FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATES OF IVABRADINE HYDROCHLORIDE
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY
ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED PROCESS FOR THE PREPARATION OF INTERMEDIATES OF IVABRADINE HYDROCHLORIDE
TECHNICAL FIELD
The present invention relates to an improved process for the preparation of N-[(4,5-Dimethoxybenzocyclobut-1-yl) methyl] amine (Formula-V), racemic N-[(4,5-Dimethoxybenzocyclobut-1-yl) methyl] - N- (methyl) amine (Formula-II) and the preparation of a novel intermediate, S (+) N-[ (4,5-Dimethoxybenzocyclobut-l-yl) methyl] - N- (methyl) amine mandelic acid salt (Formula-IIa), the intermediates of Ivabradine hydrochloride
BACKGROUND OF THE INVENTION
Ivabradine hydrochloride, chemically known as (S)-7,8-Dimethoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-1-yl) methyl] -N- (methyl) amino} propyl}-1,3,4,5-tetrahydro-2H- 3-benzazepin -2- one of formula-I is an antianginal agent.

Formula-I
It has very valuable pharmacological and therapeutic, particularly bradycardic properties that make this compound useful in the treatment/prevention of myocardial ischemia such as angina pectoris, myocardial infarct, associated rhythm disturbances and various pathological situations involving supraventricular rhythm disturbances and in the treatment of the heart failure.
Synthesis of Ivabradine hydrochloride is first disclosed in Adir's US5296482 patent.

The process for the preparation of Ivabradine hydrochloride of formula I, comprises the condensation of (S)-N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-methyl amine of formula II, with 7,8-dimethoxy-3-[3-iodopropyl]l,3-dihydro-2H-3-benzazepin-2-one of formula-Ill to give (S)-7,8-Dimefhoxy -3-{3-{N [(4,5-dimethoxybenzocyclobut-1-yl) methyl] -N- (methyl) amino} propyl}-l,3- dihydro-2H- 3-benzazepin -2- one, which on reduction gives Ivabradine hydrochloride of formula 1.
The racemic N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N- (methyl) amine of formula-ll is prepared by using l-cyano-4,5-dimethoxybenzocyclobutane of formula-IV.
'482 reveals three stages to convert compound of formula-IV into racemic compound of formula-II by reacting compound of formula-IV with borane in tetrahydrofuran to give N-[(4,5-dimethoxybenzocyclobuta-l-yl)methyl] amine hydrochloride of formula-V. This on coupling with ethyl chloroformate gives carbamate, N-[(4,5-dimethoxybenzocyclobuta-l-yl)methyl]-N- (ethoxy carbonyl) amine of formula-VI, which on reduction with lithium aluminium hydride gives the racemic product of formula-H.
Racemic N-[ (4,5-dimethoxybenzocyclobut-l-yl) methyl]-N- (methyl) amine of formula-II is resolved by using (d)-camphor sulfonic acid and ethanol as a solvent followed by its subsequent crystallization in solvents like ethyl acetate and acetonitrile to give pure chiral intermediate of formula-lib. The schematic representation of this process is given in the following scheme I:
Scheme-I:


This '482 disclosed process involves low yield as well as use of expensive resolving agent which is difficult to recover such as camphor sulfonic acid. Also, the use of lithium aluminium hydride and THF during reduction of carbamate involves the operational hazards and not feasible for commercial manufacturing.
US20050261376 (Lerestif, Jean-Michel et.al, 2005) relates to a process for the synthesis of compound of formula-V by reduction of nitrile of formula-IV by Raney nickel catalyzed hydrogenation in an ammoniacal alcohol solvent or reduction by using borane complexed with tetrahydrofuran or using sodium borohydride/trifluoro acetic acid.
It also relates to a process for the resolution of compound of formula-V, wherein the amine of formula-V is reacted with an optically active diacid compound, particularly diacidic amino acid compound, N-acetyl-L-glutamic acid in presence of a mixture of ethanol/water or in a mixture of ethyl acetate/ethanol/water to yield a salt, which is

reacted with a base to obtain a compound of formula-Va, S(+)N-[(4,5-dimethoxybenzocyclobuta-1 -yl)methyl] amine.

The optically active amine of formula-Va is reacted with ethyl chloro formate and reduced to give product of formula-IL The cumbersome preparation and use of ammoniacal alcohol and high pressure catalytic hydrogenation in an autoclave for the reduction of nitrile derivative (formula-IV) to primary amine (formula-V) is a drawback for this process.
The use of l-cyano-4,5-dimethoxybenzocyclobutane as a raw material in presence of borane with tetrahydrofuran and ethanol to prepare l-aminomethyl-4,5-dimethoxy benzocyclobutane hydrochloride is also disclosed in J. Org. Chem.37(21), 3374-76, 1972.
In US20050228177 (Lerestif, Jean-Michel et .al, 2005) relates to a process for the synthesis of Ivabradine and its pharmaceutically acceptable acid salts and hydrates, wherein 7,8-dimethoxy-3-substituted-l,3-dihydro-2H-3-benzazepin-2-one derivative is subjected to catalytic hydrogenation to give a reduced derivative, 7,8-dimethoxy-3-substituted-I,3,4,5-tetrahydro-2H-3-benzazepin-2-one derivative, which is then reacted with a salt of compound of formula-II in presence of hydrogen and a catalyst in a single step. However, the said process may involves the increased number of steps while converting the susbstituted benzazepine derivative to Ivabradine.
The use of different resolving agents to obtain chirally pure entity of formula-II is disclosed in patent applications like WO2008/146308 (Singh, S.P et al., 2008), which discloses the preparation of formula-IIa by using (d)-camphorsulphonic acid. The

yield of the product obtained by using (d)-camphorsulphonic acid was very low as reported in prior art.
The WO2009/062377 (Sun, P et.al, 2008) relates to a process for the preparation of optically active salt of formula-II by using L/D- di-p-toluoyl tartaric acid or L/D dibenzoyl tartaric acid as resolving agents in a solution of alcohol or alcohol in water to give its salts, which are resolved to give enantiomers of compound of formula- II. However, it appears that it involves the use of excessive amount of solvent during crystallization of salt.
As described above these cited literature process suffers from many drawbacks like purification of intermediates by column chromatographic techniques, difficulty in scale up on an industrial scale, relatively lower yields in various steps, especially in resolution part.
In view of the above, it was decided to develop an efficient, cost effective and eco friendly process for the preparation of pure Ivabradine intermediates.
OBJECT OF THE INVENTION
The object of the present invention is to provide an efficient and industrially scalable and advantageous process for the preparation of pure Ivabradine intermediates.
Another object of the present invention is to provide a cost effective and eco friendly process for the preparation of pure Ivabradine intermediates.
Yet another object of the present invention is to provide a process for preparing a novel intermediate of Ivabradine, for efficient preparation of Ivabradine hydrochloride.
SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparing a novel intermediate S (+)- N- [(4,5-Dimethoxybenzocyclobut-I-yl)methy]]-N-(methyl)amine mandelic acid salt, formula-IIa of Ivabradine hydrochloride

FormuIa-IIa
comprising the steps of
with formic acid in an organic solvent to get an N-formyl intermediate (VII)
a) Reacting compound of formuIa-V


b) which in situ reacted with methylating agent in presence of base and catalyst to give compound of formula-VIII

c) compound of formula-VIII of step b) on hydrolysis with aqueous base in a solvent at moderate temperature provide racemic compound of formula-II;


Formula-II
d) resolution of racemic compound of formula-II of step c) with optically active aromatic α-hydroxy acid in an organic solvent gives novel compound of formula-IIa.

FormuIa-IIa
According to another aspect of the present invention, there is provided an improved process for the preparation of an intermediate of Ivabradine of formula-V

Formula-V
by reduction of compound of formula IV, in presence of catalyst, inorganic base, metal borohydrides, and a polar protic solvent.

FormuIa-IV
Yet another aspect of the present invention is to synthesize a novel intermediate S (+)-N- [(4,5-Dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amine mandelic acid salt of formula-II a


Formula-IIa
Another aspect of the present invention is to synthesize a novel intermediate of Ivabradine of formula-VIII.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an efficient and industrially advantageous process for the preparation of pure Ivabradine intermediates. Also, the process covered in the present invention is very useful, especially during its large scale production as the storage and handling of the reagents, chemicals and intermediates are quite safe.
The present invention, represented as Scheme-II, relates to an improved process for the preparation of formuIa-V by using formula-IV as a starting material, in presence of inorganic base, catalyst, metal borohydride and polar protic solvents. The inorganic base can be selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate or alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide. The polar aprotic or protic solvents are selected from tetrahydrofuran, acetone, dimethylformamide, alcohols such as methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butanol, and acetic acid, preferably methanol or ethanol. The metal borohydrides were used for the reaction

such as sodium borohydride, lithium borohydride more preferably sodium borohydride, in presence of catalyst used in hydrogenation reaction like Raney-Nickel, Pd/C, Pt/C, more preferably raney nickel. The sc>dium borohydride added to the reaction mixture in small portions for to avoid sudden high exotherm during the reaction. The reaction is conducted at room temperature to 40°C, more preferably in the range of 28-35°C. The completion of reaction is monitored by HPLC. The organic solvent used for extraction of reaction mixture is selected from halogenated hydrocarbon such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, more preferably ethyl acetate.
Another aspect of present invention is to provide a novel process for the preparation of racemic intermediate having formula-ll. The synthesis comprises of four steps including resolution step.
The first step involves the reaction of N-[(4,5-dimethoxybenzocyclobuta-l-yl)methyl] amine, compound of formula-V with formic acid in suitable organic aprotic solvent like in toluene or xylene preferably toluene. This reaction is carried out at 60 to 110°C, preferably between 90-100°C and the progress of the reaction is monitored by HPLC. The reaction mixture is diluted with water, the layers are separated, the aqueous layer is extracted with solvent selected from chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, more preferably ethyl acetate. The distillation of the solvent gives oily mass and the compound was characterized having formula-VII, which is used directly without further purification in the next step.
In second step the product of first step N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(formyl) amine (crude) of formula-VII telescopically taken further for methylation in organic solvents like toluene, xylene, more preferably toluene with methylating reagents like methyl iodide, dimethyl sulphate, dimethyl carbonate, methyl triflate, more preferably, dimethyl sulphate in presence of base such as alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide or

alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate or alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, preferably potassium carbonate. Also catalysts used for this reaction are like Poly Ethylene Glycols (PEGs) or Phase Transfer Catalysts (PTCs) such as tertrabutyl ammonium salts like Tetra Butyl Ammonium Bromide (TBAB), Tetra Butyl Ammonium hydroxide, Tetra Butyl Ammonium Hydrogen Sulphate (TBAHS), more preferably TBAHS. The addition of the reagents is carried out at relatively low temperature and the reaction temperature is maintained in the range of 30 to 40°C. Completion of the reaction is monitored by HPLC. The reaction mixture is diluted with water, the layers are separated, the aqueous layer is extracted with solvent selected from chlorinated hydrocarbons such as methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or aliphatic esters such as methyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, more preferably ethyl acetate to obtain N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(formyl)-N-(methyl) amine, compound of formuIa-VIIl.

Formula-VIII
In the third step, N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(formyl)-N-(methyl) amine, compound of formuIa-VIIl is converted to N-methyl amine of formula-II by deformylation. This deformylation is carried out in presence of an aqueous base is selected from alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate or alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, and reaction solvent selected from C1-C4 alcohols like methanol, ethanol, propanol, butanol, preferably ethanol and the moderate temperature of the reaction is of 40-80°C , preferably 50-60°C. In the fourth step, the racemic compound of formula-II, N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(methyl) amine is taken in organic solvent which is selected from (C1-4) aliphatic alcohols or aqueous (C1-4) aliphatic alcohols, like methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol,

isobutanol, tert-butanol or aliphatic esters like ethyl acetate and mixtures thereof, preferably ethyl acetate and isopropyl alcohol.
and added chiral resoluting agents such as aromatic alpha hydroxyl acid like L(+) Mandelic acid at slightly higher temperature in the range of 40 to 80°C, preferably between 50-70 °C, cooled to give S (+)- N- [(4,5-Dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amine mandelic acid salt of formula-IIa.

Formula-IIa
The desired S-isomer is obtained by treating a mandelate salt, Formula-IIa with aqueous base and organic solvent.
By using the process of the present invention, the purity of the intermediates is superior to the process mentioned in prior art. Also, the chiral purity and yields obtained at resolution stage are better over the prior art.


Having described the invention with reference to certain preferred embodiments, the other embodiments will become apparent to one skilled in the art from consideration of the specification.
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
EXAMPLES
Example 1: Preparation of N-[(4,5-dimethoxybenzocyclobuta-l-yl) methyl] amine
A 2.0 liter round bottom flask equipped with overhead stirrer, thermometer pocket with thermometer and condenser with a calcium guard tube was charged with 1-cyano-4,5-dimethoxybenzocyclobutane (100 gm, 0.53 mole), ethanol (800 ml), activated raney nickel (100 gm), sodium hydroxide (5.0 gm) and stirred at a room temperature for 15 minutes. Sodium borohydride (50.04 gm, 1.325 moles) was added in small portions to maintain the temperature of reaction mixture below 50°C. The completion of the reaction was monitored by HPLC. The reaction mass was filtered and the solvent was distilled out under vacuum to get the residue, which was diluted with water (700 ml), extracted with ethyl acetate (400 ml), dried over sodium sulphate and the solvent distilled out under vacuum to give N-[(4,5-dimethoxybenzocyclobuta-l-yl)methyl] amine. Yield: 80%
Example 2: Preparation of S(+)-N-[ (4,5-dimethoxybenzocyclobut-l-yl) methyl] -N-(methyl) amine mandelic acid salt
Step-1 Preparation of N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(formyl) amine
In a 2.0 liter round bottom flask equipped with over head stirrer, thermometer pocket with thermometer, condenser with guard tube into a plastic tub, N-[(4,5-dimethoxybenzocyclobuta-l-yl)methyl] amine (135.0 gm, 0.699 moles) and toluene (900 ml) were added and cooled to 25-27°C. Formic acid (80.0 gms, 1.05 moles) was

added to the reaction mass and the reaction mixture was heated to 90°C. It was maintained at the same temperature till the completion of the reaction was observed by HPLC. The reaction mass was cooled to RT, diluted with water (650 ml) and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over sodium sulphate and distilled under vacuum to give N-[ (4,5-dimethoxybenzocyclobut-1 -yl) methyl]-N-(formyl) amine. Weight: 136 gms.
Step-2 Preparation of N-[(4,5-dimethoxybenzocycIobut-l-yl) methyl]-N-(formyl)-N-(methyl) amine
To a 2.0 liter round bottom flask equipped with overhead stirrer, thermometer pocket with thermometer, condenser with guard tube into a plastic tub, N-[(4,5-dimethoxybenzocyclobuta-]-y])merhyl]-N-(formyJ) amine (obtained from step-1), toluene (700 ml), potassium carbonate (117.7 gm, 2.098 moles)was charged, TBAHS (23.7 gm, 0.069 moles) and dimethyl sulphate (176.4 gm, 1.99 moles) were added to it dropwise. The reaction mass was maintained at 35-40°C till completion of the reaction, as was observed by HPLC. After completion of the reaction, the reaction mass was cooled to RT, diluted with water and the layers were separated. The aqueous layer was extracted with ethyl acetate, the organic layer was dried over sodium sulphate and distilled under vacuum to give N-[(4,5-dimethoxybenzocyclobut-1-yl) methyl]-N-(formyl)-N-(methyl) amine. Weight- 140 gms.
Step-3 Preparation of N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(methyl) amine
A 2.0 liter round bottom flask equipped with over head stirrer, thermometer pocket with thermometer, condenser with guard tube into a water bath, was charged with N-[(4,5-dimethoxybenzocyclobuta-l-yl)methyl]-N-(formyl)-N-(methyl) amine (140 gm, 0.596 moles) and ethanol (550 ml) and stirred at 20-30°C for 15 minutes. Aqueous sodium hydroxide solution was added gradually to the reaction mass, heated to 50-60°C until completion of the reaction. It was monitored by HPLC. The reaction mass was cooled, ethanol was distilled off under vacuum and the resulting residue was

diluted with water (600 ml). The aqueous layer was extracted with ethyl acetate, dried over sodium sulphate, distilled out the solvent to give N-[(4,5-dimethoxybenzocyclobut-1-yl) methyl]-N-(methyl) amine. Weight-120 gms.
Step-4 S(+)-N-[(4,5-dimethoxybedzocyclobut-l-yI)methyl ]-N-(methy))amine mandelic acid salt
To a 2.0 liter round bottom flask equipped with over head stirrer, thermometer pocket with thermometer, condenser with guard tube into a plastic tub, was charged L(+) Mandelic acid (10.0 gm, 0.066 moles) with ethyl acetate (100.0 ml) and stirred for 5 minutes to get a clear solution. Heat the reaction mixture to 50 to 70°C and maintained for 10 minutes. Racemic N-[(4,5-dimethoxybenzocyclobut-l-yl) methyl]-N-(methyl) amine (14.0 gm, 0.067 moles) dissolved in 110.0 ml of ethyl acetate. This solution was added to the mandelic acid solution. Maintained the reaction mixture at same temperature for 30 minutes, heating was stopped and cooled slowly to room temperature. Stirred at room temperature for 2 hrs, the product was filtered and washed with ethyl acetate. The product was dried at 50°C for 2 hours. The subsequent recrystallisation was performed by using isopropyl alcohol as a solvent for recrystallisation. The final product was dried at 50-60°C for 2 hours, ee->99%.

We Claim:
1. An improved process for preparing S (+)- N- [(4,5-Dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amine mandelic acid salt of formula-IIa, a novel intermediate of Ivabradine hydrochloride

Formula-IIa
comprising the steps of
with formic acid in an organic solvent to get an N-formyl intermediate (VII)

a) reacting compound of formula-V

b) which in situ reacted with methylating agent in presence of base and catalyst using aprotic organic solvent to give compound of formula-VIII

c) compound of formula-VIII of step b) on hydrolysis with aqueous base in a solvent at moderate temperature provide racemic compound of formula-II;


Formula-II
d) resolution of racemic compound of formula-II of step c) with optically active aromatic α -hydroxy acid in an organic solvent gives novel compound of formula-Ila.

2. An improved process according to claim la), wherein aprotic organic solvent is selected from xylene, toluene or mixtures thereof, preferably toluene and reaction temperature is 60 to 110°C, preferably 90-100°C
3. An improved process according to claim lb), wherein the methylating agent is selected from methyl iodide, dimethyl sulphate, dimethyl carbonate and methyl triflate, preferably dimethyl sulphate, and aprotic organic solvent is selected from xylene, toluene and mixtures there of, more preferably toluene.
4. An improved process according to claim lb), wherein the base is selected from alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates like lithium bicarbonate, sodium bicarbonate or potassium bicarbonate or alkali metal carbonates such as lithium carbonate, sodium carbonate or potassium carbonate, preferably potassium carbonate.
5. An improved process according to claim lb), wherein the catalyst is selected from poly ethylene glycols (PEGs) or phase transfer catalysts like tetra butyl ammonium bromide, tetra butyl ammonium hydroxide or tetra butyl ammonium hydrogen sulphate, preferably tetra butyl ammonium hydrogen sulphate.

6. An improved process according to claim lc), wherein aqueous base is selected from alkali metal carbonates like lithium carbonate, sodium carbonate, potassium carbonate or alkali metal hydroxides like lithium hydroxide, sodium hydroxide, potassium hydroxide, preferably sodium hydroxide or potassium hydroxide, and reaction solvent selected from C1-C4 alcohols like metha.nol, ethanol, propanol, butanol, preferably ethanol and the moderate temperature of the reaction is of 40-80°C preferably 50-60°
7. An improved process according to claim Id), wherein the optically active aromatic a hydroxy acid used is L (+) Mandelic acid.
8. An improved process according to claim Id), wherein organic solvent is selected from (CM) aliphatic alcohols or aqueous (CM) aliphatic alcohols, like methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butanol or aliphatic esters like ethyl acetate and mixtures thereof, preferably ethyl acetate and isopropyl alcohol.
9. An improved process according to claim Id), wherein the reaction is carried out at 40°C to 80°C, preferably 50-70 °C.
10. S (+)- N- [(4,5-Dimethoxybenzocyclobut-l-yl)methyl]-N-(methyl)amine mandelic
acid salt of formula-lla

Formula-IIa
11. An improved process for preparing a pure Ivabradine intermediate of formula-V


by reduction of compound of formula IV, in presence of catalyst, inorganic base, metal borohydrides, and a polar protic solvent.

12. An improved process according to claim 11, wherein inorganic base is selected from alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium hydroxide.
13. An improved process according to claim 11, wherein polar protic solvent is selected from alcohols or aq alcohols like methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, isobutanol, tert-butanol, preferably methanol or ethanol.
14. An improved process according to claim 11, wherein the catalyst is selected from a group consisting of Raney-Nickel, Pd/C, Pt/C, more preferably Raney Nickel.
15. An improved process according to claim 11, wherein the metal borohydrides is selected from alkali metal borohydrides like sodium borohydride, lithium borohydride, preferably sodium borohydride.
16. An improved process according to claim 11, wherein the reaction is carried out at room temperature to 40°C, preferably at 28-35°C

17. An intermediate of formula-VIII.

18. An improved process according to any of the preceding claims substantially as herein described with reference to the examples.