FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
"An Improved Process for Asymmetric Reduction"
Emcure Pharmaceuticals Limited.,
An Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER ESf WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to a novel, convenient and cost-effective process for the asymmetric reduction of compounds possessing prochiral ketone functionality. Typically, the invention relates to a process for preparation of enantiomerically pure alcohol intermediates required in the synthesis of various active pharmaceutical ingredients such as Dapoxetine, Rivastigmine, Arformoterol, Duloxetine, Fluoxetine, Atomoxetine etc. The invention, more specifically relates to the preparation of compounds of formula (I) having the desired chiral purity by asymmetric reduction of the prochiral ketones of formula (II).

wherein,
Aris phenyl, 2-thienyl, 3-hydroxy phenyl,
n is 1,2
B is H, Chloro, 1 -hydroxynaphthyl, and
in case of (I), the hydroxyl group may be located below (a) or above (P) the
plane of reference or is planar.
BACKGROUND OF THE INVENTION
Synthesis of chiral intermediates leading to enantiomerically enriched drug molecules finds wide application in the field of pharmaceutical chemistry. This is mainly due to the fact that the activity of various pharmaceutically active ingredients is attributed to a particular enantiomer of the molecule. Amongst these, chiral alcohol intermediates obtained by asymmetric reduction of the corresponding ketones forms an important area in the synthetic sequences designed for preparation of pharmaceuticals. Although different methodologies such as asymmetric hydrogenation, biocatalysis and transition metal catalysis are in use for obtaining chiral alcohols, however, asymmetric reduction using oxazaborolidine catalyst is one of the preferred methods for reduction of ketone functionality.

In oxazaborolidine catalysis, the selection of borane reductant for reaction with the optically active alcohol in oxazaborolidine reagent, such as (+) or (-) α,α-diphenyl-2-pyrrolidinyl methanol is an important aspect, especially, in case of operations carried out on industrial scales. Almost all of the chiral borane reagents are associated with serious hazards and safety related issues, especially at commercial scale, even though the hazards may not be foreseeable on laboratory scales. Use of borane reductants such as borane-tetrahydrofuran, borane-dimethyl sulfide, catechol-borane complexes, diborane, iodine-borohydride etc. for optically active a,a-diphenylprolinol catalyzed reductions is reported in the literature. However, serious limitations like high cost, handling problems and thermal decompositions limit their industrial usage. In order to circumvent the use of hazardous borane complexes, borane was generated in situ by employing tetrabutyl ammonium borohydride/methyl iodide or sodium borohydride/diiodomethane type systems. However, the genotoxic nature of alkyl halides used in the process and the associated strict regulatory norms for genotoxic entities prevent these methods from being pursued for commercial scale.
Reports are also available wherein borane-Lewis base complexes such as N,N-diethylaniline borane have been used as a reagent in α,α-diphenylprolinol catalyzed reductions of prochiral ketones. Utilization of iodine for generation of borane from sodium borohydride makes it extremely difficult for practice on an industrial scale.
US 7,365,212 discloses synthesis of chiral intermediates from α,α-diphenylprolinol-borane complex comprising use of sodium borohydride, N,N-diethylaniline and dimethyl sulfate. However, the process employs a volatile, highly toxic, corrosive and an environmentally hazardous reagent like dimethyl sulfate, which renders the process unviable for industrial application.
Thus, considering the wide scope of application of the chiral alcohol intermediates in pharmaceutical industry, the present inventors felt about the growing need for an improved methodology for preparation and use of oxazaborolidine catalyst, especially for asymmetric reduction of ketones.

The present inventors have developed an inexpensive, convenient and safe process for synthesis of intermediate (I) by asymmetric reduction of the corresponding ketone (II).
The compound (la), chemically known as (R)-3-chloro-l-phenyl-l-propanol, is an important intermediate in the synthesis of Dapoxetine, which is a short-acting selective serotonin reuptake inhibitor (SSRI) used in the treatment of premature ejaculation in men.

The compound of formula (Ia), derived from (IIa) wherein, Ar is phenyl, n is 2 and B is Chloro with the hydroxyl group located below the plane of reference i.e. (α).
Various methods are disclosed in the literature for synthesis of intermediate (Ia). GB 2451190 discloses a method wherein organometallic compounds with N-methanesulfonyl-l,2-diamine ligand and metals like rhodium or iridium are used for asymmetric reduction of substrates such as 3-chloro-1-phenylpropan-l-one. Although the method yields the desired alcohol with moderate enantiomeric excess and good yields, but the tedious method for such highly specific catalytic system coupled with the required technology become limiting factors for use of this method on industrial scale.
Tetrahedron Letters (1989), 30(39), 5207-10 describes stereospecific reduction of 3-chloro-1-phenylpropan-l-one with borane and chiral oxazaborolidine. Further, the use of borane as a source of boron becomes a serious constraint in the application of this process on industrial scale.
Similarly, reports for synthesis of compounds (Ic) and (Id), which are intermediates for Rivastigmine and Duloxetine respectively are also available in literature.


EP 1741693 discloses preparation of (R)-3-(l -hydroxyethyl)-phenol (Ic) by enantioselective hydrogenation of the corresponding ketone under pressure with a Ruthenium complex as catalyst.
US 7,601,667 discloses synthesis of intermediate (Ic) by catalytic hydrogenation of the respective ketone by utilizing a sulfonate catalyst having n bonding with metals like ruthenium, rhodium or iridium.
Synthesis of compound of formula (Id), (,S)-3-chloro-l-(thiophen-2-yl)-l-propanol as disclosed in Journal of Labelled Compds and Radiopharmaceuticals (1995), 36, 213-223 involves asymmetric reduction of 3-chloro-l-(thiophen-2-yl)-propan-l-one with borane-tetrahydrofuran and a oxazaborolidine catalyst.
Thus, it would be clear that the methods reported so far for asymmetric reduction of achiral ketones poses serious limitations with respect to cost of catalyst, technological requirements for preparation of catalysts or hazards during operations, especially for application on commercial scale. Therefore, there was a need to develop a process for synthesizing chiral intermediate of general formula (I) which avoids the drawbacks of the prior art processes.
The method involves asymmetric reduction of the prochiral ketone of general formula (II) by employing an insitu generated reagent synthesized from optically active α,α-diphenyl-2-pyrrolidinyl methanol, sodium borohydride and N,N-diethylaniline hydrochloride. It was found that the process yields enantiomerically pure alcohols, which are key intermediates in the synthesis of various chiral active pharmaceutical ingredients.

OBJECT OF THE INVENTION
An objective of the present invention is to provide a chiral intermediate of formula (I) by a safe, cost-effective process, which does not involve use of toxic and environmentally hazardous reagents such as iodine and dimethyl sulfate.
Another object of the invention is to provide an insitu generated catalyst for asymmetric reduction of the ketone of formula (II).
Yet another object of the present invention is to provide a simple and efficient process for preparation of enantiomerically pure alcohol intermediates which may be employed for the synthesis of Dapoxetine, Rivastigmine, Duloxetine, Fluoxetine, Atomoxetine etc.
SUMMARY OF THE INVENTION
The present invention relates to a novel process for the preparation of enantiomerically pure alcohols of general formula (I) by overcoming the problems faced in the prior art.
An aspect of the present invention relates to a process of preparing the chiral intermediates for Dapoxetine, Rivastigmine, Duloxetine having high enantiomeric purity and desired stereochemistry.
Yet another aspect of the invention relates to an improved and cost-effective process for the preparation of compound of formula (I) comprising addition of N,N-diethylaniline hydrochloride to sodium borohydride in an organic solvent, followed by addition of optically active α,α-diphenyl-2-pyrrolidinyl methanol , adding ketone of formula (II) dissolved in a second organic solvent to the mixture or vice versa and obtaining the compound of formula (I) having the desired optical purity.
These objectives of the present invention will become more apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION
The present inventors after rigorous experimentation in the pursuit of a catalyst capable for asymmetrically reducing a wide range of prochiral ketone functionalities and which can be handled conveniently on commercial scales have unexpectedly found that enantiomerically pure alcohols of general formula (I) can be easily prepared by the reaction of corresponding prochiral ketones with a reagent prepared by reaction of sodium borohydride and N,N-diethylaniline hydrochloride with an optically active α,α-diphenyl-2-pyrrolidinyl methanol. Further, this reagent can be generated in situ for the subsequent reduction reaction. The chiral alcohols of formula (I) thus obtained in good yields possesses high enantiomeric purity and do not require any additional purification.
In addition to this, the inventors have also developed simple and convenient method for recovery of the expensive reagent, a,a-diphenyl-2-pyrrolidinyl methanol, which considerably improves the economic feasibility of the process.
The asymmetric reduction methodology was applied for the synthesis of various chiral pharmaceutical intermediates utilized in the preparation of Rivastigmine, Arformoterol, Duloxetine, Dapoxetine, Fluoxetine, Atomoxetine, Eslicarbazepine etc. which belongs to diverse therapeutic areas.
Scheme 1: Method embodied in the present invention for the preparation of (R)-3-chloro-l-pheny 1-1-propanol (Ia) from 3-chloro-l-phenyl-propan-l-one (IIa)
Following the aforementioned methodology, the achiral ketone 3-chloro-l-phenyl-propan-1-one, compound (IIa) was asymmetrically reduced to give compound of formula (Ia); (R)-3 -chloro-1 -phenyl-1 -propanol.


In an embodiment, N,N-diethylaniline hydrochloride dissolved in an organic solvent was
slowly added to a suspension of sodium borohydride in a second organic solvent ,
followed by addition of optically active α,α-diphenyl-2-pyrrolidinyl methanol. The
reaction mixture was stirred in an inert atmosphere in the temperature range of 25 to
30°C.
The first organic solvent was selected from the group comprising of halogenated
hydrocarbons such as chloroform, dichloromethane, ethylene dichloride etc but
preferably dichloromethane while the second organic solvent was selected from the group
comprising of acetonitrile, 1,2-dimethoxyethane etc.
3-Chloro-l-phenyl-propan-l-one (IIa) dissolved in either of the mentioned solvents was
added to the borane catalyst mixture or vice-versa.
Although sequence of addition of reagents was not of much significance but it was
observed that the enantioselectivity of the reduction reaction was better when the
optically active (+) or (-) α,α-diphenyl-2-pyrrolidinyl methanol was added after N,N-
diethylaniline hydrochloride.
The reaction mixture was stirred at a temperature of 0 to 50°C but preferably in the range of 20 to 35°C.
It was also observed that enantioselectivity was adversely affected when molar ratio of N,N-diethylaniline hydrochloride to sodium borohydride was less than one. After completion of the reaction as monitored by HPLC, the reaction mixture was filtered and concentrated. An organic solvent such as a hydrocarbon or a chlorinated hydrocarbon like toluene or dichloromethane was added to the concentrated mass. The organic layer was separated and concentrated to give the desired (R)-(+)-3-chloro-l-phenyl-1-propanol (Ia) having enantiomeric purity greater than 97%. The isolated compound was subjected to further reaction with a-naphthol to obtain intermediate-2 for Dapoxetine Alternatively, to the concentrated organic layer containing compound (Ia), solution of a naphthol in dimethylformamide and aqueous sodium hydroxide solution were added. The reaction mixture was stirred in the temperature range of 90 to 95°C till completion of the reaction. The reaction mass was then mixed with toluene, separation of the organic layer and concentration gave (R)-3-(l-naphthalenyloxy)-l-phenyl-1-propanol.

Treatment of compound (R)-3-(l-naphthalenyloxy)-l-phenyl-l-propanol with triethylamine, methanesulfonyl chloride in methyl tertiary butyl ether at room temperature, followed by reaction with dimethylamine gave Dapoxetine (III), which was converted to dapoxetine hydrochloride (III) by treatment with hydrogen chloride. The intermediate (Ia), either in isolated form or as a solution in the organic solvent in which it was extracted, was subjected to further reactions for synthesis of Fluoxetine and Atomoxetine.
Similarly, as disclosed in Scheme-2, the intermediates (Ib; Ar: phenyl, n=2 and B= 1-naphthalenyloxy), (Ic; Ar: m-hydroxyphenyl, n=0 and B= methyl) and (Id; Ar= thiophene; n=2 and B=Cl) were prepared by following the aforementioned methodology. These intermediates were employed in the synthesis of Dapoxetine (III), Rivastigmine (VI) and Duloxetine (VII) respectively.

wherein,
Ar is phenyl, 2-thienyl, 3-hydroxy phenyl, n is 0,1,2;
B is H, Chloro, 1-hydroxynaphthyl, and
in case of (I), the hydroxyl group may be located below (a), above (P) the
plane of reference or is on the plane.
Scheme 2: Method embodied in the present invention for the preparation of intermediates (Ib), (Ic), and (Id), from the corresponding ketones (IIb), (IIc), and (IId)
Various intermediates prepared by employing the above mentioned method of asymmetric reduction and the corresponding active pharmaceutical ingredients are given below.


(R)-3-(l-naphthalenyloxy)-l-phenyl-l-propanol (Ib) Dapoxetine (III)
AR: Phenyl, B: 1-hydroxynaphthyl, n= 2 Intermediate-2 for Dapoxetine

(R)-(+)-3-chloro-l-phenyl-l-propanol (la) (R) - (-)-Fluoxetine (IV)
AR: Phenyl, B: chloro, n = 2 [Ar1 = α-4-trifluoromethylphenyl]
Intermediate for (R) - (-) Fluoxetine Atomoxetine (V)
& Atomoxetine [Ar1: 2-methylphenyl]

(R)-3-( 1 -hydroxyethyl)-phenol (Ic) Rivastigmine (VI)
Ar : 3-hydroxyphenyl, B : H, n = 1 Intermediate for Rivastigmine

(S)-3-chloro-l-thiophen-2-yl -1-propanol (Id) Duloxetine (VII)
Ar: thiophen-2-yl, B : chloro, n = 2 Intermediate for Duloxetine

Thus the invention described above encompasses a methodology for asymmetric reduction of ketones, which can be conveniently applied for synthesis of enantiomerically pure intermediates for various active pharmaceutical ingredients. The chiral purity of the desired product obtained by the above method was found to be between 85 to > 99%.
The present inventors extended the same methodology for synthesis of (R)-2-bromo-l-[(3-nitro-4-methoxyphenyl)-l-yl]-phenyl-l-ethanol, which is an intermediate for arformoterol; and also of (S)-10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine; an intermediate for eslicarbazepine. However, the attempt met with limited success since the reactions proceeded with incomplete conversion and low enantiomeric excess.
The following examples are meant to be illustrative of the present invention. These
examples exemplify the invention and are not to be construed as limiting the scope of the
invention.
Examples
Example 1: Synthesis of (R)-(+)-3-chloro-l-phenyl-1 -propanol (Ia). (Dapoxetine
intermediate-1)
N,N-diethylaniline hydrochloride (6.0Kg) in dichloromethane (9.01itres) was added
slowly to a solution of sodium borohydride (1.2Kg) in dimethoxyethane (241itres) and the
reaction mixture was stirred in inert atmosphere at 20 to 35°C. (S)-a,a-Diphenyl-2-
pyrrolidinyl methanol (450gms) dissolved in dichloromethane (600ml) was added to the
reaction mixture followed by slow addition of solution of 3-chloro-l-phenyl-propan-l-
one (Ha, 6.0Kg) in dichloromethane (9.01itres). Stirring was continued at room
temperature till completion of the reaction as monitored by HPLC.
After completion of the reaction, the resulting reaction mass was mixed with water,
concentrated hydrochloric acid and extracted with toluene. Separation and concentration
of the organic layer yielded (R)-(+)-3-chloro-l -phenyl-1 -propanol (Ia).
Yield: 5.83Kg.
Yield: 96%
Purity: 99.2%
[α]2D + 24.22° (c = 1 in chloroform)
Enantiomeric excess: 95%.

Example 2: Synthesis of (R)-3-(1-naphthalenyloxy)-1 -phenyl-1 -propanol (Ib)
(Dapoxetine intermediate-2) from the alcohol intermediate (Ia)
α-Naphthol (5.58Kg) in dimethylformamide (12.01itres) was added to (R)-(+)-3-chloro-l-
phenyl-1-propanol (5.83kg), followed by addition of aqueous sodium hydroxide solution
(1.8 kg in 1.8 litres water). The reaction mass was stirred at 90 to 95°C till completion of
the reaction, as monitored by HPLC.
After the reaction was complete, water was added to the reaction mass. The aqueous layer
was separated and extracted with toluene. The organic layer after separation was
concentrated to give a residue containing (R)-3-(l-naphthalenyloxy)-l-phenyl-l-propanol
(Ib). n-Heptane (12.01itres) was added to the residue with stirring to separate the product,
which was filtered and dried.
Yield: 6.7kg
Yield: 67.2 % (based on Ia)
Purity: 98% (HPLC).
Example 3: Synthesis of Dapoxetine hydrochloride (III)
Methanesulfonyl chloride (4.0 kg) was gradually added to a stirred solution of (R)-3-(l-
naphthalenyloxy)-l-phenyl-1-propanol (6.68kg) and triethylamine (4.87kg) in methyl
tertiary butyl-ether (33.41itres) at 5 to 10°C. Dimethylamine (10.0kg) was added to the
reaction mass at 5 to 10°C and reaction mixture was stirred at 25 to 30°C. After
completion of the reaction as monitored by HPLC, water was added to the reaction mass
and the organic layer was separated. Hydrochloric acid (6.68 litres), aqueous dimethyl
formamide (6.68 litres) in water (26.7 litres) was added to the organic layer, followed by
stirring and layer separation. The separated aqueous layer was basifled with sodium
hydroxide and extracted with toluene. Addition of hydrogen chloride to the organic layer
and followed by filtration and drying of the obtained solid gave Dapoxetine
hydrochloride (III).
Yield: 4.8 kg
Yield: 60 % (based on Ia)
Purity: 99.9 % (HPLC)
[a]25D= +135.5° (c = 2.18 in methanol)
Enantiomeric excess: 99.9 %

Example 4: Synthesis of (R)-3-(1-naphthalenyloxy)-l-phenyl-l-propanol (Ib)
(Dapoxetine intermediate-2) from the corresponding ketone (IIb)
N,N-Diethylaniline hydrochloride (6.14 g) in dichloromethane (15 ml) was added slowly
to a mixture of sodium borohydride (1.23 g) in dimethoxyethane (40 ml) and the reaction
mixture was stirred in inert atmosphere at 20 to 35°C. (S)-α,α-Diphenyl-2-pyrrolidinyl
methanol (0.50gms) in dichloromethane (15ml) was added to the reaction mixture
followed by slow addition of 3-(l-naphthalenyloxy)-l-phenyl-propan-l-one (IIb, 10g) in
dichloromethane (20 ml). Stirring was continued at room temperature till completion of
the reaction as monitored by HPLC.
The reaction mass was mixed with aqueous hydrochloric acid and extracted with toluene.
Separation and concentration of the organic layer yielded a residue containing (R)-3-(l-
naphthalenyloxy)-l-phenyl-1-propanol (lb). N-heptane was added to the residue for the
product to separate out, which was then filtered and dried.
Yield: 8.0gms.
Yield: 80 %
Purity: 99.0 % (HPLC)
[a]25D= - 61.3 ° (c = 1 in methanol)
Enantiomeric excess: 97.8 %
Example 5: Synthesis of (R)-3-(l-hydroxyethyl)-phenol (Ic) (Rivastigmine intermediate)
The compound of formula (Ic) was synthesized from the respective ketone, 3-hydroxy acetophenone (IIc) by following the procedure disclosed for synthesis of compounds (Ia) and (Ib). A mixture of (IIc, 10g) in dimethoxyethane (40 ml) was added to a mixture of sodium borohydride (2.5g), N,N-diethylaniline hydrochloride (12.3g) in dichloromethane (15 ml) and (S)-α,α-Diphenyl-2-pyrrolidinyl methanol (1.0g) till completion of reaction. The reaction mixture was filtered and diluted with toluene (100ml). The organic layer was separated and concentrated to give an oily residue containing (R)-3-(l-hydroxyethyl)-phenol compound (Ic). Yield: 9.0gms Yield: 95 %

Purity: 99% (HPLC) Enantiomeric excess: 86.0 %
Example 6: Synthesis of (S)-3-chloro-l-(thiophen-2-yl)-l-propanol (Id). (Duloxetine intermediate)
The compound of formula (Id) was synthesized from the respective ketone, 3-chloro-l-(thiophen-2-yl)-propan-l-one (IId) following the procedure disclosed for synthesis of compounds (Ia) and (Ib). A mixture of (IId; 50gms) in dimethoxyethane (200 ml) was added with stirring to a mixture of sodium borohydride (9.63gms) and N,N-diethylaniline hydrochloride (48.1gms) and (R)-α,α-diphenyl-2-pyrrolidinyl methanol (3.98gms) in dichloromethane (75ml) till completion of reaction as monitored by HPLC. Toluene (300ml) was added to the mixture; the organic layer was separated and concentrated. An oily residue containing (R)-3-chloro-l-(thiophen-2-yl)-l-propanol (Id) was obtained. Yield: 45gms (90 %) Purity: 98.5 % (HPLC)

[a] 25 D= -10.70 (c = 2.06. in isopropyl alcohol) Enantiomeric excess: 91.3 %

We Claim:
1. A process for the preparation of compound of formula (I), comprising addition of N,N diethylaniline hydrochloride to sodium borohydride in an organic solvent with stirring at 25 to 30°C, followed by addition of optically active α,α-diphenyl-2-pyrrolidinyl methanol, adding ketone of formula (II) dissolved in a second organic solvent to the mixture or vice versa and obtaining compound of formula (I) having desired optical purity.

wherein,
Ar is phenyl, 2-thienyl, 3-hydroxy phenyl, n is 0, 1, 2;
B is H, chloro, 1-hydroxynaphthyl, and
in case of (I), the hydroxyl group is located below the plane (a), above
the plane (p) or is in plane
2. A process as claimed in claim 1, wherein the organic solvent is selected from the group comprising of dichloromethane, ethylene dichloride and chloroform.
3. A process as claimed in claim 1, wherein the second organic solvent is selected from acetonitrile and 1,2-dimethoxyethane.
4. A process as claimed in claims 1 to 4, wherein the compounds of formula (I) is utilized for the preparation of dapoxetine, duloxetine and rivastigmine.
5. A process as claimed in claim 1, wherein the reaction with ketone of formula (II) is carried out in the temperature range of 0 C to 35 C.