trials.
There are several examples of drug candidates where deuterium substitution of hydrogen has led to an enhanced metabolic rate and/or metabolic switching or no in vivo change of the molecule’s profile even after reduction in metabolic rate. A recent report has disclosed that selective deuteration of paroxetine at predicted metabolically labile positions produced analogues which demonstrated increased metabolism in vivo (Scott L. Harbeson and Roger D. Tung, Deuterium in Drug Discovery, and Development, Annual Reports in Medicinal Chemistry, 403–417 (2011)). Further, Miwa reports that deuteration of metabolically labile sites may lead to the potentiation (or switching) of alternative metabolic pathways, with undetermined consequences (Miwa, G., Lu, A., Kinetic Isotope Effects and ‘Metabolic Switching’ in Cytochrome P450-Catalyzed Reactions, Bioessays, 215–19 (1987)). Similarly, deuteration of metabolically active sites of tramadol did not lead to any increase in duration of effect (Shao et. al., “Derivatives of Tramadol for Increased Duration of Effect,” Bioorganic and Medicinal Chemistry Letters, (16),691–94 (2006).

Metoprolol is a selective ß1-adrenoreceptor antagonist widely used extensively in the treatment of a variety of cardiovascular disorders, and the pharmaceutical products containing metoprolol are marketed as a racemic mixture of (R) and (S) metoprolol (as a salt of succinate or tartrate). However, the pharmacological effect is mainly mediated by the (S)-enantiomer.
The (2S)-enantiomer has 25-fold greater Pi-adrenergic receptor affinity and there is evidence that the enantiomers are oxidatively metabolized at different rates. Its oxidative metabolism has been shown to be genetically linked to debrisoquine and bufurolol hydroxylation, and the a-hydroxylation pathway shows a high degree of product stereoselectivity in the presence of rat liver microsomes.

WO2007139923A1 discloses a deuterated aminoglycidyl compounds and process for preparing the same. Umesha Shetty et al. discloses a stereospecific synthesis of deuterated metoprolol enantiomers from chiral starting material (4S) -(+)-2,2-Dimethyl-1,3-dioxolane-4-methanol. (Journal of Labelled Compounds and Radiophamceuticals-Vol. XXVII, No. 10).

The present inventors after considering the advantages of deuterated derivatives in other drugs and the risks associated with it, have developed deuterated S (-) metoprolol compounds of Formula-1, Formula-2 and Formula-3 and its pharmaceutically acceptable succinate salt.

Formula-1 Formula-2

Formula-3
Deuterated S (-) Metoprolol Succinate compounds

OBJECT OF THE INVENTION
The primary object of the present invention is to synthesize deuterated S (-) metoprolol succinate compounds of formulae 1, 2 and 3.
Another objective of the present invention is to provide deuterated S (-) metoprolol succinate compounds of formulae 1, 2 and 3 which complies with regulatory specifications.
Another objective of the present invention is to provide deuterated S (-) metoprolol succinate compounds of formulae 1, 2 and 3 which have substantially improved pharmacokinetic and pharmacodynamics properties.
Yet another objective of the present invention is to provide a commercially viable and cost-effective process for the preparation of deuterated S (-) metoprolol succinate compounds of formulae 1, 2 and 3.

SUMMARY OF THE PRESENT INVENTION
An aspect of the present invention is to provide a process for the preparation of deuterated S
(-) metoprolol succinate compounds of formulae 1, 2 and 3 having increased half-life and therapeutic advantages.
In one Aspect, the present invention provides deuterated S (-) metoprolol succinate compound of formula I:

Deuterated S (-) Metoprolol Succinate (Formula-1)
According to a first aspect of the invention there is provided a process for preparing a deuterated S (-) metoprolol succinate compound of formula-1, wherein the process comprises the steps of:
a) treating a compound of formula-B with sodium methoxide in a suitable solvent to obtain compound of formula-G;
b) treating the compound of formula-G obtained in step a) with sodium borodeuteride in a suitable solvent to obtain compound of formula-H,
c) treating the compound of formula-H obtained in step b) with boron trifluoride diethyl etherate and triethyl silane in a suitable solvent to obtain a compound of formula-I,
d) treating the compound of formula-I obtained in step c) with epichlorohydrin in presence of benzyltriethyl ammonium chloride with a suitable base and in a solvent to obtain a compound of formula-J,
e) treating the compound of formula-J obtained in step d) with isopropyl amine in a suitable solvent to obtain compound of formula-Ja; and
f) treating the compound of formula-Ja obtained in step e) with succinic acid in presence of suitable solvent to obtain deuterated S (-) metoprolol succinate compound of formula-1.

In a second aspect, the present invention provides deuterated S (-) metoprolol succinate compound of formula-2,

Deuterated S (-) Metoprolol Succinate (Formula-2)
According to a second aspect of the invention, there is provided a process for preparing deuterated S (-) metoprolol succinate compound of formula-2, wherein the process comprises the steps of:
a) treating phenol with chloroacetyl chloride in presence of a catalyst and in a suitable solvent to obtain compound of formula-A,
b) hydrolysing the compound of formula-A obtained in step a) in presence of a base and in a suitable solvent to obtain a compound of formula-B,
c) reacting the compound of formula-B obtained in step b) with deuterated methanol in presence of a base and in a suitable solvent to obtain compound of formula-C;
d) treating the compound of formula-C obtained in step c) with sodium borodeuteride in suitable solvent to obtain a compound of formula-D;
e) reducing the compound of formula-D obtained in step d) in presence of boron trifluoride diethyl etherate and triethyl silane in a suitable solvent to obtain a compound of formula-E,
f) converting the compound of formula-E obtained in step e) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in a suitable solvent to obtain a compound of formula-F;
g) treating the compound of formula-F obtained in step f) with isopropyl amine in presence of suitable solvent to obtain a compound of formula-Fa; and
h) treating the compound of formula-Fa obtained in step g) with succinic acid in presence of suitable solvent to obtain deuterated S (-) metoprolol succinate compound of formula-2.

In the third aspect, the present invention provides deuterated S (-) metoprolol succinate compound of formula-3.

Deuterated S (-) Metoprolol Succinate (Formula-3)
According to the third aspect of the invention, there is provided a process for preparing deuterated S (-) metoprolol succinate compound of formula-3, wherein the process comprises the steps of:
a) treating the compound of formula-G with sodium borodeuteride in a suitable solvent to obtain compound of formula-H;
b) treating the compound of formula-H obtained in step a) with phosphorus pentachloride in a suitable solvent to obtain a compound of formula-K;
c) treating the compound of formula-K obtained in step b) with Sodium borodeuteride in presence of tributyltin chloride and light in suitable solvent to obtain a compound of formula-L;
d) converting the compound of formula-L obtained in step c) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in presence of a base and in a suitable solvent to obtain compound of formula-M;
e) reacting the compound of formula-M obtained in step d) with isopropyl amine in presence of suitable solvent to obtain compound of formula-Ma, and
f) treating the compound of formula-Ma obtained in step e) with succinic acid in a suitable solvent to obtain deuterated S (-) metoprolol succinate compound of formula-3.

DETAILED DESCRIPTION OF THE INVENTION
In the first embodiment of the invention there is provided a process for preparing a deuterated S (-) metoprolol of a compound of formula-1, wherein the process comprises the steps of:
a) treating a compound of formula-B with sodium methoxide in methanol to obtain a compound of formula-G,

b) treating the compound of formula-G obtained in step a) with sodium borodeuteride in presence of acetic acid and in methanol to obtain a compound of formula-H;

c) treating the compound of formula-H obtained in step b) with boron trifluoride diethyl etherate and triethyl silane in methylene dichloride to obtain compound of formula-I,

d) treating the compound of formula-I obtained in step c) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in presence of a suitable base and in a solvent to obtain compound of formula-J,

e) treating the compound of formula-J obtained in step d) with isopropyl amine in water to obtain compound of formula-Ja; and

f) treating the compound of formula-Ja obtained in step e) with succinic acid in acetone to obtain deuterated S (-) metoprolol of compound of formula-1.

Reaction of compound of formula-G with sodium borodeuteride in step b) is carried out at a temperature between 0? and 20?. The reaction is carried out in a suitable solvent(s) selected from alcohols consisting of methanol, ethanol, isopropyl alcohol, and its mixtures thereof.

The step of treating the compound of formula-I with epichlorohydrin in presence of benzyltriethyl ammonium chloride according to step d) of the present invention is carried out in a suitable solvent selected from a group comprising of aliphatic hydrocarbons selected from hexane or heptane; aromatic hydrocarbons selected from toluene or benzene; chlorinated hydrocarbons selected from dichloromethane or chloroform; alcohols selected from ethanol or methanol; and mixtures thereof, preferably dichloromethane.
The step of treating the compound of formula-Ja with succinic acid according to the step f) of the present invention, is carried out at a temperature between 30? to 60? for 2 to 12 hours.

The compound of formula-Ja is deuterated to obtain deuterated S (-) metoprolol compound of formula-1 in step f). The reaction is carried out in a suitable solvent selected from polar organic solvent comprising of alcohol selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; nitrile such as acetonitrile; dipolar aprotic solvents such as dimethylformamide; dimethyl sulfoxide; aromatic hydrocarbon selected from toluene or benzene; aliphatic hydrocarbon selected from hexane or heptane; and mixtures thereof.

In the second embodiment of the invention, there is provided a process for preparing a deuterated S (-) metoprolol succinate compound of formula-2, wherein the process comprises the steps of:
a) treating phenol with chloroacetyl chloride in presence of aluminium chloride and in methylene dichloride to obtain compound of formula-A,

b) hydrolyzing the compound of formula-A obtained in step a) in presence of sodium hydroxide and mixture of methanol and water to obtain compound of formula-B,

c) reacting the compound of formula-B obtained in step b) in presence of deuterated methanol and in presence of sodium hydroxide and water to obtain compound of formula-C,

d) treating the compound of formula-C obtained in step c) with sodium borodeuteride in methanol to obtain compound of formula-D,

e) reducing the compound of formula-D obtained in step d) in presence of boron trifluoride diethyl etherate and triethyl silane in methylene dichloride to obtain a compound of formula-E;

f) converting the compound of formula-E obtained in step e) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in potassium hydroxide and water to obtain a compound of formula-F;

g) treating the compound of formula-F obtained in step f) with isopropyl amine in water to obtain a compound of formula-Fa; and

h) treating the compound of formula-Fa obtained in step g) with succinic acid in acetone to obtain deuterated S (-) metoprolol of compound of formula-2.

The step of reacting a phenol compound with chloroacetyl chloride in presence of catalyst to obtain a compound of formula-A according to step a) is aluminium trichloride.

The step of hydrolysing the compound of formula-A as disclosed in step b) of the present process is carried out in presence of a base selected from a group of inorganic bases such as sodium hydroxide, potassium hydroxide and calcium hydroxide.
The step of substitution reaction according to step c) of the present invention is carried out in a suitable solvent selected from a group comprising of aliphatic hydrocarbons selected from hexane or heptane; aromatic hydrocarbons selected from toluene or benzene; chlorinated hydrocarbons selected from dichloromethane or chloroform; alcohol selected from ethanol or methanol; and mixtures thereof, preferably methanol.

The step of reacting the compound of formula-B obtained in step c) is carried out in presence of a base and deuterated methanol. The base selected from sodium hydroxide, potassium hydroxide and calcium hydroxide.
In the third embodiment of the invention there is provided a process for preparing a deuterated S (-) metoprolol succinate compound of formula-3, wherein the process comprises the steps of:
a) treating the compound of formula-G with sodium borodeuteride in methanol to obtain a compound of formula-H;

b) treating the compound of formula-H obtained in step a) with phosphorus pentachloride in a methylene dichloride as solvent to obtain a compound of formula-K;

c) treating the compound of formula-K obtained in step b) with Sodium borodeuteride in methanol and in presence of tributyltin chloride and light to obtain a compound of formula-L,

d) converting the compound of formula-L obtained in step c) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in potassium hydroxide and water to obtain compound of formula-M,

e) reacting the compound of formula-M obtained in step d) with isopropyl amine in water to obtain a compound of formula-Ma; and

f) treating the compound of formula-Ma obtained in step e) with succinic acid in acetone to obtain deuterated S (-) metoprolol of a compound of formula-3.

The suitable solvent is selected from a group comprising of aliphatic hydrocarbons selected from hexane or heptane; aromatic hydrocarbons selected from toluene or benzene; chlorinated hydrocarbons selected from dichloromethane or chloroform; alcohol selected from ethanol or methanol; and mixtures thereof, preferably methanol.
The source of light used in step c) is tungsten lamp.
The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES
Example 1: Preparation of Deuterated S (-) Metoprolol Succinate (Formula-1)

Deuterated S (-) Metoprolol Succinate (Formula-1)
Step-I: Preparation of 2-chloro-1-(4-hydroxyphenyl)ethanone (Compound B):
A mixture of 4-(2-chloroacetyl)phenyl chloroacetate (250 g) and methanol (1250 ml) was stirred at a temperature of 0 to 10°C. An aqueous solution of sodium hydroxide solution (44.53 gms sodium hydroxide in 1000 ml of water) was slowly added, stirred and reaction monitored on TLC/HPLC. After completion of reaction, adjusted the reaction mixture pH to 6-7 at 0 to 10°C with hydrochloric acid which was then filtered, and dried to give 2-chloro-1-(4-hydroxyphenyl)ethanone.
Yield: 89.0gms; Purity: >95%.

Step-II: Preparation of 1-(4-hydroxyphenyl)-2-methoxyethanone (Compound G).
2-Chloro-1-(4-hydroxyphenyl)ethanone (Compound B; 85.0gms) was added to a mixture of sodium methoxide (270gms) in methanol (850g) at 20-40°C and the reaction mixture was stirred for 8 to 24 hours. The reaction was monitored by HPLC/TLC and after completion the reaction mixture was concentrated under reduced pressure. Water (465ml) was added to the residue and the pH adjust pH to 4-7 with dilute HCl. The aqueous layer was extracted with methylene dichloride (5000ml). The organic layer was distilled under reduced pressure and product filtered and dried to give 1-(4-hydroxyphenyl)-2-methoxy ethanone (Compound G).
Yield: 60.2gms; Purity: >95%.

Step-III: Preparation of 4-(1-(1D )Hydroxy-2-methoxyethyl)phenol (Compound H):
1-(4-Hydroxyphenyl)-2-(1D)methoxyethanone/Compound G (15gms) was dissolved in methanol (150ml) with stirring. The mixture was cooled to 0-10°C and sodium borodeuteride (7.55gms) was gradually added. The reaction mixture was stirred and monitored by HPLC/TLC. After reaction completion, the pH of the reaction mixture was adjusted to 5 to 7 at 0-10°C with acetic acid. The solvent was distilled out under reduced pressure. Ethyl acetate (45ml) was added with stirring and filtered. The filtrate was concentrated under reduced pressure to give 4-(1-(1D)Hydroxy-2-(1D)methoxyethyl)phenol.
Yield: 9.1gms; Purity: >95%.

Step-IV: Preparation of 4-(2-methoxy(1D)ethyl)phenol (Compound I)
Triethyl silane (2.70gms) in methylene dichloride (50ml) was stirred under nitrogen and boron trifluoro diethyl etherate (6.6gms) was added at 0-10°C. 4-(1-(1D)Hydroxy-2-methoxy ethyl)phenol (Compound H; 4.0gms) in methylene dichloride (50ml) solution was added to the reaction mixture, with TLC/HPLC monitoring. After reaction completion, the mixture was washed with 20% sodium chloride solution under stirring. The organic layer was washed with water (100ml) and concentrated under reduced pressure. Ethyl acetate was added to the residue and cyclohexane was added to obtain 4-(2-methoxy(1D)ethyl)phenol.
Yield: 2.0gms; Purity: >95%.

Step-V: Preparation of 2-{[4-(2-methoxy(1D)ethyl)phenoxy]methyl}oxirane (Compound J)
Epichlorohydrin (2.96gms) and Benzyltriethyl ammonium chloride (0.03gms) were dissolved in water (20ml). A mixture of 4-(2-(1D) methoxy(1D) ethyl) phenol (2.0gms) solution and potassium hydroxide (0.934gms) in water (10ml) was added at -5 to 5°C. After completion of reaction based on TLC/HPLC monitoring, the reaction mixture was extracted with methylene dichloride (150ml) and the organic layer after washing with 10% sodium chloride solution was concentrated to obtain 2-{[4-(2-(1D)methoxy(1D)ethyl) phenoxy]methyl}oxirane.
Yield: 2.0 gms; Purity: > 95%

Step-VI: Preparation of Deuterated S (-) Metoprolol (Compound Ja)
Isopropyl amine (20.0ml) was added to 2.0gms of 2-{[4-(2-methoxy(1D)ethyl) phenoxy]methyl}oxirane) in water (2.0ml) at 0-5°C. The reaction mixture was stirred at room temperature and monitored by TLC/HPLC. After reaction was complete, the reaction mixture was concentrated under reduced pressure and water added (10ml) to the residue and extracted with toluene (40ml). The organic layer was washed with water (25ml) and concentrated and the residue purified by column chromatography with hexane / ethyl acetate mixture followed by Ethyl acetate/methanol mixture to obtain deuterated S (-) Metoprolol (Compound Ja)
Yield: 1.6gms; HPLC Purity: 99.41%.

Step-VII: Preparation of Deuterated S (-) Metoprolol Succinate (Formula- 1)
Acetone (1.5ml) was added to deuterated S (-) Metoprolol (Compound Ja; 0.75gms) with stirring. Succinic acid (0.196gms) dissolved in acetone (6.5ml) was added and the reaction mixture stirred at 40-55°C for 2 to 12 hours. The mixture was cooled, the product filtered and dried to obtain Deuterated S (-) Metoprolol succinate.
Yield: 0.2gms; HPLC purity 99.41%,
1H NMR (CDCl3 400MHz): d1.2(6H,t), 2.46(2H,s), 2.7(1H,t), 3.0(2H,m), 3.2(1H,t), 3.3(3H,s) 3.5(2H,d), 3.8(1H,m ), 3.9(1H,m), 4.3(1H,brs) 6.78(2H,d), 7.0(2H,d), 8.3(4H,brs)

Example 2: Preparation of Deuterated S (-) Metoprolol Succinate (Formula-2)

Deuterated S (-) Metoprolol Succinate (Formula-2)
Step-I: Preparation of 4-(2-chloroacetyl) phenyl chloroacetate (Compound A).
Phenol (100 gms) in methylene dichloride (214 ml) was stirred and mixed gradually with aluminium trichloride (357.4 gms) at 0-10°C. Chloroacetyl chloride (278.74 gms) dissolved in methylene dichloride (320ml) was added to the mixture slowly. The temperature was raised to room temperature and stirred till reaction completion as monitored by TLC/HPLC. The reaction mass was added to cold water (4000ml) and hydrochloric acid (250 ml) mixture. The reaction mixture was extracted with methylene dichloride (1500ml) and the organic layer washed with water and concentrated to give 4-(2-chloroacetyl) phenyl chloroacetate
Yield: 251 gms; Purity: > 95%.

Step-II: Preparation of 2-chloro-1-(4-hydroxyphenyl) ethanone (Compound B).
4-(2-Chloroacetyl)phenyl chloroacetate/Compound-A (250 gms) was dissolved in methanol (1250 ml) and cooled with stirring to 5-10°C. An aqueous solution of sodium hydroxide (44.53gms in 1250ml water) was added and the temperature raised to room temperature and the reaction mixture stirred till completion based on TLC/HPLC. The pH of the reaction mixture was adjusted to 6-7 and the solid separating out was filtered and dried to give 2-chloro-1-(4-hydroxyphenyl) ethanone.
Yield: 89gms; Purity: > 95%.

Step-III: Preparation of 1-(4-hydroxyphenyl)-2-(3D) methoxyethanone (Compound C).
2-Chloro-1-(4-hydroxyphenyl)ethanone/Compound B (5gms) was added to methanol D4 (15ml) under stirring, Aqueous sodium hydroxide solution (5.0gms/15ml water) was added at 5-10° and the temperature raised to ambient temperature till completion of reaction based on TLC/HPLC. After reaction completion, the reaction mixture was distilled out under reduced pressure. Water (50ml) was added, and the pH adjusted to 6-7 with cooling. The reaction mixture was extracted with ethyl acetate (50ml), and the organic layer washed with 10% sodium chloride solution (50ml ) and the organic layer concentrated under reduced pressure to give 1-(4-hydroxyphenyl)-2-(3D)methoxyethanone.
Yield: 4.7 gms; Purity: > 95%.

Step-IV: 4-(1-(1D) Hydroxy-2-(3D) methoxyethyl) phenol (Compound D)
1-(4-Hydroxyphenyl)-2-(3D)methoxyethanone (Compound C; 4.5gms) was stirred in methanol (45ml) and sodium borodeuteride (2.23gms) was added at a 0-10°C. The reaction mixture was stirred and monitored by HPLC/TLC. After reaction completion, the pH was adjusted to 5 to 7 by addition of acetic acid at 10°C. The reaction mixture was distilled under reduced pressure and ethyl acetate (45ml) was added to the residue and filtered. The filtrate was concentrated under vacuum to give 4-(1-(1D)Hydroxy-2-(3D)methoxy ethyl) phenol
Yield: 4.13gms; Purity: >95%.

Step-V: Preparation of 4-(2-(3D) methoxy(1D) ethyl) phenol (Compound E)
Triethyl silane (3.57gms) in methylene dichloride (50ml) was stirred under nitrogen and boron trifluoro diethyl etherate (8.24gms) was added at 0-10°C. 4-(1-(1D)hydroxy-2-(3D) methoxyethyl) phenol (Compound D; 5gms in methylene dichloride 50 ml) was added to the reaction mixture and the reaction monitored by TLC/HPLC. After reaction completion, the reaction mixture was washed with 20% sodium chloride followed by water (100ml) and concentrated under reduced pressure to provide a compound which was purified by passing through column using a mixture of cyclohexane and ethyl acetate to obtain 4-(2-(3D)methoxy(1D)ethyl)phenol.
Yield: 2.0gms; Purity: >95%.

Step-VI: 2-{[4-(2-(3D)methoxy(1D)ethyl)phenoxy]methyl}oxirane (Compound F)
Epichlorohydrin (2.96gms) and benzyltriethyl ammonium chloride (0.03gms) in water (20ml) were added to an aqueous solution of 4-(2-(3D)methoxy(1D)ethyl)phenol (2.0gms) solution containing potassium hydroxide (0.93g) in water (10ml) at -5 to 5°C. The reaction was monitored by TLC/HPLC and after reaction completion of the mixture was extracted with methylene dichloride (75 ml). The organic layer was washed with 10% sodium chloride solution (50ml) followed by water (50ml) and concentrated under reduced pressure to obtain 2-{[4-(2-(3D) methoxy(1D) ethyl) phenoxy]methyl}oxirane
Yield: 2.0gms; Purity: >95%.

Step-VII: Preparation of Deuterated S (-) Metoprolol (Compound-Fa)
Isopropyl amine (20gms) was added to a mixture of water (20ml) and 2.0 gms of 2-{[4-(2-(3D) methoxy (1D) ethyl) phenoxy]methyl}oxirane; 2gms) cooled to 10°C. The reaction mixture was stirred at room temperature and monitored by TLC/HPLC. After reaction completion, the mixture was distilled at reduced pressure and to the residue was added water (10ml) and extracted with toluene (40ml). The organic layer was washed with water (25 ml) and concentrated to give a compound which was purified by column chromatography using hexane and ethyl acetate mixture followed by Ethyl acetate/methanol mixture to obtain S (-) deuterated Metoprolol (Compound-Fa)
Yield: 1.6gms; Purity: >95%.

Step-VIII: Preparation of Deuterated S (-) Metoprolol Succinate (Formula-2)
Acetone (1.5ml) and S (-) deuterated Metoprolol (Compound-Fa) (0.75gms) were stirred in a clean and dry flask. Succinic acid (0.196gms) dissolved in acetone (6.5ml) was added and stirred at 40-50°C for 10 to 12 hours. The mixture was cooled to 0-5°C and filtered to obtain deuterated S (-) Metoprolol succinate (Formula-II)
Yield: 0.2gms; Purity: >95%.
1H NMR (CDCl3 400MHz): d1.0(6H,d) 2.25(2H,s), 2.7(1H,m), 2.94(1H,t) 3.2(1H,s) 3.48(2H,m), 3.86(3H,m ), 6.85(2h,d), 7.1(2H,d).

Example 3: Preparation of Deuterated S (-) Metoprolol succinate (Formula-3)

Deuterated S (-) Metoprolol succinate (Formula-3)

Step-I: 4-(1-(1D) Hydroxy-2-methoxyethyl)phenol (Compound H)
1-(4-Hydroxyphenyl)-2-(3D) methoxyethanone /Compound G (15gms) was added to methanol (150ml) with stirring and sodium borodeuteride (7.55gms) was added at (0-10°C). The reaction mixture was stirred and monitored by HPLC/TLC till completion. The reaction mixture pH was adjusted between 5 and 7 by adding acetic acid. The reaction mixture was concentrated and the residue was extracted with ethyl acetate (150ml). The organic layer was filtered, and the filtrate concentrated under reduced pressure to give 4-(1-(1D)Hydroxy-2-(3D)methoxyethyl)phenol.
Yield: 9.1gms; Purity: > 95%.

Step-II: Preparation of 4-(2-methoxy(1D,1Chloro) ethyl phenol (Compound K):
4-(1-(1D)Hydroxy-2-methoxyethyl)phenol (Compound H; 9gms) was stirred in methylene dichloride (90ml) at 0-5°C and phosphorus pentachloride (13.2gms) was added gradually in nitrogen atmosphere. The reaction mixture was monitored by HPLC/TLC and after reaction completion the mixture was poured in ice cold water. The organic layer was separated and washed with sodium chloride solution followed by water, concentrated under reduced pressure to give crude compound which was purified by column chromatography using Hexane/ethyl acetate mixture to give 4-(2-methoxy(1D,1Chloro)ethylphenol (Compound K)
Yield: 3.2gms; Purity: >95%.

Step-III: Preparation of 4-(2-methoxy(1-2D)ethylphenol (Compound L):
Add 4-(2-Methoxy(1D,1Chloro) ethylphenol (Compound K) (3gms) in methanol (30ml) under nitrogen with stirring. Tributyl tin chloride (0.3gms) followed by Sodium borodeuteride (0.83gms) was then added to the mixture at 5-10°C and subjected to light from a tungsten lamp light source. The reaction mixture was stirred and monitored by TLC/HPLC till completion of reaction. The pH of the reaction mixture was then adjusted to 5-7 with acetic acid and concentrated under reduced pressure to get a residue. Methylene dichloride was added to the reaction mixture and filtered to remove an insoluble impurity and the filtrate was then concentrated under reduced pressure to get crude product which was purified by column chromatography utilizing a mixture of hexane and ethyl acetate isolate pure 4-(2-methoxy(1-2D)ethylphenol (Compound L)
Yield: 0.40 gms; Purity: >95%

Step-IV: 2-{[4-(2-methoxy(1-2D)ethyl)phenoxy]methyl}oxirane (Compound M)
Epichlorohydrin (2.96 gms) and benzyltriethyl ammonium chloride (0.03g in 20 ml water) were added to 4-(2-(3D)methoxy(1-2D)ethyl)phenol (2.0gms) solution containing potassium hydroxide (0.934g in 10 ml water) at -5 to 5°C. The reaction was monitored by TLC/HPLC. After reaction was complete, the reaction mixture was extracted with methylene dichloride (150ml) and the organic layer washed with sodium chloride solution, followed by water and concentrated to obtain 2-{[4-(2-methoxy(1-2D)ethyl)phenoxy] methyl}oxirane.
Yield: 2.0gms; Purity: >95%.

Step-V: Preparation of Deuterated S (-) Metoprolol (Compound-Ma).
Isopropyl amine (20.0ml) and water (2.0ml) mixture solution were added to 2-{[4-(2-methoxy (1-2D)ethyl)phenoxy]methyl}oxirane (2.0g) at 0-5°C. The reaction mixture was stirred at 20-30°C and monitored by TLC/HPLC. After reaction was complete, the reaction mixture was concentrated, and water (10 ml) was added to the residue and extracted with toluene (40ml). The organic layers was washed with 25 ml water and concentrated to give a residue which was purified by column chromatography with a mixture of hexane and ethyl acetate followed by a mixture of ethyl acetate and methanol to obtain deuterated S (-) Metoprolol (Compound-Ma).
Yield: 1.6gms; Purity>95%.

Step-VI: Preparation of Deuterated S (-) Metoprolol succinate (Formula-3)
Acetone (1.5ml) and deuterated S (-) Metoprolol (Compound-Ma). (0.75g ) were stirred in a clean and dry flask. A solution of succinic acid (0.196gms) in acetone (6.5 ml) was added and stirred at 40-50°C for 2 to 12 hours. The mixture was cooled to 5-10°C, filtered, dried to obtain Deuterated S (-) Metoprolol succinate (Formula-III).
Yield: 0.2gms; Purity->95%.
1H NMR (CDCl3 400MHZ): d1.39(6H,t) 2.5(2H,s), 2.79(1H,S), 2.79(1H,D), 3.2(1H,m) 3.24(1H,s) 3.3(3H, s) 3.4(1H,t), 3.9(1H,s ),4.0(1H,d), 4.48(1H,s) 6.8(2h,d), 7.10(2H,d), HPLC purity 94.53%,
,
Claims:We claim:
1. A process for the preparation of compound of formula-1

comprising the steps of:
a) treating a compound of formula-B with sodium methoxide in methanol to obtain a compound of formula-G;

b) treating the compound of formula-G obtained in step a) with sodium borodeuteride in presence of acetic acid and methanol to obtain a compound of formula-H;

c) treating the compound of formula-H obtained in step ii) with boron trifluoride diethyl etherate and triethyl silane in methylene dichloride to obtain a compound of formula-I;

d) treating the compound of formula-I obtained in step c) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in presence of a suitable base and in a solvent to obtain a compound of formula-J;

e) treating the compound of formula-J obtained in step d) with isopropyl amine in water to obtain compound of formula-Ja; and

f) treating the compound of formula-Ja obtained in step e) with succinic acid in actone to obtain deuterated S (-) metoprolol of a compound of formula-1.

2. The process as claimed in Claim 1(b), wherein the step of reacting the compound of formula-G with sodium borodeuteride is at a temperature between 0? and 20?.
3. The process as claimed in claim 1, wherein the suitable solvents are selected from a group comprising of aliphatic hydrocarbons selected from hexane or heptane; aromatic hydrocarbons selected from toluene or benzene; chlorinated hydrocarbons selected from dichloromethane or chloroform; alcohol selected from ethanol or methanol; and mixtures thereof.
4. A process for the preparation of compound of formula-2,

comprising the steps of:
a) treating phenol with chloroacetyl chloride in presence of aluminium chloride and methylene dichloride to obtain a compound of formula-A;

b) hydolysing the compound of formula-A obtained in step a) in presence of sodium hydroxide and mixture of methanol and water to obtain a compound of formula-B;

c) reacting the compound of formula-B obtained in step b) in presence of deuterated methanol and in presence of sodium hydroxide and water to obtain a compound of formula-C,

d) treating the compound of formula-C obtained in step c) with sodium borodeuteride in methanol to obtain compound of formula-D,

e) reducing the compound of formula-D obtained in step d) in presence of boron trifluoride diethyl etherate and triethyl silane in methylene dichloride to obtain a compound of formula-E;

f) converting the compound of formula-E obtained in step e) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in potassium hydroxide and water to obtain a compound of formula-F;

g) treating the compound of formula-F obtained in step f) with isopropyl amine in presence of water to obtain a compound of formula-Fa; and

h) treating the compound of formula-Fa obtained in step g) with succinic acid in acetone to obtain deuterated S-(-) metoprolol of a compound of formula-2.

5. The process as claimed in claim 4, wherein the reaction of compound of formula-B obtained in step c) with deuterated methanol is in presence of a potassium hydroxide as the base.
6. The process as claimed in claim 4, wherein the suitable solvent is selected from a group comprising of aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons and alcohol.
7. A process for the preparation of compound of Formula-3,

comprising the steps of:
a) treating the compound of formula-G with sodium borodeuteride in methanol to obtain a compound of formula-H;

b) treating the compound of formula-H obtained in step a) with phosphorus pentachloride in a methylene dichloride as solvent to obtain compound of formula-K,

c) treating the compound of formula-K obtained in step b) with Sodium borodeuteride in methanol and in presence of tributyltin chloride and light to obtain a compound of formula-L;

d) converting the compound of formula-L obtained in step c) with epichlorohydrin in presence of benzyltriethyl ammonium chloride in potassium hydroxide and water to obtain compound of formula-M;

e) reacting the compound of formula-M obtained in step d) with isopropyl amine in water to obtain a compound of formula-Ma; and

f) treating the compound of formula-Ma obtained in step e) with succinic acid in acetone to obtain deuterated S (-) metoprolol of a compound of formula-3,

8. The process as claimed in claim 7, wherein the suitable solvent is selected from a group comprising of aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons and alcohol.