WO2015071831A1

WO2015071831A1 - An improved process for minimising the formation of dehalogenated byproducts

Info

Publication number: WO2015071831A1
Application number: PCT/IB2014/065978
Authority: WO
Inventors: Shashikant KADAM; Rajshekar ARADDY; Venkateswara Rao KONDRAGUNTA; Yogesh HULAVALE; Narender Rao SOMISETTI; Suneel Manohar Babu Chennamsetty; Sivaramakrishnan Hariharan
Original assignee: Piramal Enterprises Limited
Priority date: 2013-11-18
Filing date: 2014-11-12
Publication date: 2015-05-21
Also published as: IN2013MU03596A

Abstract

The present invention provides an improved process for preparation of organic compounds represented by Formula-Z; wherein effectively minimising the formation of dehalogenated by-products is achieved. In the process, the reduction is carried out using suitable reducing agent; more preferably Lithium Aluminium Hydride (LAH) in a solvent system, wherein at least one of the solvent is selected from halogenated solvents, which acts as co-solvent. The process of the present invention is useful for minimising of the formation of dehalogenated by-products during synthesis of various active pharmaceutical ingredients such as Paroxetine Hydrochloride, Cinacalcet, Eletriptan and Asenapine.

Description

AN IMPROVED PROCESS FOR MINIMISING THE FORMATION OF

DEHALOGENATED BYPRODUCTS

FIELD OF THE INVENTION

The present invention generally relates an improved process for the preparation of an organic compound (described herein by the compounds of Formula-Z), which is a therapeutically active compound. Particularly, the process of the present invention minimises the formation of the undesired dehalogenated by-products. The organic compounds synthesised by the process of the present invention includes the compounds containing one or more halogen atoms.

BACKGROUND OF THE INVENTION

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

Certain haloaryl-3-carbinol piperidine compounds represented by the following general Formula-2 are known to be therapeutically active compounds;

R

Formula-2 wherein, X is a halogen selected from F, CI, Br or I; and R is hydrogen, alkyl, aryl or arylalkyl.

The compounds encompassed in the above Formula-2 have been found to be especially useful in the treatment of CNS disorders such as depression and Parkinson's disease. Paroxetine hydrochloride, a representative compound falling in the class of the compounds represented by Formula 2 is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4'-fluorophenyl)- 3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate represented by the following Formula-3. This drug is marketed by the innovator, GlaxoSmithKline under the trademark of PAXIL®.

Formula-3

Numerous industrially and commercially viable synthetic routes for the preparation haloaryl- 3-carbinol piperidine compounds of formula-2 are reported in the prior art. Most of the reported processes involve use of alkalimetalhydride reagents for reduction of the carbonyl group.

US Patent No.3, 912,743 describes a process involving reduction of 4-aryl-3- piperidinecarboxylic acid esters represented by the following Formula (2a), using lithium aluminium hydride;

Formula-2a

Wherein X is halogen, hydrogen, -OCH₃or -SH, R is alkyl or aryl; and Ri is (Ci-C₄)alkyl.

US Patent No. 4,902,801 describes a process wherein reduction of 4-aryl-2, 6-dioxo-3- piperidine carboxylic acid ester represented by the following general Formula- 2b is carried out using lithium aluminium hydride;

Formula-2b

Wherein X is halogen, hydrogen, (Ci-C₄)alkyl, arylalkyl or trifluoroalkyl, R is hydrogen, (C_\- C₄) alkyl or arylalkyl ; and Ri is lower alkyl.

US Patent No. 6,197,960 describes a process involving reduction of trans-4-aryl-6- oxopiperidine-3-carbinols represented by the following Formula- 2c using hydrides or metal hydrides;

Formula- 2c

Wherein R is hydrogen, (Ci-C₄) alkyl or arylalkylgroup and Rl is hydrogen, lower alkyl or an aryl group or arylalkyl.

International Patent Application publication WO 96/36636 describes the reduction of a compound represented by the following Formula- 2d by using a metal hydride.

Formula-2d Wherein R is (Ci-Cs)alkyl, phenyl-(Ci-Cs)-alkyl or substituted phenyl-(Ci-C5)-alkyl.

The process(es) reported in the prior art involving use of metal hydride reagents in the reduction step, normally required use of the said reagent in excess for complete conversion of the reactant(s). Such excess use of the hydride reagent, most of the time results in an undesired hydro genoly sis side reaction leading to desfluorination of the phenyl ring. The desfluoro impurity represented by the following Formula-2DF is formed to certain extent even under mild conditions. Particularly, during large scale synthesis, the desfluoro impurity formation takes place due to the overloading of the reagent, and variation in the reaction temperature due to exothermicity.

Formula- 2DF

In the subsequent reaction step, along with the compound of Formula-2, this impurity represented by Formula-2DF also undergoes similar chemical transformation, thereby resulting in the formation of desfluoro impurity, for example, a compound represented by the following Formula-3PDF in the final product such as Paroxetine (compound of Formula-3). The limit for the content of this impurity is 0.1% as per the US pharmacopeia monograph.

Formula- 3 PDF

It is important to note that subjecting Paroxetine (the compound of Formula-3) or its intermediates to purification will not decrease the desfluoro impurity content (the compound of Formula-3PDF) substantially, as this impurity is structurally very similar to the Paroxetine and its intermediate compounds.

Also, it is important to note that the deshalo impurity such as the desfluoro impurity i.e. the compound of Formula-3PDF in paroxetine, is a commonly formed impurity in processes for the manufacture of the 'halo substituted' APIs (Active Pharmaceutical Ingredients) and their intermediates, which involves reduction of functional groups such as an acid (-COOH), an ester (e.g.-COOCH₃), amide (-CONH₂) using metal hydride reagents.

The improved process of the present invention is also directed to the compounds represented by the following Formula-4, which refer to trihalocinnamic acid and its derivatives.

Formula-4 wherein, X represents H or a halogen selected from F, CI, Br or I; provided that at least one X is halogen.

The compounds of Formula 4 constitute key intermediates in the preparation of the therapeutically active compounds such as Cinacalcet hydrochloride represented by the following Formula-5, which is a calcimimetic agent (i.e. it mimics the action of calcium on tissues) by allosteric activation of the calcium- sensing receptor that is expressed in various human organ tissues. It is marketed by Amgen under the trade name SENSIPAR®. Cinacalcet is used for the treatment of hyperparathyroidism (elevated parathyroid hormone levels), a consequence of parathyroid tumours and chronic renal failure.

Formula-5

In Tetrahedron Letters (2004), 45, 8355, a process for the preparation of a key starting material namely 3-[3(trifluoromethyl) phenyl] propionaldehyde (the compound of Formula- 5a) is described, wherein 3-(trifluoromethyl) cinnamic acid is reduced to the corresponding alcohol using lithium aluminium hydride (LAH ),followed by Swern oxidation.

Formula- 5 a

The major disadvantage associated with the above process is the formation of undesired desfluoro compound represented by the following Formula-5DF due to the use of LAH which is a strong reducing agent. The purification of the compound of Formula 5a for the removal of this impurity is a tedious process.

Formula-5DF

The improved process of the present invention is also directed to the compounds represented by the following Formula-6 which refers to methyl pyrrolidine substituted indole compounds and its derivatives.

Formula-6 wherein, X represents a halogen selected from F, CI, Br or I.

The compound of Formula-6 constitutes valuable intermediate in the preparation of therapeutically active compounds such as Eletriptan and salts thereof. Eletriptan is chemically known as 3-[[(R]-l-methyl-2-pyrrolidiny) methyl] -5- [2-(phenylsulfonyl) ethyl] indole, which is represented by the following Formula-7. Eletriptan is known to be used for acute treatment of migraine in adults. It is a selective 5-hydroxy triptamine IB/ID receptor agonist, which is administrated as Eletriptan hydrobromide. Eletriptan Hydrobromide is marketed by Pfizer under the brand name of RELPAX®.

Formula-7 The synthesis of Eletriptan and its intermediate is disclosed in US patent No. 5,545,644, which is illustrated below:

In this process, the key intermediate,5-bromo-3-[(R)-l-methyl-pyrrolidin-2-ylmethyl]-lH- indole represented by the following Formula-7b is prepared by reduction of the compound Formula-7a by using LAH. Such a process, which involves use of a strong reducing reagent such as LAH, will always lead to the formation of des-bromo impurity represented by the following Formula-7DB,

Formula-7DB

It is evident from the above representative examples that processes involving reduction step using strong reducing reagent such as Lithium Aluminium Hydride (LAH) lead to the formation of des-halogenated impurities; and that removal of such des-halogenated impurities would require further purification steps, thereby rendering the whole process costly. In view of this, it is required to develop a commercially viable process, which results in minimising the formation of des-halogenated impurities while still using strong reducing reagents such as LAH in the reduction step.

Inventors of the present invention directed their efforts in solving the underlying problem and have developed an improved process, which involves reduction using strong reducing reagent such as Lithium Aluminium Hydride (LAH) wherein the formation of desfluoro impurity can be avoided or minimized to very lower extent. The process does not involve use of any additional costly reagent, hence it is eco-friendly, cost effective and scalable process. SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an improved process for the preparation of an organic compound represented by the following general Formula-Z;

Formula-Z wherein ring A is selected from the following formula (i), (ii), (iii), (iv) or (v),

Xi represents a halogen selected from F, CI, Br or I, that minimises the formation of dehalogenated by-products.

In another aspect, the present invention relates to an improved process for the preparation of an organic compound represented by the general Formula-Z; which comprises, reacting a compound of general Formula-H with Lithium Aluminium Hydride (LiAlH₄ or LAH) in a solvent system consisting of two or more solvents, wherein at least one of the solvent is selected from halogenated solvents which acts as a co- solvent.

According to another aspect of the present invention, there is provided an improved process for the preparation of (4-(4-fluorophenyl)-l-methylpiperidin-3-yl)-methanol represented by Formula-3B ("the compound of Formula-3B" as described herein), which is an intermediate for the preparation of Paroxetine; wherein the said process effectively minimises the formation of desfluoro by-products represented by the compound of Formula 3-Desfluoro. According to yet another aspect of the present invention, there is provided an improved process, which results in minimising the formation of deshalo by-products substantially below 0.1% w/w.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of an organic compound represented by the following general Formula-Z;

Formula-Z wherein ring A is selected from the following formula (i), (ii), (iii),(iv) or (v),

Xi represents a halogen selected from F, CI, Br or I;

comprising reacting a compound of general Formula-H (as described herein) with Lithium Aluminium Hydride (LAH) in a solvent system consisting of two or more solvents, wherein at least one of the solvent is selected from halogenated solvents which acts as a co-solvent.

The process of the present invention as described above is illustrated in the following

Scheme A.

SCHEME A wherein, Ring A is as defined above; and

Riis H, OH, 0(Ci-C₄) alkyl or -NX₂X₃; wherein X₂ and X₃ are independently selected from H or (Ci-Cio) alkyl.

The said process of the present invention as described herein results in minimising the formation of deshalo by-products substantially below 0.1% w/w.

In the context of the present invention, the term "dehalogenated by-products" or "dehalogenated by-product" refers to at least one compound that is formed as a by-product in the process of the present invention; wherein in the said by-products at least one of the halogen atom present in the ring A (selected from the formula (i), (ii), (iii), (iv) or (v)) of the compounds of formula H, is removed during the step of reduction using Lithium Aluminium Hydride (LAH). The terms "dehalogenated by-products" and "deshalo by-products" are used interchangeably. However, the formation of deshalo or dehalogenated by-products is substantially below 0.1% w/w.

Thus, the present invention provides an improved process for the preparation an organic compound represented by Formula (Z), wherein the formation of dehalogenated by-products is effectively minimised.

In the context of the present invention, the term "effectively minimised" used in reference to the dehalogenated by-products means that the said by-product is formed in a concentration of less than 0.1 % w/w.

In an embodiment, the process of the present invention comprises reacting a compound of general Fomula-H (as described above) with Lithium Aluminium Hydride (LAH) in a solvent system consisting of two or more solvents; wherein at least one of the solvent is selected from halogenated solvents which acts as a co-solvent. In an embodiment, the improved process of the present invention is useful for minimising the formation of the undesired dehalogenated by-products during the synthesis of known therapeutically active agents selected from Paroxetine Hydrochloride, Cinacalcet, Eletriptan and Asenapine that are encompassed in the above formula Z.

The scope of the present invention is not limited to the specified therapeutically active agents and can be extended to all the known therapeutic agents or investigational drugs wherein there is a possibility of the formation of dehalogenated by-products during their synthesis.

In a specific embodiment, the process for the preparation of an organic compound represented by the Formula-Z (as described above) comprises the steps of;

(a) dissolving a compound of general Formula-H in a solvent system consisting of two or more solvents; wherein at least one of the solvent is selected from halogenated solvents, which acts as a co- solvent.

(b) preparing a solution of Lithium Aluminium Hydride (LAH) in a solvent or a mixture of the solvents,

(c) slowly adding the solution of step (a) to the solution of step (b) under inert atmosphere, and at a temperature below 25°C to obtain a reaction mixture,

(d) stirring the reaction mixture as obtained in step (c) at a temperature higher than25°C,

(e) the reaction mixture of step (d) is treated with a base in an aqueous medium to obtain the compound of formula Z;

wherein in the said process the formation of dehalogenated by-products is effectively minimised.

Accordingly, the present invention provides a process for the preparation of the compound of Formula-Z which results in the formation of des-halogenated by-products insubstantially less concentration i.e. below 0.1% w/w.

Unless otherwise indicated, the term "solvent system" refers to a combination of two or more solvents; wherein at least one of the solvent is a halogenated solvent, which acts as a co- solvent.

The term "two or more" used in reference to the solvent system, particularly, in reference to the solvents, means that at least two solvents as described herein can be used in combination. For example, two or three or four or more solvents (as described herein can be used, provided that at least one of the solvent is a halogenated solvent, which acts as a co-solvent.

The term "halogenated solvent" refers to any solvent selected from, but is not limited to, dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene, or chloroform. More preferably, the halogenated solvent is dichloromethane or 4-bromotoluene.

The solvent, other than the halogenated solvent, used in the solvent system can be selected from water, an alcohol selected from the group consisting of methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ether selected from the group consisting of tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4- dioxane; and an aprotic solvent selected from the group consisting of acetonitrile, N,N- dimethyl formamide (DMF), Ν,Ν-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N- methylpyrrolidone (NMP); or an aromatic solvent selected from the group consisting of toluene, xylene and benzene or a mixture thereof.

The term "temperature of below 25°C" referred to in step (c) of the process can range from - 10°C to 20°C. Preferably, the temperature can range from -5°C to 10°C.

The term "temperature higher than 25°C"referred to in step (d) of the process can range from 25°Cto 50°C.Preferably, the temperature can range from 30°C to 40°C.

The base used in step (e) can be any suitable base selected from, but not limited to, sodium hydroxide, potassium hydroxide or sodium bicarbonate. Preferably, sodium hydroxide is used as the base in step (e).

The compound of formula Z obtained in step (e) of the process can be isolated by any suitable method including filtration, filtration under vacuum, centrifugation or decantation. The product i.e. the compound of formula Z obtained may be further or additionally dried to achieve the desired moisture content. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.

In an embodiment, the present invention relates to an improved process for the preparation of the compound of formula Z (as described above) wherein ring A represents Formula (i) or (v) (wherein X₁ is F)) corresponding to the compound of Formula 3B (as described below); which is an intermediate for the preparation of Paroxetine, a therapeutically active compound.

Accordingly, in an embodiment of the present invention, there is provided an improved process for the preparation of (4-(4-fluorophenyl)-l-methylpiperidin-3-yl)-methanol represented by Formula-3B ("the compound of Formula-3B"), wherein the said process effectively minimises the formation of desfluoro by-product i.e. the compound of Formula 3-Desfluoro as described below.

The process of the present invention as described in the above embodiment, is illustrated in the following Scheme B.

Formula-3A Formula-3B Formula-3Desfluoro

SCHEME B wherein, R^p is hydrogen or (Ci-C₄)alkyl .

In an embodiment, the process for the preparation of the compound of Formula-3B comprises reacting piperidine 2,6-dione ester represented by Fomula-3A with Lithium Aluminium Hydride (LAH) in a solvent system consisting of two or more solvents, wherein at least one of the solvent is selected from halogenated solvents; and that the halogenated solvent is used as a co- solvent.

The processes for the preparation of above intermediate of Paroxetine (the compound of Formula-3B) as reported in the prior art involves reduction of 3-alkyl carbonyl-4-(4'-fluoro phenyl)-N-methyl piperidine 2,6-dione ester by using LAH. It is found that in the processes of the prior art, desfluoro impurity (Formula-3 Desfluoro) i.e. 4-(4-phenyl)-l -methyl piperidn- 3- yl)-methanol is formed as the major impurity, and is present in an amount of about 0.5% w/w. Even by using different crystallisation methods, the desfluoro impurity cannot be reduced substantially. As per Pharmacopoeia prescriptions, particularly for Paroxetine hydrochloride USP; the content of the des-fluoro paroxetine present therein, should be less than 0.1%. The des-fluoro paroxetine corresponds to the compound of Formula-3Desfluoro as described herein.

Inventors of the present invention have found that when reduction of 3-alkyl carbonyl-4-(4'- fluoro phenyl)-N-methyl piperidine 2,6-dione ester(the compound of Formula-3A)solution using LAH is carried out in a suitable solvent system consisting of two or more solvents; wherein one of the solvent is methylenechloride (MDC) or 4-bromotoluene ; which is used as a co-solvent in 1 volume to 0.1 volume, the desfluoro by-product (compound of Formula 3- Desfluro) is substantially reduced to below 0.1% w/w.

Accordingly, in an embodiment, the present invention provides for an improved process which involves reduction of ethyl 4-(4-fluorophenyl)-l-methyl-2,6-dioxopiperidine-3- carboxylate(the compound of Formula-3A, wherein R^p is ethyl)using a strong reducing reagent such as Lithium Aluminium Hydride (LAH) ,and the reduction step is carried out in the presence of solvent system essentially consisting of a halogenated solvent as a co-solvent; by which the formation of desfluoro impurity can be avoided or substantially minimized to very lower extent below 0.1% w/w.

The afore discussed advantages of the process of the present invention is substantiated by a comparison of the amount of desfluoro impurity formed when the product corresponding to the compound of Formula-3B is obtained by the present process vis-a-vis that obtained when the product is formed by following one or more processes reported in the prior art. For the purpose, inventors of the present invention followed the prior art process for the preparation of the compound of formula 3B involving reduction of the compound of Formula 3A with LAH using THF (tetrahydrofuran) or Toluene-THF solvent system. Whereas, the process of the present invention for the preparation of the compound of formula 3B involved using a solvent system consisting of toluene, THF and a halogenated solvent; for example, Toluene+THF+ DCM. The halogenated solvent is selected from dichloromethane (DCM) or

4- Bromotoluene. The halogenated solvent is used as a co-solvent. The results of this comparative study are presented in the following Table(s) A and B respectively. In the following Table-A and Table-B; reference to the 1^st Experiment, the 2^nd Experiment and the 3 Experiment indicates that same experiment is repeated three times in order to ascertain the consistency in the results. The column- 1 and column-2 of the Table-A as well as that of the Table-B represents the results of the experiments that are carried out in the absence of a halogenated solvent as the co-solvent. Similarly, the column-3 and column-4 of the Table-A as well as that of Table-B represents the results of experiments that are carried out in the presence of a halogenated solvent as the co- solvent.

Table-A: Comparative data of desfluoro impurity formation using Toluene + THF and mixture of Toluene+THF+ DCM.

Table-B: Comparative data of desfluoro impurity formation using THF and mixture of Toluene+ THF+ 4-Bromotoluene.

Thus, it is evident from the comparative data presented in the above Tables that the process of the present invention results in substantial reduction in the formation of the undesired desfluoro impurity (the compound of Formula-3Desfluro as described above). In an embodiment, the present invention relates to an improved process for the preparation of the compound of formula Z (as described above wherein ring A represents Formula (iii) (wherein Xi is F) which is an intermediate for the preparation of Cinacalcet, a therapeutically active compound. The process of the present invention can substantially minimise formation of desfluoro impurity represented by the following Formula - 5DF.

Formula-5DF

In an embodiment, the present invention relates to an improved process for the preparation of the compound of formula Z (as described above wherein ring A represents Formula (iv) (wherein X₁ is Br) which is an intermediate for the preparation of Eletriptan, a therapeutically active compound. The process of the present invention can substantially minimise formation of desfluoro impurity represented by the following Formula-7DB

Formula-7DB

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES

Example-1: Preparation of (4-(4-fluorophenyl)-l-methylpiperidin-3-yl)methanol (compound of Formula-3B, an intermediate for Paroxetine) using dichloromethane as co-solvent:

ethyl 4-(4-fluoroplienyl)- l - (4-(4-f1uorophenyl)-1 - (l-methyl-4-pheriylpiperidin- metrryl-2,6-dioxopiperidine- methylpiperidin 3-yi)methanol

3-carboxylate -3-yl)methanol (Desfluoro impurity)

Charged 225 g of (0.805 moles) of 3-ethoxy carbonyl-4-(4'-fluoro phenyl)-N-methyl piperidine 2,6-dione in a reaction flask- 1 and 675 mL of toluene was added at 30°C and stirred to dissolve, followed by adding 112.5 ml (0.5 volumes) of dichloromethane (MDC) (as co- solvent).

To another reaction flask-2 charged THF (112.5 ml) and toluene (927 ml) under N₂† atmosphere. LAH solution (456 g) (15 % solution in THF +toluene, 0.747 moles) was mixed with the solvent mixture of reaction flask-2.

The reaction mixture of the reaction flask- 1 was slowly added to the LAH solution of the reaction flask-2 at a temperature ranging between -15°C and +10°C under N₂ blanket. The reaction mixture was stirred at temperature of 30-40°C for 2.5 h under N₂† atmosphere. The resulting reaction mixture was further treated with demineralised water and sodium hydroxide solution to yield the title compound.

Yield: 125.3 g (75.0%)

Purity by HPLC: 98.9%

Desfluoro impurity content (compound of Formula-3Desfluoro): 0.07 % w/w Example-2: Preparation of (4-(4-fluorophenyl)-l-methylpiperidin-3-yl)methanol (intermediate for Paroxetine) using 4-Bromotoluene as co-solvent:

ethyl 4-(4-fhiorophenyl)-l - (4-(4-f luorophenyl)- 1 - (1 -methyl-4-phenylpiperidin- methyl-2,6-dioxopiperidine- methylpiperidin 3-yl)methanol

3-carboxylate -3-yl)methanol (Desfluoro impurity)

Charged 225 g of (0.805 moles) of 3-ethoxy carbonyl-4-(4'-fluoro phenyl)-N-methyl piperidine 2,6-dione in a reaction flask- 1 and 675 ml of toluene was added at 30°C and stirred to dissolve, followed by adding 33.05g of (0.175 moles) of 4-bromotoluene (as co- solvent).

To another reaction flask-2 charged THF (112.5 ml) and toluene (927 ml) under N₂† atmosphere. LAH solution (456 g) (15 % solution in T H F +toluene, 0.747 moles) was mixed with the solvent mixture of reaction flask-2.

The reaction mixture of the reaction flask- 1 was slowly added to the LAH solution of the reaction flask-2 at a temperature ranging between -15°C and +10°C under N₂ blanket. The resulting reaction mixture was stirred at temperature of 30-40°C for 2.5 h nder N₂† atmosphere. The reaction mixture was further treated with demineralised water and sodium hydroxide solution to yield the title compound.

Yield: 126 g (72.3%)

Purity by HPLC: 99.13%

Desfluoro impurity content (compound of Formula-3Desfluoro): 0.03 % w/w.

Claims

WE CLAIM

1. A process for the preparation of an organic compound represented by the general Formula-Z;

Xi represents a halogen selected from F, CI, Br or I;

Comprising the step of, reduction of a compound of the general Formula-H,

Forres aia-W wherein Riis H, OH, 0(Ci-C₄) alkyl, -NX₂X₃; wherein X₂ and X₃ are independently selected from H or (Ci-Cio) alkyl; using Lithium Aluminium Hydride (LAH) in a solvent system consisting of two or more solvents, wherein at least one of the solvent is selected from halogenated solvents which acts as a co-solvent.

2. The process as claimed in claim 1, wherein the solvent other than the halogenated solvent is selected from water, toluene, tetrahydrofuran(THF), cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, Ν,Ν-dimethyl formamide (DMF), Ν,Ν-dimethyl acetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP),xylene, benzene and/or mixtures thereof.

3. The process as claimed in claim 1 or claim 2, wherein the halogenated solvent is

selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform.

4. The process as claimed any one of the claims 1 to 3, wherein in the said process the formation of dehalogenated by-products is substantially below 0.1% w/w.

5. A process for the preparation of (4-(4-fluorophenyl)-l-methylpiperidin-3-yl)- methanol represented by the compound of Formula-3B,

comprising the step of, reduction of the com ound of Formula-3A

wherein, R^p is hydrogen or (Ci-C₄) alkyl; using Lithium Aluminium Hydride (LAH) in a solvent system consisting of two or more solvents, wherein at least one of the solvent is selected from halogenated solvents which acts as co-solvent.

6. The process as claimed in claim 5, wherein in the compound of Formula-3 A, R^p is ethyl.

7. The process as claimed in claim 5, wherein the solvent other than the halogenated solvent is selected from water, toluene, tetrahydrofuran(THF), cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, acetonitrile, Ν,Ν-dimethyl formamide (DMF), Ν,Ν-dimethyl acetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), xylene, benzene and/or mixtures thereof.

8. The process as claimed in claim 5 or claim 7, wherein the halogenated solvent is

9. The process as claimed in any one of the claims 5 to 8, wherein in the said process the formation of desfluoro by-product, the com ound Formula 3-Desfluoro

is substantially below 0.1% w/w.