FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR PREPARING PROPANAL INTERMEDIATE USEFUL FOR THE PREPARATION OF
CINACALCET


Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India

The following specification particularly describes the invention


PROCESSES FOR PREPARING PROPANAL INTERMEDIATE USEFUL FOR THE PREPARATION OF CINACALCET
FIELD OF THE INVENTION:
The present invention relates to an improved process for preparing 3-(3-trifluoromethylphenyl) propanal (III), which is the key intermediates for the preparation of cinacalcet and its pharmaceutically acceptable salts and solvates, as well as the use of compound of formula (III) prepared by instant process for the preparation of cinacalcet and its pharmaceutically acceptable salts and solvates.
BACKGROUND OF THE INVENTION:
Cinacalcet belongs to the calcimimetics class of compounds, which is useful for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma. Cinacalcet is described chemically as N-[l-(R)-(-)-(l-naphthyl)ethyl]-3-[3-(trifluoromethy!)phenyl]-l-aminopropane hydrochloride, which has the structural formula

Cinacalcet hydrochloride is marketed as Sensipar® in the USA and as Mimpara® in Europe. It is available as 33, 66 and 99 mg tablets of cinacalcet hydrochloride equivalent to 30, 60 and 90 mg of cinacalcet free base respectively.
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U.S. Patent No. 6,011,068 generally describes cinacalcet and it's pharmaceutical^ acceptable acid addition salts, but does not discJose any specific examples for the preparation of the same.
U.S. Patent No. 6,211,244 describes cinacalcet and its pharmaceutically acceptable acid chloride addition salt and process for the preparation of the same in analogues way. According to this patent, Cinacalcet may be produced by reacting 1-acetyl naphthalene with 3-(3-(trifluoromethy!)phenyl)propylamine in the presence of titanium isopropoxide to produce an imine corresponding to Cinacalcet, followed by treatment with methanolic sodium cyanoborohydride and resolution of the racemic Cinacalcet base by chiral liquid chromatography.
Further, according to the process disclosed in U.S. Pat. No. 6,211,244, as well as DRUGS OF THE FUTURE (2002) 27 (9): 831 the desired Cinacalcet enantiomer may be produced by reacting (R)-l-(l-naphthyl)ethylamine (IT) with 3-(3-trifluoromethyIphenyl) propanal (HI) in the presence of titanium isopropoxide to produce the imine that corresponds to Cinacalcet, followed by treatment with ethanolic sodium cyanoborohydride, according to the scheme-1.
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Scheme-1

There are several processes for the preparation of 3-(3-trifluoromethylphenyl) propanal (HI) are reported in the literature.
EP 0194764 discloses a process for preparing compound of formula (III) in which 3-trifluoromethylbromobenzene is reacted with propargyl alcohol using bis(triphenylphosphine) palladium chloride and cuprous iodide in triethylamine, followed by catalytic hydrogenation to give the corresponding alcohol, which is then converted to compound III by a Swern oxidation. This synthetic procedure is illustrated in Scheme-2.
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Scheme-2

International patent application WO 2008035212 discloses process for the preparation of propanal intermediate (III) by the oxidation of 3-(3-trifluromethylphenyl)propan-l-ol in the presence of nitroxyl oxidizing agent like TEMPO.
Tetrahedron Letters 2004, 45(45), 8355-58 discloses that compound of formula (III) can be prepared from 3-trifluoromethylcinnamic acid by reduction of the double bond and reduction of the carboxylic acid group into the corresponding alcohol followed by a Swern oxidation reaction, which is illustrated in Scheme 3.
Scheme -3

An alternative process for the preparation of compound of formula (III) is disclosed in Journal of Medicinal Chemistry 1968, 11, 1258-62.
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According to US 7250533. the Swern-oxidation reaction disclosed in prior arts involve the use of reagents, such as oxalyl chloride and DMSO, which are not environmentally friendly and doesn't result in good yield, makes the process laborious to apply at industrial scale.
US 7361789 discloses the process for the preparation of compound of formula (III) comprises catalytic hydrogenation of 3-trifluoromethylcinnamic provides 3-(3-trifluoromethylphenyl) propanoic acid, which is subsequently reduced by BMS/THF complex followed by PCC (pyridinium chlorochromate) oxidation to give the compound of formula (III).
WO 20070122591 also discloses the same process for the preparation of compound of
formula (III) as disclosed in US 7361789 except WO 20070122591 discloses the use of
BH3/THF instead of BMS/THF complex for the reduction of 3-(3-
trifluoromethyiphenyl) propanoic acid.
There still exists a need for a process for the preparation of compound of formula (III), which is the key intermediate for the preparation of cinacalcet and its pharmaceutically acceptable salts, which may be scaled up for commercial production.
SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for the preparation of compound of formula (III):


'CHO (til)
comprising the reduction of compound of formula (VI)


wherein, alkyl is straight chain or branched C1-C6 alky], with a suitable reducing agent in the presence of an inert solvent.
In another aspect, the present invention provides a process for the preparation of compound of formula (III):

comprising the steps of:
(i) reacting a compound of formula (VIII) with an halogenating agent and an amine RR'NH, wherein R & R' are independently H, alkyl or ary!, optionally joined together with or without heteroatom selected from 0, N and S, to give compound of formula (IX).

or reacting a compound of formula (VIII) with acid activating agent selected from N,N'-carbonyldiimidazole orN,N'-carbonylditriazole to obtain reactive intermediate of formula (X), wherein Y is CH orN.
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(ii) reducing the compound obtained in step (i) with a suitable reducing agent in the presence of an inert solvent.
In another aspect, the present invention provides a process for the preparation of compound of formula (HI):

comprising the steps of:
(i) reacting a compound of formula (VII) with an halogenating agent and an amine RR'NH, wherein R & R' are independently H, alkyl or aryl, optionally joined together with or without heteroatom selected from O, N and S, to give compound of formula (XI).


or reacting a compound of formula (VII) with acid activating agent selected from N,N'-carbonyldiimidazoIe orN,N'-carbonylditriazole to obtain reactive intermediate of formula (XIII), wherein Y is CH orN.
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(ii) reducing the compound obtained in step (i) with a suitable reducing agent in the presence of an inert solvent to provide the compound of formula (XII).

(iii) converting the compound of formula (XII) into the compound of formula (III) with suitable reducing agent in the presence of an inert solvent.
In yet another aspect, the present invention provides an improved process for the preparation compound of formula (III).
In yet another aspect, the present invention provides a process for the preparation of compound of formula (III) and its use for preparation of cinacalcet and its pharmaceutical^ acceptable salt by method known in the art.

DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.
The present invention may, however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
The present invention relates, in general, to an improved process for preparing 3-(3-trifluoromethylphenyl)propanal (III), which is the key intermediate for the preparation of cinacalcet and its pharmaceutically acceptable salts, as well as the use 3-(3-trifluoromethylphenyl)propanaI (III) prepared according to the present invention for the preparation of cinacalcet and its pharmaceutically acceptable salts.
In general, the present invention provides process of preparation of 3-(3-trifluoromethylphenyl) propanal (III) in various ways as illustrated in scheme-4, 5 & 6.
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Scheme-4

Scheme-6

(VI!) (XIII) (XII)
In step (a), Alkyl-3-trifluoromethylcinnamate (V), wherein alkyl is straight chain or branched C1-C6 alkyl, preferably methyl, ethyl, propyl, n-butyl or iso-butyl can be prepared from trifluromethyl benzaldehyde (IV) by any means known to the skilled artisan, such as by method as disclosed in US 6211244 and US 4785004. Generally, the compound of formula (V) is prepared by reacting the trifluromethy/ benzaldehyde (IV) with trialkyl-phosphonoacetate or ethoxycarbonylmethylenetriphenylphosphorane in inert solvent preferably dimethylformamide or dichloromethane optionally in the presence of base such as sodium hydride at any suitable range of temperature generally at 20-100°C. After the completion of the reaction, the targeted compound i.e. (V) can be isolated by any method known in the art.
In step (b), Alkyl-3-trifluoromethylcinnamate (V), wherein alkyl is straight chain or branched C1-C6 alkyl, preferably methyl, ethyl, propyl, n-butyl or iso-butyl undergoes catalytic hydrogenation (i.e. with hydrogen in the presence of catalyst). The catalytic hydrogenation can be performed by any method known to one of ordinary skill in the art. For example, compound (V) may be taken in a lower alcohol, i.e., a C1-C4 aliphatic, straight chain or branched alcohol, and exposed to H2 pressure in the presence of a catalyst that includes, but is not limited to, Pd/C, Pt02, Pd(OH)2 or Raney nickel. Preferably, the hydrogenation is carried out over a period of about 3 to about 24 hours, and more preferably about 3 to about 6 hours, to obtain 3-(3-trifluoromethylphenyl) propanoic acid alkyl ester (VI). Compound (VI) may then be recovered by any method known to one of skill in the art.

In step (c), 3-(3-trifluoromethylphenyl) propenoic acid (VII) can be prepared by a reaction of trifluoromethyl benzaldehyde (IV) with an aliphatic carboxylic acid, such as acetic acid, propanoic acid, butanoic acid, and malonic acid, or with dicarboxylic anhydride, such as acetic, maleic, succinic, and phthalic anhydrides without using additional solvent at temperatures that range from about 20°C to about 200°C.
In step (d), 3-(3-trifluoromethylphenyl) propenoic acid (VII) is reduced to 3-(3-trifluoromethylphenyl) propanoic acid (VIII) by catalytic hydrogenation in same way as described in above step (b).
In step (e), 3-(3-trifluoromethylphenyl) propanoic acid alkyl ester (VI), wherein alkyl is straight chain or branched C1-C6 alkyl, preferably methyl, ethyl, propyl, n-butyl or iso-butyf can be prepared from 3-(3-trifluoromethy[phenyf) propanoic acid (VIII) by any means known to the skilled artisan. In general, ester may be prepared from carboxylic acid by direct reaction of a carboxylic acid and an alcohol catalyzed by a concentrated sulphuric acid. The esterification of carboxylic acid to prepare ester can be generally carried out at reflux temp.
In step (el), Alkyl-3-trifluoromethylcinnamate (V), wherein alkyl is straight chain or branched C1-C6 alkyl, preferably methyl, ethyl, propyl, n-butyl or iso-butyl can be prepared from 3-(3-trifluoromethylphenyl) propenoic acid (VII) by any means known to the skilled artisan. In general, ester may be prepared from carboxylic acid by direct reaction of a carboxylic acid and an alcohol catalyzed by a concentrated sulphuric acid. The esterification of carboxylic acid to prepare ester can be generally carried out at reflux temp.
It is also possible to carry out the procedure in the absence of solvent or in a mixture with a inert solvent such as aromatic hydrocarbon or cyclic alkanes such as toluene or heptane. At the end of the reaction, the solid may be separated by simple filtration or any other equivalent means.
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In step (f), 3-(3-trifluoromethylphenyl) propanoic acid (VIII) is converted into the amide (IX) wherein, R and R' are independently H, alkyl or phenyl, optionally joined together with or without a heteroatom such as 0, N or S and alkyl is straight chain or branched C1-C6 alkyl using an halogenating agent and an amine RR'NH.
In the above reaction i.e. in the formation of amide (IX) from acid (VIII), the amine RR'NH can be selected from the group of primary or secondary amines. The primary amine is selected from aliphatic or aromatic primary amine, whereas the secondary amine is selected from cyclic secondary amines or non-cyclic secondary amines, wherein substitution on nitrogen is independently aliphatic or aromatic or combination thereof. Preferably, secondary amines can be used. More preferably, secondary amines, which are cyclic amines, are used.
The amines can be selected from the group comprising of dimethylamine, diethylamine, N-methylphenylamine, pyrrolidine, piperidine, N,0- dimethylhydroxylamine and morpholine.
The halogenating agent can be selected from the group comprising of thionyl chloride (SOCh), thionyl bromide (S0Br2), phosphorous pentachloride (PCI5), phosphorous trichloride (PCI3), phosphorous pentabromide (PBr5), phosphorous tribromide (PBr3), oxalyl chloride [(COCl)2], and oxalyl bromide [(COBr)2], in the presence of an acid (HC1, H2S04).
Preferably, compound (VIII) is first converted into its acyl halide by preparing solution of compound (VIII) in a solvent selected from the group consisting of dichloromethane, toluene, acetonitriJe and tetrahydrofuran and carried out the reaction at suitable temp, in the presence of catalyst, such as DMF.
Preferably, the conversion of compound (VIII) into the acyl halide is carried out at a temperature of about 0°C to about 50°C and the conversion is accomplished over a time period of about 0.5 to about 20 hours, however the appropriate time and temperature will
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vary based on the other parameters, such as reagent choice. The acyl halide may be recovered by any method known to one of skill in the art.
The above obtained acyl halide may be directly converted into the amide (IX) without isolating acyl halide by reacting with RR'NH. Preferably, the conversion of acyl halide into the amid (IX) is carried out at a temperature of about 0°C to about 100°C and the conversion is accomplished over a time period of about 0.5 to about 20 hours, however the appropriate time and temperature will vary based on the other parameters, such as reagent choice, solvent etc. The amide (IX) may be recovered by any method known to one of skill in the art.
In step (fl), 3-(3-trifluoromethylphenyl) propenoic acid (VII) is converted into the amide (XI) wherein, R and R' are independently H, alkyl or phenyl, optionally joined together with or without a heteroatom such as 0. N or S and alkyl is straight chain or branched C1-C6 alkyl using an halogenating agent and an amine RR'NH by employing the almost same reaction conditions as described herein above step (f).
In step (g), the compound of formula (VIII) is activated through the acid activating agent is selected from N,N'-carbonyldiimidazoIe or N,N'-carbonyIditriazole, preferably N,N'-carbonyldiimidazole, in amounts ranging from I to 5 equivalents, preferably from 1.1 to 2.0 equivalents. The reaction solvent is selected from toluene, chlorinated solvents, preferably dichloromethane, esters, preferably ethyl acetate, ethers, preferably diethyl ether, tetrahydrofuran, dipolar aprotic solvents, preferably dimethylformamide, cyclohexane, ketones, preferably acetone, in amounts ranging from 1 to 10 volumes. The reaction is carried out at a temperature ranging from -80 to 80° C.
In general, the obtained reactive intermediate of formula (X) undergoes in-situ reduction i.e. without isolation of intermediate (X) by using a suitable reducing agent.
In step (gl), the compound of formula (VII) is activated through the acid activating agent is selected from N,N'-carbonyldiimidazole or N,N'-carbonylditriazole. preferably N,N'-
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carbonyldiimidazole, by employing the almost same reaction conditions as described herein above step (g).
In general, the obtained reactive intermediate of formula (XIII) undergoes in-situ reduction i.e. without isolation of intermediate (XIII) by using a suitable reducing agent.
In step (h), the compound of formula (IX), (X) or (VI) is reduced to obtain compound of formula (III) by using a suitable reducing agent selected from but not limited to the group comprising of Vitride (sodium bis (2-methoxyethoxy)aluminium hydride), Vitride-NMP (N-methyl piperazine) reagent. DIBAL-H (diisobutylaluminum hydride), DIBAL-BOT (diiosobutylaluminum butylated oxy toluene), lithium diethoxyaluminium dihydride and lithium tri-tert-butoxy aluminium hydride.
In step (h), the reduction of the resulting intermediates (IX) or (VI) may be carried out with or without isolating intermediated (IX) or (VI) by using a suitable reducing agent to provide the propanal intermediate of formula (III).
In case of compound of formula (VIII), when it reacts with acid activating agent, the obtained reactive intermediate of formula (X) is in-situ reacts with a suitable reducing agent to provide the propanal intermediate of formula (III).
The reduction is expediently carried out in a inert solvent. Inert solvent can selected from but not limited to the group comprising lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butanol, isobutanol, aromatic hydrocarbon such as toluene, xylene, chlorinated solvents such as dichloromethane, esters such as ethyl acetate, ethers, diethyl ether, tetrahydrofuran, dipolar aprotic solvents such as dimethylformamide, cyclohexane, ketones, acetone, cyclic or acyclic alkanes such as hexane, heptane, methylcyclohexane, etc.
The reduction is expediently carried out at a temperature from -80 to 80° C and the conversion is accomplished over a time period of about 0.5 to about 20 hours, however
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the appropriate time and temperature will vary based on the other parameters, such as reagent choice, solvent etc. The propanal intermediate (III) may be recovered by any method known to one of skill in the art.
In step (hi), the compound of formula (XI). or (XIII) is reduced to obtain compound of formula (XII) by using a suitable reducing agent and same reaction conditions as described herein above step (h).
In step (i), the compound of formula (III) is prepared by converting the compound of formula (XII) to compound of formula (HI) by the reduction of the double bond by any method known in the art like catalytic hydrogenation, using sodium borohydride in the presence of cobalt catalyst, etc. Usually the reduction of double is carried out by catalytic hydrogenation (i.e. with hydrogen in the presence of catalyst) as described herein above step (b).
It is known that cinnamldehyde derivatives like compound of formula (XII) i.e.3-(3-trifluoromethyl)phenyl-prop-2-enal can be prepared by reacting trifluromethyl benzaldehyde (IV) with acetaldehyde in the presence of basic catalyst i.e. by aldol condensation., such as by a method described by US 2,976,321 & US 2, 529, 186.
Further, the obtained compound of formula (111) can be purified by any means known to the skilled artisan, such as by using sodium bisulfite adduct if required.
Another aspect of the present invention is the use of compound (III) to prepare cinacalcet and its salts by method known in the art, such as comprises the reaction of compound of formula (III) with (R)-l-(l-naphthyl) ethylamine (II) in the absence of titanium isopropoxide to provide imine, which is subjected to reduction by employing suitable reducing agent such as NaBH4.
The various embodiments of the invention having thus been generally described, several examples will hereafter be discussed to illustrate the inventive aspects more fully.
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The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention.
Example-1:
Preparation of 3-(3-trifluoromethylphenyI) propanoic acid ethyl ester (VI-A)
A stirred solution of sodium hydride (2.173 gm, 60% in oil, 54.325 mmol) in dimethylformamide (100 ml) was treated dropwise with triethyl phosphonoacetate (12.47 gm, 55.65 mmol) and stirred 30 min at room temperature (RT). After this time, a solution of trifluromethyl benzaldehyde (IV) (9.152 gm, 52.6 mmol) in dimethylformamide (50 ml) was added dropwise and the solution stirred 30 min at RT and 30 min at lOO.degree. C. The reaction was quenched by the addition of water and transferred to a separatory ftmnef using diethyl ether (500 ml). The ether solution was washed with saturated ammonium chloride (4.times.500 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to afford Ethyl-3-trifluoromethylcinnamate (V-A). The obtained ethyl ester in ethanol (100 ml) was reduced under 60 p.s.i. hydrogen using a catalytic amount (10% by weight) palladium hydroxide. After reduction (2 hrs, RT) the reaction was filtered and concentrated to afford 3-(3-trifluoromethylphenyl) propanoic acid ethyl ester (VI-A) in the form of oil (9.4 gm).
Example-2:
Preparation of 3-(3-trifluoromethylphenyl) propenoic acid (VII):
A round bottom flask was containing Trifluromethyl benzaldehyde (IV) (8 gm) & acetic anhydride (3.1 gm) and stirred for 20 minutes. The reaction mass was heated to 170-175°C and stirred for about 4-5 hours. After completion of the reaction, the reaction mass was cooled to about 70-80°C followed by addition of water (-50 ml) and stirred for 20 minutes. pH of the reaction solution was adjusted to - 9.5-10 by addition of 100 ml of 10% sodium carbonate solution and stirring for about 15 minutes. The water was distilled under vacuum and the separated solid was filtered. The obtained filtrate was charged into another round bottom flask and cooled to about 0-5°C. pH of the solution was adjusted to
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about - 2 by the addition of concentrated HC1 (25 ml) and stirred till the solid isolated. The obtained solid was filtered and washed with water and the resultant solid was dried under vaccum at about 40-50°C to afford 2.1 gm of the compound (VII).
Example-3:
Preparation of 3-(3-trifluoromethyIphenyl) propenoic acid (VII):
3-Trifluoromethylbenzaldehyde (40 gm), malonic acid (26.32 gm) and piperidine (3.0 gm) in dry pyridine (65 ml) were heated at 110- 120°C for 4-5 h. After the completion of the reaction, the mixture was cooled to room temperature and chilled water (300 ml, 0-5°C) was added to the reaction mass and stirred for 1 hour. pH of the reaction mass was adjusted to - 2 with concentrated HCI solution at 5 - 10°C and stirred for 1 hour. The resulting solid was filtered, washed with chilled water and dried at 40-50°C to afford 35 gm of the compound (VII).
Example-4:
Preparation of 3-(3-trifluoromethyIphenyl) propanoic acid (VIII)
A solution of 3-[3-(trifluoromethyl) phenyl]-2-propenoic acid (80 gm) in methanol (480 ml) was taken into an autoclave vessel, and palladium-carbon (10% w/w) (22 g) was added to it. 4 kg/cm2 of anhydrous hydrogen gas pressure was passed into the reaction suspension under agitation at about 25-35°C for about - 3-3.5 hours. After the completion of the reaction, the reaction suspension was filtered on a celite bed and the celite bed was washed with methanol (80 ml). The filtrate was distilled completely at about 50° C under a vacuum of about 650 mm/Hg to afford 75 gm compound of formula (VIII).
Example-5:
Preparation of 3-(3-trifluoromethylphenyl) propanoic acid ethyl ester (VI-A)
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A solution of 3-(3-trifluoromethylphenyl) propanoic acid (VIII) (10 g) in anhydrous ethanol (22 ml) containing concentrated sulphuric acid (1.3 ml) was heated at reflux for 24 hours and was then poured into water (75 ml). The mixture was extracted with diethyl ether and the ethereal extract was washed with water, with aqueous sodium carbonate solution (2 N), and with water, then dried over magnesium sulphate and evaporated. The resulting residue was distilled, to give 3-(3-trifluoromethylphenyl) propanoic acid ethyl ester (VI-A) (8.4 g) in the form of a colourless oil.
Example-6:
Preparation of 3-(3-trifluoromethyIphenyI) propanoic acid piperidine amide (IX-A)
120 ml of toluene and 0.8 ml of dimethyl formamide were added to 44.4 gm of 3-(3-trifluoromethylphenyl) propanoic acid (VIII) under stirring at room temperature. Thionyl chloride (32 g) was added and the reaction mixture heated to 45-50° C and maintained for 2 hours. Thionyl chloride and toluene were distilled out under reduced pressure. To the reaction mixture. 160 ml of toluene was further added and cooled. To this, 88 ml of piperidine was slowly added at room temperature and stirred for 30 min. The reaction mixture was acidified using dilute HCI. The aqueous layer was extracted with toluene and the combined organic layers washed with dilute HCI followed by water. The organic solvent was removed under reduced pressure to obtain 43 gm of the compound of formula (IX-A).
Example-7:
3-(3-trifluoromethylphenyl) propanal (HI)
To 43 gm of 3-(3-trifluoromethylphenyl) propanoic acid piperidine amide (IX-A) was added 400 ml of toluene. To it, vitride solution (mixture of 44 g vitride in toluene) was slowly added at 10 to 15°C. Methanol was added to the reaction mixture which was then acidified using dilute HCI. The reaction mixture was extracted with toluene and concentrated under reduced pressure to provide 27 gm of the compound of formula (III).
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Example-8:
3-(3-trifluoromethylphenyl) propanal (III)
To 1.15 gm of 3-(3-trifluoromethylphenyl) propanoic acid ethyl ester (VJ-A) was added 600 ml of toluene. To it, vitride solution (9 ml of vitride solution in toluene) was slowly added at -20°C under nitrogen atmosphere. Methanol was added to the reaction mixture which was then acidified using dilute HCI. The reaction mixture was extracted with toluene and concentrated under reduced pressure to provide 0.71 gm of the compound of formula (III).
Example-9;
3-(3-trifluoromethylphenyl) propanal (III)
To 2.0 gm of 3-(3-trifluoromethylphenyl) propanoic acid ethyl ester (VI-A) was added 600 ml of toluene. To it, vitride solution (15 ml of vitride/N-methyl piperazine solution in toluene) was slowly added at -20°C to -30°C under nitrogen atmosphere. Methanol was added to the reaction mixture which was then acidified using dilute HCI. The reaction mixture was extracted with toluene and concentrated under reduced pressure to provide 1.23 gm of the compound of formula (III).
Example-10: 3-(3-trifluoromethylphenyl) propanal (TIT)
To a stirred solution of 2.5 gm of 3-(3-trifluoromethyIphenyl) propanoic acid (VIII) in 25 ml of THF were added 1.9 gm of l,l'-carbonyl bis[lH-imidazole]. The solution was stirred at 20-25°C for 1 hour to form compound (X) insitu. The solution was cooled to -40°C temperature under N2. 20ml of vitride solution was added dropwise slowly in 30 minutes. Reaction was stirred for 30 minutes. Methanol was added to the reaction mixture which was then acidified using dilute HCI. The reaction mixture was extracted with toluene. The extract was washed with 10% hydrochloric acid solution, water and sodium hydrogen carbonate solution and concentrated under reduced pressure to provide 1.32 gm of the compound of formula (III).
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Example-11:
Preparation of Ethyl-3-trifluoromethylcinnamate (V-A)
A solution of 3-(3-trifluoromethylphenyl) propenoic acid (VII) (10 g) in anhydrous ethanol (22 ml) containing concentrated sulphuric acid (1.3 ml) was heated at reflux for 24 hours and was then poured into water (70 ml). The mixture was extracted with diethyl ether and the ethereal extract was washed with water, with aqueous sodium carbonate solution (2 N), and with water, then dried over magnesium sulphate and evaporated. The resulting residue was distilled, to give Ethyl-3-trifluoromethylcinnamate (V-A) (8.3 g).
Example-12:
Preparation of 3-(3-trifluoromethylphenyl) propenoic acid piperidine amide (XI-A)
118 ml of toluene and 0.7 ml of dimethyl formamide were added to 43.9 gm of 3-(3-trifluoromethylphenyl) propenoic acid (VII) under stirring at room temperature. Thionyl chloride (32 g) was added and the reaction mixture heated to 45-50° C and maintained for 2 hours. Thionyl chloride and toluene were distilled out under reduced pressure. To the reaction mixture, 160 ml of toluene was further added and cooled. To this, 88 ml of piperidine was slowly added at room temperature and stirred for 30 min. The reaction mixture was acidified using dilute HCI. The aqueous layer was extracted with toluene and the combined organic layers washed with dilute HCI followed by water. The organic solvent was removed under reduced pressure to obtain 42 gm of the compound of formula (XI-A).
Example-13:
3-(3-triflu oromethyl)phenyI-prop-2-en al (XII)
To 42 gm of 3-(3-trifluoromethylphenyl) propenoic acid piperidine amide (XI-A) was added 380 ml of toluene. To it, vitride solution (mixture of 44 g vitride in toluene) was slowly added at 10 to 15°C. Methanol was added to the reaction mixture which was then
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acidified using dilute HCI. The reaction mixture was extracted with toluene and concentrated under reduced pressure to provide 26 gm of the compound of formula (XII).
Example-14: 3-(3-trifluoromethyl)phenyl-prop-2-enal (XII)
To a stirred solution of 2.4 gm of 3-(3-trifluoromethylphenyl) propenoic acid (VII) in 25 ml of THF were added 1.9 gm of l,r-carbonyl bis[lH-imidazole]. The solution was stirred at 20-25°C for 1 hour to form compound (XIII-A) insitu. The solution was cooled to -40°C temperature under Ni. 20 ml of vitride solution was added drop wise slowly in 30 minutes. Reaction was stirred for 30 minutes. Methanol was added to the reaction mixture which was then acidified using dilute HCI. The reaction mixture was extracted with toluene. The extract was washed with 10% hydrochloric acid solution, water and sodium hydrogen carbonate solution and concentrated under reduced pressure to provide 1.3 gm of the compound of formula (XII).
Example-15: 3-(3-trifluoromethyl)phenyl-propanal (HI)
An ethanolic solution of 3-(3-trifluoromethyl)phenyl-prop-2-enal (XII) (26 gm) was hydrogenated in the presence of palladium on carbon (10%o w/w of starting material) for 10-15 hrs at room temperature. After then catalyst was filtered out and the ethanol was evaporated to dryness to give a compound of formula (III) (20.2 gm).

\th
Dated this 30m January, 2009

>HARMA<
for TORRENT PHARMACEUTICALS LTD. PRAVEEN CHAND GANDHI

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