FORM 2
THE PATENTS ACT, 1970
(Act 39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
(See Section 10 & rule 13)
"A PROCESS FOR PREPARING NEBIVOLOL HYDROCHLORIDE"
ZCL CHEMICALS LIMITED
'A'- 806/807,
215 ATRIUM CHAKALA,
ANDHERI (EAST), MUMBAI-400 059,
MAHARASHTRA, INDIA.
(An Indian Organization)
The following specification particularly describes the invention and the manner in which it is to be performed.

A PROCESS FOR PREPARING NEBIVOLOL HYDROCHLORIDE
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of nebivolol hydrochloride of formula I thereof,

BACKGROUND OF THE INVENTION
Nebivolol with a chemical name (±)-[2R*[lS*,5S*(S*)]]-α,α'-[iminobis (methylene)]bis[6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanoI] is a long acting, cardio selective beta-blocker currently licensed for the treatment of hypertension. Nebivolol is a racemate of two enantiomers, SRRR- nebivolol (or d- Nebivolol) and RSSS- nebivolol (or /- Nebivolol), As disclosed in The Merck Index and E-journal of Chemistry 2009, 6(3), 915-919, it combines two pharmacological activities: (i) it is a competitive and selective β1Vrecepter antagonist which is attributable to the d-enantiomer; (ii) it has mild vasodilating properties, possible due to an interaction with the L-arginine/nitric oxide pathway. It is given by mouth as the hydrochloride although doses are expressed in terms of base. The usual dose is 5 mg daily. An initial dose of 2.5 mg daily is employed in the elderly and in patients with renal impairment. As reported in Vasc Health Risk Manag. 2006, 2(3): 303-308 and Angiology 1990, 4l(2):95-105, the selectivity of Nebivolol in b1-adrenocepter antagonism is greater than that of clinically used atenolol, pindolol and propranolol. Nebivolol is a racemic mixture with beta-blocker activity residing in the d-isomer; in contrast, /-nebivolol is far more potent in facilitating NO release.
US patent 4,654,362 discloses a process for preparation of Nebivolol hydrochloride. The isomeric mixture of isomer A and isomer B is separated by

column chromatography to obtain isomer A and isomer B, The isomer A is treated with benzylamine to obtain benzylated isomer A which is reacted with isomer B to get benzylated nebivolol. Then after benzylated nebivolol is first purified via column chromatography and then converted to oxalate salt of benzylated nebivolol followed by crystallization from ethanol. The obtained pure oxalate salt may be treated with an alkali to isolate free base of benzylated nebivolol. It is further reacted with 10% palladium on carbon in methanol in the presence of hydrogen gas. The catalyst is filtered and filtrate is evaporated. The obtained residue is extracted in dichloromethane, further evaporated and dried in vacuuo to get nebivolol free base which is then converted to nebivolol hydrochloride by treating with saturated IPA.HC1 as described in scheme 1. Scheme 1:

The main disadvantages of above patent include more unit operations, purification by column chromatography and isolation at various stages, tedious

process and difficult to operate, makes the process uneconomical and less productive. Moreover that benzylated nebivolol required chromatographic purification as well as oxalate salt formation and salt breaking to purify benzylated nebivolol which is additional stage leads to yield loss.
EP patent 2 163 551 discloses a process for preparing nebivolol hydrochloride from starting material, (±)-[lS*(R*)]-6-fluoro-3,4-dihydro-α-[[(phenylmethyl) amino] methyl]-2H-l-benzopyran-2-methanol is generated by the known prior art method described in US Patent 4,654,362, in which isomer A is reacted with benzylamine in isopropyl alcohol. Further the obtained material is reacted with isomer B in methanol at 65-70°C for 15-18 hours. The reaction mass is diluted with more methanol followed by sequence wise addition of benzyl chloride, palladium on carbon into the hydrogenator. The reaction mixture is heated at 48 to 52°C for 2-3 hours, cooled and catalyst is separated by filtration. The methanol is distilled off and cooled to get nebivolol hydrochloride as depicted in scheme-2. Scheme-2:

Benzyl chloride is well known for its high reactivity (relative to alkyl chlorides). Since benzyl chloride is quite volatile at room temperature, it can easily reach the mucous membranes where the hydrolysis takes place with production of hydrochloric acid. This explains why benzyl chloride is a lachrymator and has been

used as a war gas. It is also very irritating to the skin. Moreover that, the scientists of the present invention observed benzyl chloride liberate hydrochloric acid during hydrogenation which forms nebivolol hydrochloride, Chiral purity is not improving by generated toluene in the process from benzyl chloride. Hence it requires further purification to get desired chiral purity ratio of pharmaceutical grade nebivolol hydrochloride. Benzyl chloride used in process liberates HC1 which converted nebivolol base in-situ to nebivolol hydrochloride. Using benzyl chloride during hydrogenation process is highly hazardous, tedious to handle at plant level and the hydrogenation needs 5-6 Kg/cm2 pressure. Hence such reagents are not suitable for large scale at plant level and needs special and expensive equipments like hastelloy autoclave. Furthermore, chiral purity of nebivolol hydrochloride is very important and critical parameter which should meet the specific criteria to prepare a quality API. The patent is silent about chiral purity and disclosed HPLC purity is 99.5% which may need further purification to meet the regulatory as well as customer requirements. Hence the purification step will further lead the process to lose the yield.
PCT application WO2006/025070 discloses process for preparation of nebivolol and its pharmaceutically acceptable salts. In the synthetic steps isomer A is added to isopropanol followed by addition of benzylamine and refluxed to get benzylated isomer A which is purified in isopropanol. The obtained benzylated isomer A is reacted with isomer B in methanol and isolated at -10 to -15°C temperature after 10-15 hours of stirring to isolate desired isomer of benzylated nebivolol. Benzylated nebivolol is then debenzyiated with 10% palladium on charcoal at hydrogen pressure about 160-170 psi i.e 11-12 Kg/cm2 pressure to give nebivolol base in isolated form, followed by treating with hydrochloric acid in an organic solvent to give nebivolol hydrochloride. The obtained nebivolol hydrochloride is then purified in isopropanol as described in scheme-3.

The disadvantages of the patent application include isolation of intermediates at the various stages and purification lead the process to yield loss. The overall yield of the process is just ~0.44w/w from isomer A. Use of high amount of solvents for purification and for isolation generates effluent in huge quantity which is very difficult to handle and treatment cost is high as well. Furthermore, benzylated nebivolol is isolated at -10 to -15°C and required total 35-40 hours time to complete reaction including drying which increases usage of utility, man power and energy consumption make the process commercially and industrially not viable. Yet furthermore, it is very difficult to handle 11-12 Kg/cm2 hydrogen pressure for debenzylation at plant scale. Scheme-3:

US 2011/0250454 Al discloses a process for preparing nebivolol hydrochloride wherein isomer A is treated with benzylamine in isopropanol. After

completion of reaction, the solvent is distilled off followed by hexane addition and cooled to 0-5°C. The formed solid is filtered, washed with hexane and dried under vacuum to give benzylated isomer A in 73% yield having HPLC purity 97.17%. Benzylated isomer A and isomer B condensed in isopropanol to isolate benzylated nebivolol having unspecified purity. Then after benzylated nebivolol is underwent debenzylation in methanol, in the presence of 10% palladium on carbon and ammonium formate to isolate impure nebivolol free base. Then more step for the hydrochloride salt formation of nebivolol free base to afford only around 38% yield. Yet one more step of purification of nebivolol hydrochloride in methanol, which is heated to reflux followed by 65-75% distillation of solvent and cooled to room temperature. The formed solid is filtered and dried to give 75% yield having (R*S*S*S*):(R*S*R*R*) ratio of 98.93:1.06. The obtained material is further treated with methanol, ethanol and hexane and dried to afford 75% yield having (R*S*S*S*):(R*S*R*R*) ratio of 99.79:0.2.
The major disadvantages of the process include isolation of intermediates at the various stages which increases usage of utility, man power and energy consumption make the process commercially and industrially not viable. Distillation of solvent at various stages makes the process cumbersome and tedious. The process is losing yield around 44% at purification stage only, make the process uneconomical. Moreover that the process is not productive as overall yield of the process is just around 0.30w/w from isomer A.
Thus, present invention fulfills the need of the art to provide an improved and industrially applicable process for preparation of nebivolol hydrochloride by avoiding use of hazardous reagents and isolation of intermediates at various stages as well which makes the process plant friendly and economically viable.

OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide a process for preparation of nebivolol hydrochloride to overcome or ameliorate one of the disadvantages of the prior art processes.
Another prime objective of the invention is to provide an efficient, improved and industrially advantageous process for preparation of nebivolol hydrochloride which is conveniently applicable to industrial scale.
Yet another primary object of the present invention is to provide nebivolol hydrochloride consisting ratio of d-nebivolol and /-nebivolol between 48.5% to 51.5% with total chiral purity more than 99%.
Yet another leading objective of the present invention is to avoid use of hazardous reagents.
One more principal objective of the present invention is to provide an in situ process for the preparation of the technical nebivolol hydrochloride.
One more objective of the present invention is purifying nebivolol hydrochloride in an organic solvent at particular cooling condition.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of nebivolol hydrochloride of formula I, comprises the ratio of d-nebivolol and l-nebivolol within 48.5 to 51.5%,


which proves to be efficient and industrially viable. The process comprises the steps of:
a), treating benzylamine with isomer A in a suitable solvent;

b). isolating compound of formula II:

c). condensing the compound of formula II with isomer B in an organic solvent;

d). forming benzylated nebivolol of formula III in-situ;

e). deprotecting compound of formula III in-situ by catalytic hydrogenation
in autoclave to form nebivolol free base; f). treating nebivolol free base in-situ with alcoholic hydrochloric acid; g). isolating technical nebivolol hydrochloride; and

h). purifying technical nebivolol hydrochloride in suitable solvent to get pure nebivolol hydrochloride of formula I.
Accordingly, the present invention provides a process for the preparation of compound of formula II, process comprises the steps of:
a), providing isomer A in a suitable solvent;
b). providing benzylamine in a suitable solvent;
c). adding solution of step a) into solution of step b) drop wise or lot wise; and
d). isolating compound of formula II.
Accordingly, the present invention provides an in-situ process for the preparation of technical nebivolol hydrochloride; the process comprises the steps of:
b). forming benzylated nebivolol of formula III;

a), condensing the compound of formula II with isomer B in an organic solvent;


c). deprotecting compound of formula III by catalytic hydrogenation in
autoclave to form nebivolol free base; d). treating formed nebivolol free base with alcoholic hydrochloric acid in
different reaction vessel; and e). isolating technical nebivolol hydrochloride.
Accordingly, the present invention provides a purification process for the preparation of nebivolol hydrochloride of formula I, process comprises the steps of.
a), dissolving technical nebivolol hydrochloride in methanol;
b). refluxing the reaction mixture;
c). filtering the reaction mixture;
d). distilling methanol;
e). cooling at temperature 37 to 39°C; and
f). isolating nebivolol hydrochloride of formula 1.
Accordingly, the present invention provides a process for the preparation of technical nebivolol hydrochloride, consists the steps of; providing reaction mixture of nebivolol free base in autoclave; transferring the reaction mixture into glass vessel from autoclave; adding alcoholic hydrochloric acid in to reaction mixture; isolating technical nebivolol hydrochloride.
Accordingly, the present invention provides a process for the preparation of nebivolol hydrochloride as described in detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally" and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are

understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term "in-situ" typically means "in the reaction mixture". The term "technical nebivolol hydrochloride" herein after means "the nebivolol hydrochloride isolated at stage 2 of the present invention".
The present invention provides an improved and efficient process for the preparation of nebivolol hydrochloride of formula I.
According to the embodiment of the invention provides an industrially feasible and economically viable process for preparation of nebivolol hydrochloride starting from compound of isomer A.
Stage 1:
Benzylamine is reacted with isomer A to give compound of formula II. Generally the reaction involves treatment of solution of isomer A in suitable solvent with solution of benzylamine in suitable solvent. Suitable organic solvent include water, lower alcohols such as methanol, ethanol, n-propanol, isopropylalcohol or mixtures thereof. After completion of addition, the reaction mixture is maintained at 30 to 35°C under stirring for 1 to 24 hours, preferably for 4-5 hours. The reaction mixture is cooled to about 10 to -10°C, preferably at 0 to -5°C. The solid is filtered and washed with organic solvent to obtain compound of formula II.
Particularly, the solution of isomer A in isopropylaicohol is added into solution of benzylamine in isopropylaicohol. drop wise or lot wise within about 6 hours at temperature 18 to 22°C. After completion of addition, the reaction mixture is maintained at 30 to 35°C under stirring for about 4 hours. The reaction mixture is then cooled to about 0 to -5°C and maintained for 2 hours, The solid is filtered and washed

with chilled isopropylalcohol to obtain compound of formula II having HPLC purity more than 99.5%.
The major attraction of this particular stage is addition sequence of solution of isomer A and solution of benzylamine which is the key parameter to obtain very good yield. The prior art processes involves addition are just mixing the components or addition of liquid benzylamine into the solution of isomer A. The addition of isomer A into the benzylamine solution is reverse addition than reported prior art processes. Both the reacting components individually in organic solvent media i.e in dissolved form provides very smooth condition to react and the temperature of addition (drop wise or lot wise) at 18 to 22°C provide an extra edge to the reaction to complies. Moreover, the scientists of the present invention observed that, the reverse addition impede the formation of dimer which is unwanted isomer of benzylated base. Moreover that the purity as well as yield is better than disclosed in available prior art. The difference between prior art processes and present invention is depicted in below scheme-4. Scheme-4: As per prior art processes:



As per present invention:
The comparison of the present invention process of stage 1 with prior art processes shows that present invention is ameliorating one of the disadvantages of prior art processes and gives better yield as well as quality as depicted in below table.
(±)-[1S*(R*)]-6-Fluoro-3,4-dihydro-α-[[(phenylmethyl)amino]methyl]-2-H-l-benzo-pyran-2-methanol (Stage 1)

Patent No./ Assignee KSM
Purity Benzyl Amine Solvent Solvent Volume Reaction temperature Yield
w/w Purity
by
HPLC
US 4,654,362 Silent 3.0 eq M Ethanol 15.38V Reflux 1.11 Silent
EP 2 163 551 Silent 5.0 eqM 1PA 5V 25-30°C 1.25 99.0%
WO 2006/025070 78-82% 1.21 eqM IPA 3V Reflux 0.80 Silent
US 2011/0250454 Silent 3.0 eq M IPA 15V Reflux 1.13 97.17%
Present Invention 95% 4.98 eq M IPA 5V 30-35°C 1.37 >99.5%

Stage 2:
The compound of formula II is reacted with isomer B to form benzylated nebivolol of formula III followed by hydrogenation with catalyst to give nebivolol free base which is then treated with alcoholic hydrochloric acid to isolate nebivolol hydrochloride. Generally the reaction involves condensation of formula II and isomer B in organic solvent, Suitable solvent include lower alcohols such as methanol, ethanol, n-propanol, isopropylalcohol or mixtures thereof. The reaction mixture is heated at temperature 50 to 70°C, preferably at 65 to 70°C and maintained at the same temperature for 15-24 hours, preferably 18-20 hours. After adding organic solvent in the reaction mixture is treated with hydrogenation catalyst for the deprotection of benzylated nebivolol. Hydrogenation catalysts include palladium on carbon, raney nickel, palladium hydroxide, platinum on carbon, platinum oxide and the like. The reaction mixture is heated and maintained for about 3-4 hours at about 40 to 55°C, preferably 48-52°. Completion of reaction confirmed by the HPLC, hydrogen pressure is removed followed by cooling the reaction mixture at temperature 35 to 45°C. Nebivolol free base is formed in-situ. Alcoholic hydrochloric acid is added to the reaction mixture and maintained for 1-2 hours at 50 to 70°C, preferably for about 30 minutes at temperature 55 to 60°C. Alcoholic hydrochloric acid includes methanolic hydrochloric acid, ethanolic hydrochloric acid, isopropanolic hydrochloric acid, preferably methanolic hydrochloric acid. The reaction mixture is maintained at temperature 55 to 60°C for 1 hour to 30 minutes and catalyst is filtered off followed by workup to isolate technical nebivolol hydrochloride.
Particularly, the reaction involves condensation of formula II and isomer B in methanol. The reaction mixture is heated at temperature 65 to 70°C and maintained at the same temperature for 18-20 hours. After adding methanol in the reaction mixture is treated with palladium on carbon in the presence of hydrogen pressure at 5-5.5 Kg/cm for the deprotection of benzylated nebivolol. The reaction mixture is maintained for about 3 hours at about 48 to 52°C. Completion of reaction is confirmed by the HPLC followed by removal of hydrogen pressure and cooled at

temperature 35 to 45°C. The reaction mixture comprising nebivolol free base transferred to glass vessel from the autoclave. Methanolic hydrochloric acid is added into the reaction mixture and maintained for 30 minutes at temperature 55 to 60°C and catalyst is Filtered off. The solvent is distilled atmospherically and further cooled to 37 to 39°C, filtered and washed with methanol. The obtained solid is dried to get technical nebivolol hydrochloride in good yield.
The advantages of this particular stage are reducing the quantity of hydrogenation catalyst in the reaction than quantity used in the prior art processes and avoiding use of hazardous reagents like benzyl chloride in the reaction as source of hydrochloride salt formation. Furthermore, after removal of hydrogenation pressure and reaction mixture is shifted to glass vessel from autoclave, methanolic hydrochloric acid is added into the reaction mixture to form nebivolol hydrochloride which gives good yield, purity as well as desired stereo isomeric salt separation. Nebivolol hydrochloride has purity more than 95%, preferably more than 98%, more preferably greater than 99.5%. Moreover that, the main problem solving approach of the process is to prevent possible damage of autoclave from strong acidic media like benzyl chloride. As per observation of the scientists of the present invention, use of strong acidic media can be cause of autoclave corrosion; hence the present invention ameliorate disadvantages of the prior art processes and make the process plant friendly, safe, environment friendly and economically viable.
Stage 3:
The reaction involves purification of technical nebivolol hydrochloride to give pure nebivolol hydrochloride of formula I.
Particularly, technical nebivolol hydrochloride is treated with methanol and refluxed for the sufficient time. The reaction mixture is then filtered, distilled off and cooled to 35 to 40°C, preferably at temperature 37 to 39°C. The reaction mixture is filtered, washed with methanol and dried at 50 to 55°C to get pure nebivolol

hydrochloride of formula I having HPLC purity more than 99.8% and chiral purity more than 99.7%.
EP patent 2 163 551 discloses only yield and HPLC purity without showing chiral purity. To achieve chiral purity more than 99.7% as well as desired chiral ratio of d-nebivolol hydrochloride and 1-nebivolol hydrochloride, purification of nebivolol hydrochloride is required due to the significance of regulatory requirement. Due to the purification, process results in yield loss. Moreover that, as per observation of the scientists, without purifying nebivolol hydrochloride results in very poor chiral purity as well as chiral ratio of nebivolol hydrochloride.
The comparison of the present invention process of nebivolol hydrochloride from formula II with prior art processes shows that present invention is ameliorating one of the disadvantages of prior art processes and gives better yield as well as quality as depicted in below table.
(±)-[2R*[lS*, 5S*(S*)]]-α, α'-Iiminobis (methylene)] bis [6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanol] hydrochloride (Nebivolol hydrochloride)

Patent No./ Assignee Pd/C Solvent/ Volume Pressure Temp. °C HCI Source w/w
Yield
from
Isomer
-A HPLC
Purity Chiral Purity
US 4,654,362 0.66
w/w Methanol 40 V "Normal pressure Room
temp. IPA HCI - - -
EP 2 163 551 -0.25
w/w Methanol 30 V 5.0-5.5 kg/cm2 48-52 Benzyl Chloride -0.82 99.5% Silent
WO2006/025070 0.06
w/w 2-
Methoxy
ethanal
20 V 160-170 psi 70-75 HCI -0.44 99.8% Silent
US2011/0250454 0.5 w/w Methanol 10V Reflux Aq. HCI -0.30 - R*R*R*S *to
R*S*R*R
*
99.79:0.2
0##
Present Invention 0.05
w/w Methanol 30 V 5.0-5.5 kg/cm2 48-52 MeOH HCI -0.65 >99.8% 99.7 %
## with 44% yield loss in p urification.

The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES:
Example-l: (±)-[lS*(R)*)]-6-Fluoro-3, 4-dihydro-α-[[(phenyl methyl) amino] methyl]-2H-l-benzopyran-2-methanol of formula II
A solution of (±)-[lS*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-l-benzopyran (95% by HPLC) (50 gm, 0.2574mol) in isopropyl alcohol (100 ml) was drop wise added in the solution of benzyl amine (137.5gm, 1.2832mol) in isopropyl alcohol (150 ml) within 6 hours at 18 to 22°C temperature. The reaction was maintained at 30 to 35°C for 4 hours till the completion of reaction. The reaction mass was cooled to 0 to -5°C and maintained for 2 hours. The solid was filtered, washed with chilled isopropyl alcohol and dried at 50 to 55°C to obtain 68.5 gm of (±)-[lS*(R)*)]-6-Fluoro-3,4-dihydro-a[[(phenyl methyl) amino] methyl]-2H-l-benzopyran-2-methanol. HPLC purity >99.5%.
Example-2: (±)-[2R*[lS*,5S*(S*)]]-α,α'-[iminobis (methylene)]bts[6-fluoro-3,4-dihydro-2H-l-benzopyran-2-methanol] hydrochloride (Technical nebivolol hydrochloride).
(±)-[lS*(R)*)]-6-Fluoro-3,4-dihydro-a-[[(phenylmethyl)amino]methyl]-2H-l-benzopyran-2-methanol (66 gm, 0.2190 mol) and (±)-[lR*(R*)]-6-fluoro-3,4-dihydro-2-oxiranyl-2H-l-benzopyran (46.2 g. 0.2378 mol) were added in methanol (330 ml) and heated to 65 to 70°C. The reaction mass was maintained at the same temperature for 18-20 hours till the completion of the reaction. After cooling at the ambient temperature, methanol (1650 ml) was added in the reaction mass and transferred it in to hydrogenator. 10% Palladium on carbon (3.3 g) was added to

reaction mass. The pressure was applied 5.0-5.5 kg/cm with hydrogen gas and heated it to 48 to 52°C. The reaction mass was maintained for 3 hours till the completion of reaction, hydrogen pressure was removed followed by cooling at temperature 35 to 45°C. The reaction mixture comprising nebivolol free base transferred to glass vessel from the autoclave. Methanolic HC1 (91,26 gm, 2.0 mol, 17.51%) was added in to the reaction mixture. Reaction mass was further maintained for 30 minutes at 55 to 60°C, and catalyst was isolated through filtration. -85% of methanol was distilled off atmospherically and cooled to 37 to 39°C. filtered and washed with methanol. The solid was dried at 50-55°C to obtained 37 gm technical nebivolol hydrochloride. HPLC purity >99.5%.
Example -3: Pure nebivolol hydrochloride of formula I
Technical nebivolol hydrochloride (37 gm) was dissolve in methanol (1110 ml) at reflux temperature, filtered and distilled off at atmospheric pressure up to 85%. The reaction mass was cooled to 37-39°C, filtered, washed with methanol and dried at 50 to 55°C to get 31.2 gm pure Nebivolol hydrochloride. SOR [α]D between (-) 1o to (+) 1°; HPLC purity >99.8%,Chiral purity >99.7%

WE CLAIM:
1. An improved process for the preparation of nebivolol hydrochloride of formula I, comprising the ratio of d-nebivolol and /-nebivolol within 48.5% to 51.5%,

the process comprising the steps of: a), treating benzylamine with isomer A in suitable solvent;

b). isolating compound of formula II;

c). condensing the compound of formula II with isomer B in an organic solvent;

d). forming benzylated nebivolol of formula III in-situ;


e). deprotecting compound of formula III in situ by catalytic hydrogenation
in autoclave to form nebivolol free base; f). treating nebivolol free base in situ with alcoholic hydrochloric acid; g). isolating technical nebivolol hydrochloride; and h). purifying technical nebivolol hydrochloride in suitable solvent to get
pure nebivolol hydrochloride of formula I.
2. The process according to claim 1, wherein
in step a), suitable solvent is selected from lower alcohols such as methanol,
ethanol, n-propanol, isopropylalcohol or water or mixtures thereof;
in step c), organic solvent is selected from lower alcohols such as methanol,
ethanol, n-propanol, isopropylalcohol or mixtures thereof;
in step e), hydrogenation catalyst is selected from palladium on carbon, raney
nickel, palladium hydroxide, platinum on carbon or platinum oxide; and
in step g), nebivolol hydrochloride is isolated at temperature 37-39°C.
3. A process for the preparation of compound of formula II, process comprising
the steps of:
a), providing isomer A in a suitable solvent;
b). providing benzylamine in a suitable solvent;
c). adding solution of step a) into solution of step b) drop wise or lot wise;
and d). isolating compound of formula II.
4. The process according to claim 3, wherein organic solvent is selected from
lower alcohols such as methanol, ethanol, n-propanol, isopropylalcohol or
water or mixtures thereof.
5. An in-situ process for the preparation of technical nebivolol hydrochloride;
the process comprising the steps of:
a), condensing the compound of formula II with isomer B in an organic solvent;

b). forming benzylated nebivolol of formula III;


c). deprotecting compound of formula III by catalytic hydrogenation in
autoclave to form nebivolol free base; d). treating formed nebivolol free base with alcoholic hydrochloric acid in
different reaction vessel; and e). isolating technical nebivolol hydrochloride.
6. The process according to claim 5, wherein
in step a), organic solvent is selected from lower alcohols such as methanol, ethanol, n-propanol, isopropylalcohol or mixtures thereof; in step c), hydrogenation catalyst is selected from palladium on carbon, raney nickel, palladium hydroxide, platinum on carbon or platinum oxide; and in step e), nebivolol hydrochloride is isolated at temperature 37-39°C.
7. A process for the purification of technical nebivolol hydrochloride, the
process comprising the steps of:
a), dissolving technical nebivolol hydrochloride in methanol; b). refluxing the reaction mixture; c). filtering the reaction mixture;

d). distilling methanol;
e), cooling at temperature 37 to 39°C; and
f). isolating pure nebivolol hydrochloride of formula I.
8. A process for the preparation of technical nebivolol hydrochloride, consisting the steps of; providing reaction mixture of nebivolol free base in autoclave; transferring the reaction mixture into glass vessel from autoclave; adding alcoholic hydrochloric acid in to reaction mixture; and isolating technical nebivolol hydrochloride.
9. The process according to claim 8, wherein reaction mixture of nebivolol free base obtained after deprotection of formula III.
10. Nebivolol hydrochloride consisting ratio of d-nebivolol and /-nebivolol between 48.5% to 51.5% with total chiral purity more than 99%.