DESC:FORM 2
THE PATENTS ACT, 1970
[39 of 1970]
&
PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

AN INDUSTRIAL PROCESS FOR
PREPARATION OF PHENYL PROPANOL DERIVATIVE

IND-SWIFT LABORATORIES LIMITED,
S.C.O. NO. 850, SHIVALIK ENCLAVE,
NAC, MANIMAJRA,
CHANDIGARH-160 101
(AN INDIAN ORGANIZATION)

The following application particularly describes the invention and the manner in which is to be performed
FIELD OF THE INVENTION
The present invention relates to an industrial process for the preparation of a phenyl propanol derivative, namely 3-(3-trifluoromethyl-phenyl)-propanol. In particular present invention relates to an industrially advantageneous, cost effective, operationally safe method for the preparation of a phenyl propanol derivative, an important intermediate in preparation of cinacalcet hydrochloride.

BACKROUND OF THE INVENTION
Cinacalcet hydrochloride, is a novel calcimimetic agent that modulate the extra cellular calcium sensing receptor by making it more sensitive to the calcium suppressive effects on parathyroid hormone and is chemically known as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-l-aminopropane hydrochloride and represented by below structure.

Cinacalcet hydrochloride is used in the treatment of primary and secondary hyperparathyroidism. Hyperparathyroidism is characterized by high levels of circulating calcium due to an increased secretion of parathyroid hormone by one or more of the parathyroid glands. Hyperparathyroidism can lead to osteoporosis; patients with renal failure suffering from secondary hyperparathyroidism have for example an increased risk of renal bone disease, soft-tissue calcifications and vascular disease.

Calcium receptor-active molecules like cinacalcet and its pharmaceutically acceptable salts thereof are disclosed in PCT publication WO 1994/018959, US patents 6,211,244, 6,313,146, 6,031,003, 6,001,068, 6,011,884, 5,962,314, 5,858,684, 5,841,368, 5,763,569 and 5,688,938 etc. US patent 6,211,244 discloses a process for preparation of calcium receptor-active molecules like cinacalcet, but do not provide any specific example for preparation of cinacalcet and its pharmaceutically acceptable salt thereof.
The methods disclosed in the above patents for preparation of these compounds include reductive amination of an aldehyde or a ketone with a primary amine in the presence of sodium cyanoborohydride or sodium triacetoxy borohydride.

Alternatively, some compounds are prepared by condensation of a primary amine with an aldehyde or a ketone in the presence of titanium (IV) isopropoxide. The resulting imine intermediate is then reduced in situ by action of sodium cyanoborohydride, sodium borohydride, or sodium triacetoxyborohydride and resulting enamines are then catalytically reduced using palladium dihydroxide on carbon. Various compounds are prepared by diisobutylaluminium hydride (DIBAL-H) mediated condensation of an amine with a nitrile. The resulting imine intermediate is reduced in situ by the action of sodium cyanoborohydride or sodium borohydride. The intermediate alkene is reduced by catalytic hydrogenation in ethanol using palladium on carbon. Further, compounds obtained by using above processes are converted to corresponding hydrochloride salts by treatment of free base with hydrogen chloride gas in ether or hexane in combination with hydrogen chloride gas. The processes disclosed involve use of expensive reagents and further involve purification by using column chromatography.

An article, namely, Drugs of future 2002, 27(9), 831-836 discloses a process for preparation of cinacalcet, similar to general process, as disclosed in US patent 6,211,244. The process involves reaction of 1-acetylnaphthalene with 3-[3-(trifluoromethyl)phenyl]propyl amine in presence of titanium isopropoxide to produce an imine which on treatment with methanolic sodium borohydride gives racemic base which is then resolved by chiral chromatography.

US Patent 7,250,533 herein referred as US ‘533 discloses a process for synthesis of cinacalcet by involving use of phenyl propanol derivative, namely 3-(3-trifluoromethylphenyl)propanol. Process involves conversion of hydroxyl moiety of phenyl propanol derivative, into a good leaving group and further condensing the resulting derivative with (R)-1-naphthylethylamine, in presence of a base, in an organic solvent to obtain cinacalcet, according to following scheme.

The starting compound, phenyl propanol derivate, namely 3-(3-trifluoromethyl phenyl)propanol is prepared by Heck coupling of 1-bromo-3-trifluoromethyl benzene with ethylacrylate to give unsaturated ester, followed by reduction to give corresponding saturated alcohol.

There are several methodologies reported in literature such as US 8,575,393 US2011/0172455; WO2008/058235, wherein 3-(3-trifluoromethylphenyl) propanol has been used as key starting material for synthesizing cinacalcet hydrochloride. Therefore, phenyl propanol derivative is an important key intermediate for synthesizing cinacalcet hydrochloride. Various methods are reported in literature, wherein processes of preparation of phenyl propanol derivative, have been disclosed and some are discussed herein.

US patent 7,834,028 herein referred as US ‘028 discloses a process for the preparation of phenyl propanol derivative as shown in below scheme.

Above process involves reaction of 3-(3-trifluoromethyl-phenyl)-propanoic acid with borane in tetrahydrofuran in inert atmosphere. The reaction mixture is maintained and stirred at room temperature for 24 hours and after completion of reaction, methanol and water are added. The desired product is extracted in organic layer and concentrated under reduced pressure to give a phenyl propanol derivative. The resulting phenyl propanol derivative is then purified using flash chromatography.

US patent 8,129,361 and US patent application 2011/0105514 disclose similar methodology as described in US ‘028 for preparing phenyl propanol derivative, except method of isolation.
The said processes suffered from several drawbacks such as process is very much time consuming, purification is done by using flash chromatography, use of borane, which is not safe because borane is unstable in air, spontaneously flammable in atmosphere and have an unpleasant odor. In view of these, said processes are not industrially attractive.

US patent 8,575,393 herein referred US‘393 discloses a process for preparation of phenyl propanol derivative as shown in below scheme.

The said process involves reduction of 3-(3-trifluoromethyl-phenyl)-propanoic acid with a suitable reducing agent selected from borane gas, diborane, borane dimethylsulfide, preferably borane dimethylsulfide to give phenyl propanol derivative. Phenyl propanol derivative, thus formed is then treated with methane sulphonyl chloride to form corresponding ester derivative, which is further condensed with (R)-naphthylethylamine to prepare cinacalcet.

US patent application 2011/0172455 also discloses same methodology for synthesizing phenyl propanol derivative, which involves reduction of 3-(3-trifluoromethyl-phenyl)-propanoic acid using borane dimethylsulfide as described in US ‘393. Further hydroxyl moiety of phenyl propanol derivative is converted into a good leaving group, followed by condensation with N-nosylate protected naphthylethylamine to give N-nosylate protected cinacalcet, which on deprotection in the presence of hydrochloric acid, give cinacalcet hydrochloride.
The main drawback of said processes is use of borane dimethylsulfide, during preparation of phenyl propanol derivate, which is an expensive reducing agent and highly flammable. Therefore, it is not an attractive method for synthesizing phenyl propanol derivative for industrial scale with respect to cost prospective and safety.

PCT publication WO2008/058235 discloses a process for the preparation of phenyl propanol derivative from the corresponding acid derivative as shown in below scheme.

The above disclosure, describes the process for synthesizing phenyl propanol derivative by treating 3-(3-trifluoromethyl)-phenyl propanoic acid with lithium aluminum hydride. Further hydroxyl moiety of phenyl propanol derivative is converted into good leaving group and resulting compound is condensed with (R)-naphthylethylamine to give cinacalcet. Generically reducing agents disclosed in specification for converting 3-(3-trifluoromethyl)-phenyl propanoic acid to phenyl propanol derivative are selected from palladium on carbon, rhodium, Raney nickel, lithium aluminum hydride, sodium borohydride in acidic conditions, sodium borohydride in pyridine, and sodium dihydro-bis-(2-methoxyethoxy)aluminate solution ("Vitride") to give propanol derivative.
However, said reduction for synthesizing phenyl propanol derivative is exemplified only with lithium aluminum hydride and there is no teaching how to prepare phenyl propanol derivative using other reagents like sodium borohydride in acidic conditions. In absence of specific acidic reaction condition, the said methodology is tried in lab for synthesizing phenyl propanol derivative, by making use of sodium borohydride-sulphuric acid in 1:1 molar ratio, at temperature of 5°C to ambient temperature. it is observed that using sodium borohydride-sulphuric acid, as specified, does not results in desired product formation. Therefore mere statement of using sodium borohydride in acidic conditions is not suitable for said conversion. The use of sodium borohydride in pyridine for synthesizing propanol derivative is not preferable at industrial scale, as pyridine is highly toxic in nature. The main disadvantage of above process is use of lithium aluminum hydride as reducing agent, which is dangerously reactive towards water.

An article, namely, European Journal of Organic Chemistry, volume: 2012, Issue: 15, Pages: 2990-3000 discloses a process for preparation of phenyl propanol derivative as shown in below scheme:

The process comprises of reacting 3-(3-trifluoromethyl)-phenyl propanoic acid with lithium aluminum hydride in tetrahydrofuran and isolated the product involves no acid workup to give crude propanol derivative. The resulting crude is purified by column chromatography to give phenyl propanol derivative. The resulting phenyl propanol derivative is then condensed with (R)-naphthylethyl amine to give cinacalcet.
The above process suffers from several drawbacks such as the process is very time consuming and tedious since resulting phenyl propanol derivative is purified by column chromatography.

One another article, namely, Beilstein Journal of Organic Chemistry, Volume: 8, Pages: 1366-1373, No. 158, Journal, 2012 discloses a preparation of phenyl propanol derivative as shown in below scheme:

The process comprises of reacting 3-(3-trifluoromethyl)-phenyl propanoic acid with methanol to give corresponding methyl ester, which is then reacted with sodium borohydride in the presence of tetrahydrofuran to prepare phenyl propanol derivative. Further phenyl propanol derivative is converted to cinacalcet hydrochloride by known methods.

The above process for synthesizing phenyl propanol derivative is not attractive as it involves one extra step of preparation of an ester intermediate in between, while converting corresponding acid to said phenyl propanol derivative.

In view of the above, there is an urgent need to develop an industrially advantageous, cost effective, operationally safe method for the preparation of phenyl propanol derivative, an intermediate in preparation of cinacalcet hydrochloride. Therefore, the present invention fulfills the need in the art and provides an industrially advantageous, cost effective process for preparing propanol derivative which avoids use of hazardous and expensive reducing agents and over comes the draw backs of known methods, as described above.

OBJECT OF THE INVENTION
It is a main object of the present invention to provide an industrially advantageous, cost effective and operationally safe method for the preparation of phenyl propanol derivative, an intermediate in preparation of cinacalcet hydrochloride.

Another object of the present invention is to provide an industrially advantageous process for the preparation of phenyl propanol derivative by utilizing safe and mild reducing agent.

Yet another object of the present invention is to provide an industrially advantageous process for the preparation of phenyl propanol derivative, by avoiding use of hazardous and costly reducing agents.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an industrially advantageous, cost effective, operationally safe method for preparation of phenyl propanol derivative of formula I,

Formula I

comprises the step of:
a) reacting 3-(3-trifluoromethyl)-phenyl propanoic acid of formula II,

Formula II
with a mild reducing agent, in the presence of a suitable additive, in a suitable solvent;
b) isolating phenyl propanol derivative of formula I.

In a specific embodiment, the present invention provides an industrially advantageous, cost effective, operationally safe method for preparation of phenyl propanol derivative of formula I,

Formula I

comprises the step of:
a) reacting 3-(3-trifluoromethyl)-phenyl propanoic acid of formula II,

Formula II

with a mild reducing agent such as sodium borohydride in the presence of a suitable additive, in a suitable solvent;
b) isolating phenyl propanol derivative of formula I.
In one more embodiment, the present invention provide a process for the preparation of cinacalcet hydrochloride comprising of:
a) reacting 3-(3-trifluoromethyl)-phenyl propanoic acid of formula II,

Formula II

with a mild reducing agent such as sodium borohydride in the presence of a suitable additive, in a suitable solvent at suitable temperature for suitable time;
b) isolating phenyl propanol derivative of formula I

Formula I

c) converting compound of formula I into cinacalcet hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an industrially advantageous, cost effective, operationally safe method for the preparation of phenyl propanol derivative of formula I by reacting 3-(3-trifluoromethyl-phenyl)-propanoic acid of formula II with a suitable mild reducing agent in the presence of an additive in a suitable solvent.
According to one embodiment, process involves reduction of 3-(3-trifluoromethyl)-phenyl propanoic acid of formula II with a suitable mild reducing agent in the presence of an additive in a suitable solvent at a suitable temperature for sufficient time.
Since, the reduction of aldehydes, ketones and carboxylic acid derivatives to the corresponding alcohols is an important transformation in synthetic chemistry. Hydrides and boranes are amongst the most commonly used reagents for this purpose. These highly reactive hydrides, however have severe limitations such as the need for anhydrous solvents, hazardous handling, incompatibility with other functionality, and incomplete reaction. In view of the above, use of mild reducing agent is highly desirable since mild reducing agents are more convenient, less expensive, and safer to use. Mild reducing agent, as such, does not reduce carboxylic acid derivatives, the activity of mild reducing agents can be enhanced by addition of a suitable additive. The reaction of carboxylic acids with mild reducing agent in the presence of subsequent addition of suitable additives is known. Therefore, the choice of mild reducing agent and a suitable additive play a key role for synthesizing phenyl propanol derivative of formula I.

The suitable mild reducing agent used in the reaction includes, but not limited to sodium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or like.
Preferably, the suitable mild reducing agent used in the reaction is sodium borohydride.
The suitable additive for facilitating the reduction reaction and to broaden the utility of sodium borohydride includes, but not limited to boron trifluoride etherate; boron trichloride, boron trifluoride, boron tribromide; aluminium chloride; cerium chloride; calcium chloride; manganese chloride; zinc chloride; zirconium chloride; trimethylsilyl chloride; tin chloride; copper sulfate; iodine; carbonyldiimidazole; and alkylchloroformate and the like.
Preferably, the suitable additive for facilitating the reduction reaction and to broaden the utility of sodium borohydride are boron trifluoride etherate and iodine. The addition of a suitable additive play a key role, either it enhances the reactivity of mild reducing agent or convert carboxylic acid to more reactive group and generate in-situ anhydride or mixed anhydride to make it more active to react with mild reducing agent and convert to alcohols.
The suitable solvent used in reduction reaction includes, but not limited to ethereal solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane; ketonic solvent such as acetone, methyl ethyl ketone; alcohols such as methanol, ethanol, propanol, isopropyl alcohol; distilled water and the like or mixture thereof.
Preferably, the suitable solvent used in said reduction reaction can be selected from ethereal solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane; distilled water and the like or mixture thereof.
The reaction can be carried out at a temperature of 0ºC to 40ºC for 10 minutes to few hours or till completion of reaction.
Preferably, the reaction can be carried out at a temperature of 5ºC to 30ºC for 10 minutes to 60 minutes. The progress of reaction can be monitored by suitable chromatographic technique such as thin layer chromatography [TLC], high pressure liquid chromatography [HPLC], ultra pressure liquid chromatography [UPLC], gas chromatography [GC] and the like.
After completion of reaction, the resulting reaction mixture may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration or any other techniques for removal of solids.
Alternatively, the product may be isolated directly from the reaction mixture itself after the reaction is complete or after conventional workup with techniques such as quenching with a suitable reagent, extraction or the like.
The isolation of product may involve method including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with solvent and the like.
Generally, after completion of the reaction, desired phenyl propanol derivative of formula I can be isolated from reaction mixture by using different techniques, which include, but not limited to layer separation i.e. extraction, vacuum distillation or filtration. The isolation technique is dependent on the choice of additive used for facilitation of reduction reaction.
Particularly,after completion of reaction, the reaction mixture can be quenched followed by isolation of phenyl propanol derivative of formula I either by removal of solvent or by extraction technique. The process of extraction comprises of adding a second solvent or solution of acid to the reaction mixture under stirring at suitable temperature for sufficient time. Thereafter, layers are separated and organic layer is washed with aqueous solution/ or mild basic solution/ and/ or brine solution. Then, solvent is removed by using a suitable technique such as distillation, evaporation etc. to isolate phenyl propanol derivative of formula I.
The second solvent used in the extraction can be selected from water immiscible solvent. Water immiscible solvent includes, but not limited to ester solvent such as methyl acetate, ethyl acetate; halogenated solvent like, dichloromethane; ethers like methyl-tert-butyl ether; hydrocarbons like toluene and the like. Solution of acid used during work up includes, but not limited to hydrochloric acid, hydrobromic acid.
The reaction mixture can be stirred at temperature of 20 to 40ºC for 10 minutes till final separation of layers. Preferably, the reaction mixture is stirred at 25-30ºC for 15-30 minutes.
The base are used for washing organic layer include, but not limited to metal hydroxide can be selected from sodium hydroxide, potassium hydroxide; carbonates include but are not limited to potassium carbonate, sodium carbonate, sodium bicarbonate and ammonia solution; sodium bisulphate solution; brine solution or alike. Preferably, the base is used in the reaction can be selected from metal hydroxide such as sodium hydroxide, potassium hydroxide and dilute aqueous solution is prepared. .The suitable techniques used for removal of solvent include, but not limited to evaporization, distillation etc.
In one specific embodiment, boron trifluoride etherate is used as additive to broaden the utility of sodium borohydride. When boron trifluoride etherate is used as additive, then isolation of phenyl propanol derivative of formula I after completion of the reaction comprises the step of quenching the reaction mixture with water and solvent was distilled off completely under reduced pressure. Thereafter, water immiscible solvent is added to the resulting aqueous media reaction mass to form two phases and further stirred till complete separation of layers. Organic layer is collected and washed with a aqueous solution of base followed by washing with brine solution. Finally solvent is removed under vacuum to obtain phenyl propanol derivative of formula I.
Water immiscible solvent can be selected from solvent as defined above and preferably ester solvent such as methyl acetate, ethyl acetate is used.
The base used in washing can be selected from metal hydroxide such as sodium hydroxide, potassium hydroxide; carbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate or alike.
In one another specific embodiment, iodine can be used as additive to broaden the utility of sodium borohydride. When iodine is used as additive then isolation of phenyl propanol derivative of formula I after completion of the reaction is achieved by adding aqueous solution of base and a water immiscible solvent to the reaction mass. The reaction mixture is stirred for sufficient time to separate the layers. Thereafter layers are separated and organic layer is washed subsequently with ammonia solution, sodium bisulphate solution, followed by brine solution. Organic layer is concentrated to obtain phenyl propanol derivative of formula I. Concentration of solvent can be done by any known methods such as distillation, evaporation and the like. Preferably solvent is distilled off under vacuum to obtain phenyl propanol derivative of formula I.
The water immiscible solvent, added during work up of reaction can be selected from any suitable solvent and are same as described above.
In one another embodiment, carbonyldiimidazole or alkylchloroformate such as ethylchloroformate can be used to generate anhydride or mixed anhydride in-situ before treatment with mild reducing agent.
The major advantage of the present invention is to provide industrially advantageneous, cost effective, operationally safe method for the preparation of phenyl propanol derivative of formula I by making use of mild reducing agents in combination with suitable additives.
Although, the following examples illustrate the present invention in more detail, but should not be construed as limiting the scope of the invention.
Examples
Process for preparation of 3-(3-trifluoromethyl-phenyl)-propan-1-ol.
Method 1: To a solution of 3-(3-trifluoromethyl-phenyl)-propanoic acid (100g) in tetrahydrofuran (250ml) sodium borohydride (6.94 g) and tetrahydrofuran (100ml) were added at ambient temperature. Boron trifluoride etherate (61ml) was added slowly to the reaction mixture at 25-30ºC and the reaction was stirred for further 4 hours. After completion of reaction, the reaction was quenched with distilled water (500ml) and tetrahydrofuran was distilled off completely under reduced pressure. Ethyl acetate (500ml) was added to the reaction mass and stirred for 15 minutes. Layers were separated and organic layer was collected, washed with sodium hydroxide solution (500ml) and brine solution (500ml). Finally, solvent was removed under vacuum to afford 91g of 3-(3-trifluoromethyl-phenyl)-propan-1-ol having purity 99.3 % by HPLC.

Method 2: To a solution of 3-(3-trifluoromethyl-phenyl)-propanoic acid (90g) in tetrahydrofuran (25ml); sodium borohydride (6.24 g) and tetrahydrofuran (90ml) were added at ambient temperature. Boron trifluoride etherate (54.9ml) was added slowly to the reaction mixture at 25-30ºC and the reaction was stirred for further 4 hours. After completion of reaction, the reaction was quenched with distilled water (450ml) and tetrahydrofuran was distilled off completely under reduced pressure. To the resulting reaction mass, ethyl acetate (450ml) was added and stirred for further 15 minutes. Thereafter, layers were separated and the organic layer was collected, washed successively with sodium hydroxide solution (450ml) and brine solution (450ml). Finally, the solvent was removed under vacuum to obtain 80.1g of 3-(3-trifluoromethyl-phenyl)-propan-1-ol having purity 99.2% by HPLC.

Method 3: To a solution of 3-(3-trifluoromethyl-phenyl)-propanoic acid (20g) in tetrahydrofuran (100ml) sodium borohydride (6.94g) and tetrahydrofuran (100ml) were added slowly at ambient temperature. The reaction mixture was cooled to 5-10ºC and then iodine solution was added. The resulting reaction mixture was stirred at 25-30 ºC for further 1 hour. After reaction completion, sodium hydroxide solution (100ml) and ethyl acetate (100ml) were added and stirred for 15 minutes. Layers were separated and organic layer was collected, and washed with 12% ammonia, sodium bisulphate solution (100 x 3), brine solution (100ml). Solvent was removed under vacuum to obtain 18.0g of 3-(3-trifluoromethyl-phenyl)-propan-1-ol having purity 98.27 % by HPLC.

Method 4: To a solution of 3-(3-trifluoromethyl-phenyl)-propanoic acid (2.0g) in tetrahydrofuran (20ml), carbonyldiimidazole (2.0g) was added at room temperature. Reaction mixture was cooled, and a solution of sodium borohydride (0.6g) in water (6ml) was added at 0-5 ºC. The temperature of reaction mixture was raised to 25-30ºC and stirred for 1 hour. After reaction completion, dilute hydrochloric acid (1N) was added and stirred for 15 minutes. Layers were separated and organic layer was washed with sodium bicarbonate (10%) solution followed by brine solution. Organic layer was distilled under reduce pressure to obtain 1.7 g of 3-(3-trifluoromethyl-phenyl)-propan-1-ol having purity 99.33%, measured by HPLC.

Method 5: To a solution of 3-(3-trifluoromethyl-phenyl)-propanoic acid (2.0g) in tetrahydrofuran (50ml), N-methyl morphine (2.5g) was added at room temperature. The reaction mixture was cooled to 0-5ºC and ethyl chloroformate (2.7g) was added, temperature was raised to 25 to 30ºC and stirred for further 30 minutes. The resulting insoluble salt was filtered off, and a solution of sodium borohydride (1.4g) in distilled water (15ml) was added to the reaction solution, stirred at a temperature of 0–5ºC for 1 hour. After reaction completion, solution of hydrochloric acid (1N) and ethyl acetate were added to the reaction mixture. The reaction mixture was stirred for 15 minutes and layers were separated. The organic layer was washed with sodium hydroxide followed by brine solution and thereafter organic layer was distilled out under reduce pressure to obtain 3.5g of 3-(3-trifluoromethyl-phenyl)-propan-1-ol having purity 98.80%, measured by HPLC.
Comparative Example: Process for preparation of 3-(3-trifluoromethyl-phenyl)-propan-1-ol.
To a solution of 3-(3-trifluoromethyl-phenyl)-propanoic acid (2g) in tetrahydrofuran sodium borohydride (0.7 gm) in tetrahydrofuran (15ml) was added at a temperature of 25-30ºC and the reaction mixture was cooled, stirred at 5-10ºC for 15 minutes. Then, concentrated sulfuric acid (1.79g) was added to the cooled and stirred reaction mixture. Thereafter, temperature of the reaction was raised to 25-30ºC and further, reaction mixture was stirred for 12 hours, [3-(3-trifluoromethyl-phenyl)-propan-1-ol was not formed even after 12 hours.
,CLAIMS:WE CLAIM:
1. A process for the preparation of phenyl propanol derivative of formula I,

Formula I

comprises the step of:
a) reacting 3-(3-trifluoromethyl)-phenyl propanoic acid of formula II,

Formula II
with a mild reducing agent, in the presence of a suitable additive, in a suitable solvent;
b) isolating phenyl propanol derivative of formula I.
2. The process as claimed in claim 1, wherein in step a) mild reducing agent is selected from sodium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride.
3. The process as claimed in claim 1, wherein in step a) mild reducing agent is sodium borohydride.
4. The process as claimed in claim 1, wherein in step a) additive is selected from boron trifluoride etherate; boron trichloride, boron trifluoride, boron tribromide; aluminium chloride; cerium chloride; calcium chloride; manganese chloride; zinc chloride; zirconium chloride; trimethylsilyl chloride; tin chloride; copper sulfate; iodine; carbonyldiimidazole; and alkylchloroformate.
5. The process as claimed in claim 1, wherein in step a) additive is preferably selected from boron trifluoride etherate and iodine.
6. The process as claimed in claim 1, wherein in step a) solvent is selected from ethereal solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane; ketonic solvent such as acetone, methyl ethyl ketone; alcohols such as methanol, ethanol, propanol, isopropyl alcohol and distilled water and or mixture thereof.
7. The process as claimed in claim 1, wherein in step a) solvent is preferably selected from tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, dioxane; distilled water and or mixture thereof
8. The process as claimed in claim1, wherein in step a) temperature of the reaction is in range of 0ºC to 40ºC.
9. The process as claimed in claim 1, wherein in step a) temperature of the reaction is in the range of 5ºC to 30ºC.
10. The compound of formula I, prepared by the process as claimed in claim 1, is used for preparing cinacalcet hydrochloride.

Dated this day 31st of December, 2013

..................
(Dr. Asha Aggarwal)
Head-IPM Department
Ind-Swift laboratories Limited