Title of Invention

NOVEL PROCESS FOR THE PREPARATION OF 4-ARYL-3-HYDROXYMETHYL-1-METHYLPIPERIDINES

Abstract A novel, improved, and general process for the preparation of 4-aryl-3-hydroxymethyl1-methylpiperidines is disclosed in the present invention. 4-(4-Fluorophenyl)-3hydroxymethyl- l -methylpiperidine is a well known intermediate in making the antidepressant drug, paroxetine ((-)-trans-4-p-fluorophenyl-3-(3',4'-methylenedioxyphenoxymethyl)piperidine).Novel N-methyl-N-[3-(4-substitutedphenyl(F,Me,Ome))-3hydroxy]propylamines are prepared from the Mannich salts such as 3-dimethylamino-or 3-(N-methyl-N-benzylamino)4'-substituted (F,Me, Ome) propiophenone hydrochlorides by conventional methods. The N-methyl-N-[3-(4-substitutedphenyl (H, F, Me, Ome))-3hydroxy]propylamines thus obtained are reacted with ethyl or methyl acrylate to get the corresponding Michael addition products. They hydroxy group present in the Michael addition products is converted into a facile leaving group and treated with a strong base to get 4-aryl-N-methylpiperidine-3-carboxylates via the intramolecular cyclization in good yields. Reduction of the ester group present in these piperidine-3-carboxylates gave the title compounds as crystalline solids. Present process is easily adaptable for commercial preparation of the paroxetine intermediate (4-(4-fluorophenyl)-3 hydroxy methyl-1- -methylpiperidine
Full Text

FIELD OF INVENTION
The present invention relates to an improved process for the preparation of (±)-trans-4-aryl-3-hyroxymethyl-l-methylpiperidines. The (±)-trans-4-aryl-3-hyroxy methyl-1-methylpiperidines prepared by the process of the present invention have the general formula-I, wherein X = H, F, Me, OMe.

The compound of the formula-I wherein b represents fluorine is a key intermediate used in the synthesis of (-)-trans-4-p-fluorophenyl-3-(35,45-methylenedioxyphenoxymethyl)-piperidine, a compound also known as paroxetine of the formula-II. Paroxetine, commercially available in the market as an anti-depressant inhibits 5-hydroxytryptamine (5-HT) re-uptake.
BACKGROUND OF INVENTION
For the first time compounds of the formula-I where X has the meanings given above were disclosed in the US patent no 3,912,743. Subsequently the compound of formula-I where b represents fluorine was also disclosed in the US patent no 4,007,196. Process disclosed in these patents is based on a Grignard reaction in which arecoline (methyl N-methyl-12,5,6-tetraydropiperidine-3-carboxylate) and 4-fluorophenylmagnesium bromide are reacted together to get methyl N-methyl-4-fluorophenylpiperidine-3-carboxylate,

which was reduced using lithium aluminum hydride to get the required compound of formula-lb. The main disadvantage in this process is arecoline is very irritant and harmful to the persons involved in the usage. Also, arecoline is not readily commercially available and is very expensive. Moreover, the Grignard reagent used namely 4-fluorophenylmagnesium bromide, in the process is not selective towards 1,4-addition and a 1,2-addition product can also form as a major impurity. Separation of these mixtures may thus involve complex purification. Therefore, the process may not be suitable for commercialization.
In the US patent no 4,902,801 a process for the preparation of compound of the formula-I where X has the meanings given earlier is described. This process involves the reduction of the intermediate of the formula-Ill by lithium aluminum hydride (Scheme-I). Lithium aluminum hydride is very expensive and a hazardous chemical. Also, another drawback

in this process is that the N-methylamidomalonic acid esters required in the process are not commercially available. Preparation of these esters is a low yielding process due to formation of by-product N-methylmalonamide, which will also participate in preparation of compound of formula-Ill. All of this leads to high manufacturing costs of the process.
The intermediate compound of the formula-Ill was also made (according to the patent no EP 374,675) by addition of malonic acid esters to 4-substituted-N-methaylcinnamamide

(Scheme-II). According to this variant free methylamine has to be used in making the cinnamamide and also there are no major advantages over the above-mentioned process.

Compound of the formula-I where b represents fluorine was also prepared (Scheme-Ill) by reducing trans-4-p-fluorophenyl-6-oxopiperidine-3-carboxilic acid esters of the formula-V, wherein R is alkyl and subsequent N-methylation or by N-methylation of compound of the formula-V and subsequent reduction (as disclosed in EP 802,185, ES 96 00,369, EP 812827, and WO 98 53,824).

For the reduction of nitrile group present in compound of the formula-V by hydrogenation, elevated hydrogen pressure is needed (as disclosed in EP 812,827), which also involves use of platinum oxide. This makes the process disadvantageous as the risk

of defluorination is possible during hydrogenation. Also, the use of platinum oxide increases the cost of production. The reductive cyclization step involves the generation of cis/trans mixture. The undesired cis-compound needs to be isomerized by doing an additional step. All these operations make the above-mentioned processes economically not viable for commercial production of compound of formula-I b where b represents fluorine.
Compound of the formula-I b where b represents fluorine was also prepared (Scheme-IV) by the reduction and N-methylation of a compound of the formula-VIII (as disclosed in WO 00 26,187). Compound of formula-VIII is prepared by Michael addition of malonate esters to cinnamonitrile, followed by reductive cyclization. This process is similar to the process known for the preparation of compound of formula-VI, which involves costly reagents like platinum on carbon, high pressure ammonia reaction, etc. Also the conversion of compound of formula-VIII to compound of formula-I involves lithium aluminum hydride reduction, which is very expensive and hazardous as mentioned above. Therefore the process is not economically viable for commercial production of compound of formula-I or paroxetine of formula-II.

This process involves the conversion of the compound of the formula-V making it industrially not viable for preparation of compound of formula-I b where b represents fluorine or paroxetine of the formula-II.

In the recent patent WO 02 053537 a novel process for the preparation of compound of formula-I b where b represents fluorine is disclosed via a Mannich reaction and a Knoevenagel condensation to build the tetrahydropyridine ring (Scheme-V),

The main disadvantage of this process is that it involves the usage of alkyl 3-halo-3-oxopropionate to make the intermediate compound of the formula-XL This particular reagent is not easily accessible on a commercial scale. Also, the process uses lithium aluminum hydride in the last step of the synthesis. Handling of lithium aluminum hydride on commercial scale is not safe and also leads to high manufacturing costs.
SUMMARY OF INVENTION
Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of compound of formula-I b where b represents fluorine, and recognizing the importance of this compound as an important intermediate in the synthesis of paroxetine, we aimed to develop a simple and economical and general process for the preparation of compounds of the formula-I where X has the meanings given above.

We observed that a promising approach for development of such a process is to (a) avoid the usage of costly reagents like, lithium aluminum hydride (b) avoid the usage of difficult to handle intermediates/reagents (c) use readily and easily available raw materials (d) avoid the formation of cis-isomer in the process itself. Such an approach would meet the requirements of the costs, safety, and ecology of the production of compounds of the formula-I where X has the meaning given above, particularly pharmaceutical^ active substance like, paroxetine of the formula-II
The process of the present invention for preparing the compounds of formula-I where X have the meanings given earlier is illustrated in the following Scheme-VI:


The compound of the formula-XIII shall be prepared by two routes as shown in Scheme-VII.

In route A, Mannich salt of the formula-XVIII is reduced to the corresponding known hydroxy compound of the formula-XIV by literature procedures. N-Demethylation of the compound of the formula XVI can be done by converting it into a urethane derivative and hydrolysis of the urethane derivative to get the required compound of the formula-XIII.
In route B, Mannich salt derived from N-benzylmethylamine is reduced to the corresponding hydroxy compound. Finally, N-debenzylation can be done under mild

heterogeneous hydrogenation condition to get the required compound of the formula-XIII.
The secondary amine of the formula-XIII can be reacted with acrylic acid esters to give the corresponding N-alkylated derivative of the formula-XIV. The hydroxy group present in compound of the formula-XIV can be converted as a leaving group X5 (X5 = methanesulfonyl-, toluenesulfonyl-, benzenesulfonyl, or a halogen group) to get a compound of the formula-XV.
The compound of the formula-XVI can be prepared by generation of an anion a to the ester carbon present in compound of the formula-XV and cyclizing through displacement of the leaving group X. The ester group present in compound of the formula-XVI can be reduced with a simple reagent like sodium borohydride to get the desired compound of the formula-I where X has the meanings given earlier.
DETAILED DESCRIPTION OF INVENTION
In a preferred embodiment of the present invention, the compound of the formula-XVII (X = Me, OMe) is condensed with paraformaldehyde or aqueous formaldehyde and methylbenzylamine through Mannich reaction to get the novel compound of formula-XXI (X = Me, OMe). The reaction can be carried out in a polar alcoholic or aqueous solvent. The secondary amine can be employed in the form of its inorganic or organic salt or as a free base. The suitable inorganic or organic are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, propionic acid, oxalic acid, fumaric acid, tartaric acid, adipic acid, etc. When the amine is used in free base form at least one equivalent of organic or inorganic acid is used along with the solvent.
In the second step, the known dimethylamine derived Mannich salt (compound of the formula-XVIII) is converted to the known hydroxy compound of formula-XIX by known processes. The hydroxy compound thus obtained can be de-methylated using methyl or ethyl chloroformate to get the corresponding urethane derivative of the formula-XX. The

urethane derivative can be hydrolyzed using alkali to get the secondary amine of the formula-XIII.
The Mannich salt obtained from N-benzylmethylamine (compound of the formula-XXI), can be neutralized and reduced in situ with sodium borohydride to get the hydroxy compound of the formula-XXIL The reduction can be done in alcoholic solvent. This can be converted to the secondary amine of formula-XIII by direct hydrogenation in the presence of a metal catalyst under mild hydrogenation. The hydrogenation can be done in an alcoholic solvent like methanol, ethanol, isopropanol, etc.
The secondary amine derivative of the formula-XIII is reacted with an alkyl ester of acrylic acid to get the corresponding tertiary amine derivative of the formula-XIV. The reaction can be done in an aromatic solvent (benzene, toluene, xylene, etc.), in a hydrocarbon solvent (hexane, heptane, cyclohexane, etc.), or in an ether solvent (dimethyl ether, diisopropyl ether, methyl isobutyl ether, methyl tert-butyl ether, etc.).
The hydroxy group present in compound of the formula-XIV can be converted to its mesylate or tosylate. Alternatively, it can be reacted with thionyl chloride or excess mineral acid (HBr or HC1) to get the corresponding halide as the hydrogen halide salt. The sulfonate derivatives or the halide salts of compound of the formula-XV can be reacted with a strong base (NaH, n-butyl lithium, lithium diisopropyl amide, etc.) in a dipolar aprotic solvent to get the cyclic derivative of the formula-XV. In case of halide-hydrogen halide salts at least two equivalents of base is used to carryout the cyclization step.
The cyclized compound of the formula-XV can be reduced using sodium borohydride under various conditions (sodium borohydride/borontrifluoride-etherate, sodium borohydride/t-butanol/methanol, reflux; t-butanol/acetic acid, etc.), vitride, sodium/ethanol, lithium tris-(t-butoxy)aluminum hydride, lithium aluminum hydride, etc., to get the required compound of the formula-I where X has the meanings given earlier.

The medium of the reaction can be an alcoholic solvent (for sodium borohydride), aromatic solvent for vitride, and an ether solvent for lithium reagents.
The invention provides novel compounds of the formula-XX,

wherein X = F, Me, OMe; R = Me, Et, Ph
Accordingly the invention also provides a process for the preparation of novel compounds of the formula-XX

wherein X - F, Me, OMe; R = Me, Et, Ph
which comprises N-demethylation of compounds of the formula-XIX,

with an alkyl/aryl chloroformate to get the novel urethane derivative of the formula-XX.
The alkyl/aryl chloroformate used for the N-demethylation of the compound of the formula-XIX may be selected from methyl, ethyl, or phenyl chloroformate
The invention also provides novel compounds of the formula-XIII,


wherein X = F, Me, OMe
Accordingly the invention also provides a process for the preparation of novel compounds of the formula-XIII,

which comprises:
(i) N-Demethylation of the compounds of the formula-XIX

with an alkyl/aryl chloroformate to get the novel urethane derivative of formula-XX,

wherein R and X are as defined above
(ii) Hydrolysing the novel urethane derivative with an alkali to get the novel secondary
amine of formula-XIII.

The alkyl chloroformate used for the N-demethylation of the compound of the formula-XIX in step (i) may be selected from methyl, ethyl, and phenyl chloroformate. The alkali used in step (ii) may be selected from sodium or potassium hydroxide preferably potassium hydroxide in aqueous DMSO at 60-140°C, preferably 100-120°C.
The present invention also provides novel compounds of formula-XXI,

wherein X = Me, OMe; HX' is inorganic or organic acid.
Accordingly the invention also provides a process for the preparation of novel compounds of the formula-XXI,

wherein X = Me, OMe; HX' is inorganic or organic acid.
which comprises a Mannich reaction on compound of formula-XVII
wherein X = Me, OMe
with formaldehyde (paraformaldehyde or aqueous formaldehyde) and
methylbenzylamine, or its addition salts with inorganic or organic acids, in a polar
solvent to get the compound of formula-XXI.
The present invention also provides novel compounds of the formula-XXII,


wherein X = F, Me, OMe
According to another embodiment of the present invention there is provided a process for the preparation of novel compounds of the formula-XXII

wherein X = F, Me, OMe
which comprises :
(i) Neutralizing the Mannich salt of formula-XXI

wherein X = F, Me, OMe; HX' is inorganic or organic acid
with a base in alcoholic medium
(ii) Reducing the liberated base with sodium borohydride in same alcoholic medium to
get the hydroxy compound of formula-XXII,

wherein X = F, Me, OMe

The base used in step (i) may be selected from sodium or potassium hydroxide, carbonate, bicarbonate and the like. The alcoholic medium used in reduction may be selected from methanol, ethanol, isopropanol, sec-butanol, etc., with or without water.
According to yet another embodiment of the present invention there is provided a process for the preparation of compounds of the formula-XIII,

wherein X = F, Me, OMe
which comprises:
(i) Neutralizing the Mannich salt of the formula-XXI

wherein X = Me, OMe; HX5 is inorganic or organic acid.
with a base in alcoholic medium
(ii) Reducing the liberated base with sodium borohydride in same alcoholic medium to
get the hydroxy compound of formula-XXII,

wherein R = F, Me, OMe
(iii) Debenzylation of the hydroxy compound of the formula-XXII under heterogeneous hydrogenation conditions using a metal catalyst to get the novel debenzylated compound of formula-XIII.

The base used in step (i) may be selected from sodium or potassium hydroxide, carbonate, bicarbonate and the like. The alcoholic medium used in reduction may be selected from methanol, ethanol, isopropanol, sec-butanol, etc., with or without water. The metal catalyst used in debenzylation step may be selected from Raney nickel, 2-10% palladium-on-carbon, 2-5% platinum-on-carbon and the like.
The invention also provides novel compounds of the formula-XIV.

wherein X = H, F, Me, OMe, R = Me, Et
According to still another embodiment of the present invention there is provided a process for the preparation of novel compounds of the formula-XIV,

Wherein X = H, F, Me, OMe; R = Me, Et
which comprises, reacting the compound of the formula-XIII,


wherein X = H, F, Me, OMe
with an acrylate ester in the presence of a solvent at an elevated temperature to get the
Michael addition product of the formula-XIV.
The reaction can be done in solvents such as benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, preferably toluene, cyclohexane, heptane. The temperature of the reaction can be in the range of 25-100°C, preferably 40-70°C.
The invention also provides novel compounds of the formula-XV.

Wherein X = H, X' = OMs, OBs, OTs, OAc; R = Me, Et
X = F, X' = OMs, OBs, OTs, OAc; CI, R = Me, Et X = Me, X' = OMs, OBs, OTs, OAc; CI, R = Me, Et X = OMe, X' = OMs, CI, R = Me, Et
According to yet another embodiment of the present invention there is provided a process for the preparation of novel compounds of the formula-XV


Wherein X = H, X' = OMs, OBs, OTs, OAc; R = Me, Et
X = F, X' = OMs, OBs, OTs, OAc; CI, R = Me, Et X = Me, X5 = OMs, OBs, OTs, OAc; CI, R = Me, Et X = OMe, X' = OMs, CI, R = Me, Et
which comprises:
(i) Reacting the compound of the formula-XIII,

wherein X = H, F, Me, OMe with an acrylate ester in the presence of a solvent at an elevated temperature to get the Michael addition product of the formula-XIV.

Wherein X and R is as defined above

(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X' with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.
The N-alkylation reaction can be done in solvents such as benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, preferably toluene, cyclohexane, heptane. The temperature of the reaction can be in the range of 25-100°C, preferably 40-70°C.
The conversion of hydroxy group present in compound of formula-XIV into a leaving group X' (OMs, OBs, OTs) is done by treating the compound of formula-XIV with a base and the required sulfonyl chloride in the presence of a solvent at a temperature in the range of-30 to 30°C. The base used in the reaction can be selected from inorganic base like sodium or potassium carbonate, bicarbonate, or an organic base such as pyridine, triethylamine, etc., preferably triethylamine. The solvent used in the reaction can be selected hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene dichloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene, methylene chloride or THF.
The conversion of hydroxy group present in compound of formula-XIV into a leaving group X' (OAc) is done by treating the compound of formula-XIV with acetic anhydride/acetyl chloride in the present of a solvent. The solvent used in the reaction can be selected hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene dichloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene, methylene chloride or THF.
The conversion of hydroxy group present in compound of formula-XIV into a leaving group X5 (CI) is done by treating the compound of formula-XIV with excess thionyl chloride in a solvent at elevated temperature. The solvent used in the reaction can be selected hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene dichloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene,

methylene chloride or THF. The temperature of the reaction can be in the range of 10-
60°C.
The invention also provides novel compounds of the formula-XVI

Wherein X = Me; R = Me, Et
According to still another embodiment of the present invention there is provided a
process for the preparation of novel compounds of the formula-XVI,

Wherein X = Me; R - Me, Et
which comprises:
(i) Reacting the compound of the formula-XIII


wherein X = Me with an acrylate ester in the presence of a solvent at an elevated temperature to get the Michael addition product of the formula-XIV

Wherein X = Me, R = Me, Et
(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X5 with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.

Wherein X = Me; X' = OMs, OBs, OTs; R = Me, Et
(iii) Reacting the compound of the formula-XV with a strong base in the presence of an
ether or dipolar aprotic solvent at low temperature to get the cyclized compound of
formula-XVI.
The base used in the reaction is selected from lithium diisopropylamide, sodium hydride,
potassium t-butoxide, etc. The ether solvent used in the reaction is selected from THF,
diethyl ether. The dipolar aprotic solvent used in the reaction is selected from

dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc. The temperature of the reaction is in the range of-15 to 25°C.
The invention also provides novel compounds of the formula-I,

wherein x = me and its acid addition salts
The invention also provides a process for the preparation of novel compounds of the
formula-I
wherein X = Me
which comprises:
(i) Reacting the compound of the formula-XIII


wherein X = Me with an acrylate ester in the presence of a solvent at an elevated temperature to get the Michael addition product of the formula-XIV

Wherein X = Me, R = Me, Et
(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X5 with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.


(iii) Reacting the compound of the formula-XV with a strong base in the presence of an ether or dipolar aprotic solvent at low temperature to get the cyclized compound of formula-XVI.
Wherein X = Me; R = Me, Et
(iv) Reducing the ester group present in the compound of the formula-XVI with a reducing agent to get the hydroxy compound of formula-I where X has the meanings given earlier
The invention also provides a novel process for the preparation of compounds of the formula-I

where X has the meanings given earlier which comprises: (i) Reacting the compound of the formula-XIII

wherein X = H, F, Me, OMe
with an acrylate ester in the presence of a solvent at an elevated temperature to get the Michael addition product of the formula-XIV

Wherein X = H, F, Me, OMe; R = Me, Et
(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X' with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.


Wherein X = H, F, Me, OMe; X5 = OMs, OBs, OTs, CI, Br, OAc, OBz; R = Me, Et (iii) Reacting the compound of the formula-XV with a strong base in the presence of an ether or dipolar aprotic solvent at low temperature to get the cyclized compound of formula-XVI.

Wherein X = H, F, Me, OMe; R = Me, Et
(iv) Reducing the ester group present in the compound of the formula-XVI with a reducing agent to get the hydroxy compound of formula-I where X has the meanings given earlier
The acrylate ester used in step (i) is selected from methyl or ethyl acrylate and the like. The solvent such as toluene, cyclohexane, heptane, xylene, acetonitrile, and the like preferably, toluene or cyclohexane is used in step (i). The temperature employed in step (i) is in the range of 60 to70°C.
The reagents used in step (ii) for the conversion of the hydroxy group are selected from thionyl chloride, thionyl bromide, phosphorous trichloride, phosphorous tribromide, hydrochloric acid, hydrobromic acid, methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, acetyl chloride, benzoyl chloride, trifluoromethanesulfonyl chloride, etc., preferably thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride or trifluoromethanesulfonyl chloride, more preferably thionyl chloride or methanesulfonyl chloride.

The solvent used in step (ii) is methylene chloride, ethylene dichloride, toluene, cylcohexane, heptane, etc., preferably, methylene chloride, toluene or heptane and the reaction temperature is in the range of-20 to 25°C, preferably -5 to 15°C. The base used in step (ii) is triethylamine, pyridine, lutidine, sodium or potassium carbonate, or bicarbonate, etc., preferably, pyridine or triethylamine.
The strong base used in step (iii) is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec-amyloxide, sodium amide, lithium amide, sodium methoxide, and the like, preferably sodium hydride lithium diisopropylamide.
The solvent used in step (iii) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, dimethylsulfoxide, tetrahydrofiiran, dioxane, toluene, xylene, diisopropyl ether, etc., preferably N,N-dimethylformamide, dimethylsulfoxide, pyridine, tetrahydrofiiran, more preferably N,N-dimethylformamide, tetrahydrofiiran.
The temperature of reaction in step (iii) is between -10 to 45°C, preferably -5 to 25°C. The mole ratio of base to substrate in step (iii) is 1:1.1 to 1:2.0, preferably 1:1.25.
The reducing agent used in step (iv) is selected from sodium borohydride/t-butanol/methanol, sodium borohydride in the presence of an acid catalyst like boron trifluoride-etherate, sulfuric acid, etc.; vitride, lithium aluminum hydride, lithium tris-(t-butoxy)aluminum hydride, sodium/ethanol, and the like, preferably, sodium borohydide/t-butanol/methanol, vitride, lithium aluminum hydride.
The temperature of reaction in step (iv) is -50°C to 70°C, preferably -20°C to 20°C.
In step (iii) the strong base used is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec-amyloxide, sodium amide, lithium amide, sodium methoxide, and the like, preferably sodium hydride lithium diisopropylamide.

The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of the present invention
Example 1
Preparation of N-methyI-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine of the formuIa-XIII (X = F)
(i) Preparation of N-methyl-N-carbomethoxy-N-[3-hydroxy-3-(4-fluorophenyl)]-propylamine of the formula-XX (X = F, R = methyl)
Into a 500ml three-necked RB flask was charged 25gr of 4-fluoro-a-(2-dimethyl-aminoethyl)benzyl alcohol, 150ml of chloroform, and 26gr of anhydrous powder potassium carbonate. To the reaction mixture methyl chloroformate (29.8gr) was slowly at RT and heated to reflux temperature. After maintaining for 15hrs at reflux temperature, the reaction mixture was cooled to RT and water (150ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (100ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (15gr) compound of the formula-XX (X = F, R = methyl). This can be directly used in next step. A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat): 3419, 2952, 1682, 1604, 1509, 1493, 1449, 1397, 1309, 1220, 1156, 1071, 838, and 772 cm-1. *H-NMR (300MHz, CDC13): 7.25-7.32 (m, 2H, ar.H); 6.93-7.02 (m, 2H, ar.H); 4.55-4.58 (m, 1H, -CH(OH>); 4.47 (br.s, 1H, exch. with D20, -CH(OH)-); 3.28 (s, 3H, -C02Me); 3.05-3.40 (m, 2H, -NCH2-); 2.85 (s, 3H, -NCH3); 1.81-L87 (m, 2H,-NCH2CH2-). (ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-fluorophenyI)]propylamine of the
formula-XIII (X = F)
Into a 500ml three-necked RB flask was charged 12gr of the compound of the formula-XX (X = F, R = methyl) prepared according to the process described in step (i), 40ml of DMSO, 30ml of water, and 20gr of potassium hydroxide flakes. The reaction mixture was heated to 100°C and maintained for 6hrs. The reaction mixture was cooled to RT and diluted with 250ml of water. Product was extracted into toluene (2 x 100ml). The

combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude the compound of the formula-XIII (X = F). The crude compound of the formula-XIII (X = F) was crystallized from isopropyl ether to get white crystalline solid (6.0gr). M. P. 67.0-68.0°C. IR (KBr): 3283, 3072, 2933, 2687, 2554, 1607, 1508, 1438, 1439, 1431, 1076, 905, 851, and 823 cm"1. *H-NMR (300MHz, CDC13): 7.27-7.37 (m, 2H, ar.H); 6.95-7.07 (m, 2H, ar.H); 4.54 (dd, J = 3.3Hz, 8.4Hz, 1H, -CH(OH)-); 4.14 (br.s, 2H, exch. with D20, OH and NH); 2.79-2.97 (m, 2H, -NCH2-); 2.45 (s, 3H, -NCH3); 1.68-1.90 (m, 2H, -NCH2CH2-).
Example 2 Preparation of N-methyI-N-[3-hydroxy-3-(4-fluorophenyI)]propylamine of the formula Xffl (X = F)
(i) Preparation of N-methyl-N-carboethoxy-N-[3-hydroxy-3-(4-fluorophenyl)]-propylamine of the formula-XX (X = F, R = ethyl)
Into a 500ml three-necked RB flask was charged 25gr of 4-fluoro-a-(2-dimethyl-aminoethyl)benzyl alcohol, 150ml of chloroform, and 26gr of anhydrous powder potassium carbonate. To the reaction mixture ethyl chloroformate (34.2gr) was slowly at RT and heated to reflux temperature. After maintaining for 15hrs at reflux temperature, the reaction mixture was cooled to RT and water (150ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (100ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (20gr) compound of the formula-XX (X = F, R = ethyl). This can be directly used in next step. A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat): 3423, 2982, 2937, 1678, 1604, 1509, 1492, 1445, 1407, 1385, 1306, 1221, 1156, 1097, 1069, 1014, 839, and 772 cm"1. XH-NMR (300MHz, CDCI3): 7.23-7.36 (m, 2H, ar.H); 6.96-7.05 (m, 2H, ar.H); 4.57-4.62 (m, 1H, -CH(OH)-); 4.32 (br.s, exch. with D20, 1H, -(CH(OH)-); 4.13 (q, J = 7.3Hz, 3H, -OCH2CH3); 3.00-3.15 (m, 2H, -CHr); 2.90 (s, 3H, -NCH3); 1.77-1.94 (m, 2H, -CH2-); 1.26 (t, J = 7.0Hz, 3H, -OCH2CH3).

(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-nuorophenyl)]propyIamine of the formula-X111 (X = F)
Into a 500ml three-necked RB flask was charged 15gr of the compound of the formula XX (X - F, R = ethyl) prepared according to the process described in step (i), 50ml of DMSO, 30ml of water, and 30gr of potassium hydroxide flakes. The reaction mixture was heated to 100°C and maintained for 6hrs. The reaction mixture was cooled to RT and diluted with 250ml of water. Product was extracted into toluene (2 x 100ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude the compound of the formula-XIII (X = F). The crude compound of the formula-XIII (X = F) was crystallized from isopropyl ether to get white crystalline solid (5.0gr).
Example 3 Preparation of N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine of the formula-XIII (X = F)
(0 Preparation of N-methyl-N-carbophenoxy-N-[3-hydroxy-3-(4-fluorophenyl)]-propylamine (X = F, R = phenyl)
Into a 500ml three-necked RB flask was charged 25gr of 4-fluoro-a-(2-dimethyl-aminoethyl)benzyl alcohol, 150ml of chloroform, and 26gr of anhydrous powder potassium carbonate. To the reaction mixture phenyl chloroformate (50gr) was slowly at RT and heated to reflux temperature. After maintaining for 15hrs at reflux temperature, the reaction mixture was cooled to RT and water (150ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (100ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (23gr) compound of the formula-XX (X = F, R = phenyl). This can be directly used in next step. A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat): 3434, 3069, 2943, 1716, 1604, 1509, 1475, 1401, 1307, 1209, 1163, 1132, 1071, 840, 751, and 691 cm"1. 'H-NMR (300MHz, CDC13): 6.97-7.40 9m, 10H, ar. H); 4.64-4.70 (m, 1H, -CH(OH)-); 3.81-3.95 (m, 1H); 3.52-3.60 (m, 1H); 3.16-3.29 (m, 1H); 3.10 (s, 3H, NCH3); 1.79-2.04 (m, 2H, -CH2CH(OH)-).

(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine of the formula-XIII (X = F)
Into a 500ml three-necked RB flask was charged 15gr of the compound of the formula-XX (X = F, R = phenyl) prepared according to the process described in step (i), 50ml of DMSO, 30ml of water, and 30gr of potassium hydroxide flakes. The reaction mixture was heated to 100°C and maintained for 6hrs. The reaction mixture was cooled to RT and diluted with 250ml of water. Product was extracted into toluene (2 x 100ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude the compound of the formula-XIII (X = F). The crude compound of the formula-XIII (X = F) was crystallized from isopropyl ether to get white crystalline solid(4.0gr).
Example 4 (i) Preparation of N-benzyl-N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)] propylamine of the formuIa-XXn (X = F)
Into a 1L three-necked RB flask was charged 500ml of methanol and 14.5gr of sodium hydroxide. The reaction mixture was heated to 50-55°C to get a clear solution. The solution was cooled to 10°C and added solid N-methyl-N-benzyl-N-(3-(4-fluorobenzoyl))ethylamine hydrochloride (lOOgr) in lots. After maintaining for 30min, sodium borohydride (3.75gr) was added in lots. After maintaining for 2hrs at 10°C reaction mixture was filtered and methanol distilled off from the filtrate under vaccum. The residue was partitioned between water (300ml) and toluene (300ml). Toluene layer was separated and water layer extracted with 100ml of toluene. Combined organic layer was washed with water (100ml), dried over sodium sulfate and the solvent distilled under vaccum to get the crude product. The crude product was crystallized from hexane to get the compound of the formula-XXII (X = F) as white crystalline solid (84gr). M. P. 65.5-66.0°C. IR (KBr): 3063, 2826, 1603, 1509, 1465, 1219, 1078, 1027, 832, 740, and 697 cm"1. *H-NMR (300MHz, CDC13): 7.25-7.37 (m, 6H, ar.H); 6.94-7.05 (m, 3H, ar.H); 4.87 (dd, J = 4.1Hz, 7.1Hz, 1H, -CH(OH)-); 3.65 (d, J = 2.8Hz, 1H, PhCH2); 3.46 (d, J = 2.8Hz, 1H, PhCH2); 2.75-2.90 (m, 1H); 2.52-2.64 (m, 1H); 2.27 (s, 3H, -NCH3); 1.79-1.89 (m,2H, -NCH2CH2-).

(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-fluorophenyI)]propyIamine of the formula-X111(X = F)
Into a 1L stainless steel hydrogenation kettle was charged lOOgr of compound of
formula-XXII (X = F) obtained according to step (i) above, 600ml of isopropyl alcohol
and 4gr of 5% palladium-on-carbon (50% wet) under nitrogen atmosphere. The kettle
was evacuated and filled with hydrogen. Hydrogenation was done at room temperature
and at a pressure of 40-50psi for 10-12hrs. The reaction mixture was filtered on a celite
pad to remove the catalyst. The filtrate distilled off under vaccum at 40°C to get the crude
compound of the formula-XIII (X = F). The crude compound of the formula XIII (X = F)
was dissolved in diisopropyl ether (100ml) and cooled to 15-20°C. The solids were
filtered and washed with hexane (50ml) to get 65gr of colorless crystalline compound. M.
P. 76-68°C.
Example 5
Preparation of N-methyl-N-[3"hydroxy-3-(4-methylphenyl)]propylamine of the
fbrmula-Xin (X = methyl)
(i) Preparation of N-methyl-N-carbomethoxy-N-[3-hydroxy-3-(4-methylphenyl)]-
propylamine of the formula-XX (X = R = methyl)
Into a 500ml three-necked RB flask was charged 30gr of 4-methyl-a-(2-dimethyl-aminoethyl)benzyl alcohol, 200ml of chloroform, and 30gr of anhydrous powder potassium carbonate. To the reaction mixture methyl chloroformate (40gr) was slowly at RT and heated to reflux temperature. After maintaining for 12hrs at reflux temperature, the reaction mixture was cooled to RT and water (200ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (150ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (16gr) compound of the formula-XX (X = R = methyl). A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat): 3431, 2950, 1696, 1491, 1449, 1398, 1301, 1210, 1144, 1070, 821, and 772 cm"1. *H-NMR (300MHz, CDC13): 7.12-7.27 (m, 4H, ar. H); 4.61 (t, J = 5.8Hz, 1H, -CH(OH)-; 3.70 (s, 3H, -OCH3); 3.10-3.40 (m, 2H, -CH2-); 2.89 (s, 3H, -CH3); 2.33 (s, 3h, -CH3); 1.86-1.96 (m, 2H, -CH2-).

(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)] propylamine of the formula-XIII (X = methyl)
Into a 500ml three-necked RB flask was charged 15gr of the compound of the formula-XX (X = R = methyl) prepared according to step (i), 30ml of ethylene glycol, 10ml of water, and 30gr of potassium hydroxide flakes. The reaction mixture was heated to 120°C and maintained for 8hrs. The reaction mixture was cooled to RT and diluted with 200ml of water. Product was extracted into toluene (2 x 100ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude compound of the formula-XIII (X = methyl). The crude compound of the formula-XIII (X = methyl) was crystallized from isopropyl ether to get white crystalline solid (9.0gr). M. P. 67^68°C. IR (KBr): 3281, 3047, 3017, 2974, 2920, 2836, 2798, 1638, 1510, 1488, 1449, 1425, 1352, 1333, 1262, 1239, 1200, 1174, 1144, 1105, 1080, 1053, 1017, 925, 867, 852, 803, 745, 578, and 521 cm"1. *H-NMR (300MHz, CDC13): 7.12-7.28 (m, 4H, ar.H); 4.89 (dd, J = 3.7Hz, 8.1Hz, 1H, -CH(OH)-); 3.86 (br.s, exch. with D20, 2H, -CH(OH>, -NH-); 2.81-2.89 (m, 2H, -NCH2-); 2.43 (s, 3H, NCH3); 2.33 (s, 3H, ArCH3); 1.77-1.84 (m, 2H, -CH2CH(OH)-).
Example 6 Preparation of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propylamine of the formula-XIII (X = methyl)
(i) Preparation of N-methyI-N-carboethoxy-N-[3-hydroxy-3-(4-methylphenyl)]-propylamine of formula-XIII (X = methyl, R = ethyl)
Into a 500ml three-necked RB flask was charged 30gr of 4-methyl-a-(2-dimethyl-aminoethyl)benzyl alcohol, 200ml of chloroform, and 30gr of anhydrous powder potassium carbonate. To the reaction mixture ethyl chloroformate (50gr) was slowly at RT and heated to reflux temperature. After maintaining for 12hrs at reflux temperature, the reaction mixture was cooled to RT and water (200ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (150ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (20gr) compound of the formula-XX (X = methyl, R = ethyl). A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat):

3431, 2981, 2934, 1681, 1491, 1445, 1407, 1385, 1302, 1207, 1147, 1068, 818, and 772 cm-1. 1H-NMR (300MHz, CDC13): 7.23-7.27 (m, 2H, ar. H); 7.12-7.16 9m, 2H, ar. H); 4.57 (t, J = 5.8Hz, 1H, -CH(OH)-); 4.12 (q, J = 7.00Hz, 2H, -OCH2CH3); 3.70-4.00 (m, 1H, -CH2-); 3.00-3.20 (m, 1H, -CH2-); 2.90 (s, 3H, -CH3); 2.33 (s, 3H, -CH3); 1.86-1.96 (m, 2H, »CH2-); 1.26 (t, J = 7.00Hz, 3H, -OCH2CH3).
(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propyIamine of the formula-XIII (X = methyl)
Into a 500ml three-necked RB flask was charged 15gr of the compound of the formula-XX (X = methyl, R = ethyl) prepared according to step (i), 30ml of ethylene glycol, 10ml of water, and 30gr of potassium hydroxide flakes. The reaction mixture was heated to 120°C and maintained for 8hrs. The reaction mixture was cooled to RT and diluted with 200ml of water. Product was extracted into toluene (2 x 100ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude compound of the formula-XIII (X = methyl). The crude compound of the formula XIII (X = methyl) was crystallized from isopropyl ether to get white crystalline solid (6-0gr).
Example 7 Preparation of N-methyl-N-[3-hydroxy-3-(4-methyIphenyl)]propylamine of the formula-XIII (X = methyl)
(i) Preparation of N-methyl-N-carbophenoxy-N-[3-hydroxy-3-(4-methylphenyI)]-propylamine of the formula-XX (X = methyl, R = phenyl)
Into a 500ml three-necked RB flask was charged 30gr of 4-methyl-a-(2-dimethyl-aminoethyl)benzyl alcohol, 200ml of chloroform, and 30gr of anhydrous powder potassium carbonate. To the reaction mixture phenyl chloroformate (60gr) was slowly at RT and heated to reflux temperature. After maintaining for 12hrs at reflux temperature, the reaction mixture was cooled to RT and water (200ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (150ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (25gr) compound of the formula-XX (X = methyl, R = phenyl). A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat):

3378, 3044, 2945, 1702, 1594, 1474, 1458, 1401, 1297, 1207, 1183, 1162, 1123, 1070, 856, 816, 751, and 690 cm"1.
(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propylamine of the formula-Xin (X = methyl)
Into a 500ml three-necked RB flask was charged 15gr of the compound of the formula-XX (X = methyl, R = phenyl) prepared according to step (i), 30ml of ethylene glycol, 10ml of water, and 30gr of potassium hydroxide flakes. The reaction mixture was heated to 120°C and maintained for 8hrs. The reaction mixture was cooled to RT and diluted with 200ml of water. Product was extracted into toluene (2 x 100ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude compound of the formula-XIII (X = methyl). The crude compound of the formula XIII (X = methyl) was crystallized from isopropyl ether to get white crystalline Solid (3.0gr).
Example 8 Preparation of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propyIamine of the formula-Xffl (X = methyl)
(i) Preparation of 4-methyI-3'-(N-benzyl-N-methylamino)propiophenone hydrochloride of the formula-XXI (X = methyl)
Into a 1L three-necked RB flask was charged isopropanol (150ml) and N-methylbenzylamine (80gr). The reaction mixture was cooled to 15-20°C and treated with IPA-HC1 (192gr, 13.64% HC1 content). After maintaining for lhr, p-methylcetophenone (lOOgr), and paraformaldehyde (33.4gr) were added. Slowly the reaction mixture was heated to reflux temperature and maintained for 6hrs. The reaction mixture was cooled to 40°C and acetone (200ml) added. The reaction mixture was cooled to 0-5°C under stirring and maintained for lhr before filtration. The wet cake thus obtained was suspended in acetone (320ml) and heated to reflux. After maintaining for 30min, reaction mixture was cooled to RT and filtered the purified salt (160gr) of the formula-XXI (X = methyl) as white crystalline solid. M. P. 175-6°C. IR (KBr): 3033, 2988, 2965, 2902, 2541, 2462, 1676, 1606, 1455, 1408, 1370, 1325, 1234, 1180, 935, 921, 795, 743, and 699 cm"1. !H-NMR (300MHz, DMSO-ck): 11.45 (br.s, 1H, -NET); 7.89-7.93 (m, 2H,

ar.H); 7.66-7.71 (m, 2H, ar.H); 4.27-4.52 (m, 2H, -CH2-); 3.70-3.77 (m, 2H, -CH2-); 3.20-3.50 (m, 2H, -CH2-); 2.68 (d, J = 3.7Hz, 3H, ArCH3); 2.37 (s, 3H, -NCH3). (ii) Preparation of N-benzyI-N-methyl-N-[3-hydroxy-3-(4-methyIphenyl)]propyI-amine of the formuIa-XXH (X = methyl)
Into a 1L three-necked RB flask was charged 750ml of methanol and 21.6gr of sodium hydroxide. The reaction mixture was heated to 50-55°C to get a clear solution. The solution was cooled to 10°C and added solid salt (150gr) obtained in step (i) above. After maintaining for lhr, sodium borohydride (6.0gr) was slowly added in lots keeping the temperature below 10°C. Slowly the reaction mixture was allowed to reach RT and left for 2hrs. The reaction mixture was filtered and the solvent distilled off from filtrate under vaccum. The residue was dissolved in toluene (300ml) and washed with water (300ml). Toluene was distilled off under vaccum to get the compound of the formula-XXII (X = methyl) as colorless syrup. IR (neat): 3256, 3027, 2947, 2843, 2800, 1602, 1513, 1495, 1454, 1343, 1130, 1077, 1041, 817, 738, and 699 cm'1. *H-NMR (300MHz, CDC13): 7.10-7.36 (m, 9H, ar.H); 6.80 (br.s, exch. with D20, 1H, -CH(OH)-); 3.64 (d, J = 12.8Hz, 1H, PhCH2); 3.46 (d, J = 12.8Hz, 1H, PhCH2); 2.59-2.81 9m, 2H, -CH2-); 2.33 (s, 3H, ArCH3); 2.25 (s, 3H, -NCH3); 1.82-1.92 (m, 2H, -CH2-).
(iii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propylamine of the formuIa-XIII (X = methyl)
Into a 1L stainless steel hydrogenation kettle was charged 600ml of methanol, lOOgr of above compound prepared in step (ii), and 5gr of palladium-on-carbon (5%, 50% wet). The reaction mixture was pressurized with hydrogen and shaken under hydrogen pressure (40-60psi) for 8hr at RT. After releasing the hydrogen pressure, the reaction mixture was filtered and the filtrate was taken into a 2L RB flask. Solvent was removed under vaccum and the residue thus obtained was crystallized from hexane (150ml) to get white crystalline solid (58gr) of the formula-XIII (X = methyl). M. P. 68-68.5°C.
Example 9 Preparation of N-methyl-N-[3-hydroxy-3-(4-methoxyphenyI)]propylamine of the
fonmila-XIII (X = OMe)
(i) Preparation of N-methyl-N-carbomethoxy-N-[3-hydroxy-3-(4-methoxyphenyl)]-
propylamine of the formula-XX (X = OMe, R = Me)

Into a 500ml three-necked RB flask was charged 30gr of 4-methoxy-a-(2-dimethyl-aminoethyl)benzyl alcohol, 200ml of chloroform, and 30gr of anhydrous powder potassium carbonate. To the reaction mixture methyl chloroformate (35gr) was slowly at RT and heated to reflux temperature. After maintaining for 8hrs at reflux temperature, the reaction mixture was cooled to RT and water (200ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (150ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (14gr) compound of the formula-XX (X = OMe, R = methyl). A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat): 3432, 2953, 2837, 1685, 1612, 1586, 1513, 1491, 1397, 1302, 1247, 1212, 1177, 1144, 1068, 1034, 965, 833, and 772 cm"1. 'H-NMR (300MHz, CDC13): 7.11-7.30 (m, 2H, ar. H); 6.78-6.89 (m, 2H, ar. H); 4.60 (t, J = 5.13Hz, 1H, -CH(OH»; 3.80 (s, 3H, -OCH3); 3.70 (s, 3H, -OCH3); 3.01-3.34 (m, 2H, -CH2-); 2.90 (s, 3H, -NCH3); 1.87-1.93 (m, 2H, -CH2-).
(ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methoxyphenyI)]propylamine of the formula-XIII (X = OMe)
Into a 500ml three-necked RB flask was charged lOgr of the compound prepared according to the process described in step (i), 20ml of DMSO, 10ml of water, and lOgr of potassium hydroxide flakes. The reaction mixture was heated to 100°C and maintained for 5hrs. The reaction mixture was cooled to RT and diluted with 100ml of water. Product was extracted into toluene (2 x 50ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude compound of the formula-XIII (X = OMe). The crude compound was crystallized from isopropyl ether to get white crystalline solid (5.0gr). M. P. 114-115°C. IR (KBr): 3285, 3058, 2998, 2978, 2936, 2902, 2833, 2796, 2692, 2542, 1611, 1582, 1509, 1482, 1458, 1439, 1412, 1369, 1350, 1300, 1252, 1202, 1180, 1168, 1140, 1108, 1077, 1039, 935, 908, 842, 832, 814, 579, and 552 cm-1. !H-NMR (300MHz, CDCI3): 7.25-7.32 (m, 2H, ar.H); 6.85-6.90 (m, 2H, ar.H); 4.87 (dd, J = 4.0Hz, 5.70Hz, 1H, -CH(OH)-); 3.81 (br.s. exch. with D20, 1H, -CH(OH)-); 3.79 (s, 3H, -OMe); 2.81-2.89(m, 2H, -CH2NH-); 2.43 (s, 3H, -NCH3); 1.72-1.84 (m, 2H, -CH(OH)CH2-).


(i) Preparation of N-methyl-N-carbomethoxy-N-[3-hydroxy-3-(4-methoxyphenyl)]-propylamine of the formula-XX (X = OMe, R = ethyl)
Into a 500ml three-necked RB flask was charged 30gr of 4-methoxy-a-(2-dimethyl-aminoethyl)benzyl alcohol, 200ml of chloroform, and 30gr of anhydrous powder potassium carbonate. To the reaction mixture ethyl chloroformate (40gr) was slowly at RT and heated to reflux temperature. After maintaining for 8hrs at reflux temperature, the reaction mixture was cooled to RT and water (200ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (150ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (15gr) compound of the formula-XX (X = OMe, R = ethyl). A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat); 3431, 2937, 2837, 1682, 1612, 1586, 1514, 1491, 1465, 1444, 1408, 1385, 1302, 1248, 1200, 1176, 1144, 1066, 1035, 835, and 772cm-1. ^-NMR (300MHz, CDC13): 7.26-7.31 (m, 2H, ar. H); 6.85-6.89 (m, 2H, ar. H); 4.59 (t, J - 4.3Hz, 1H, -CH(OH)-); 4.14 (q, J = 7.00Hz, 2H, -OCH2CH3); 3.80 (s, 3H, -OCH3); 3.00-3.25 (m, 2H, -CH2-)i 2.90 (s, 3H, -NCH3); 1.89-1.95 (m, 2H, -CH2-), 1.26 (t, J = 7.00Hz, 3H, -OCH2CH3). (ii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methoxy phenyl)] propylamine of the formula-XIII (X = OMe)
Into a 500ml three-necked RB.flask was charged lOgr of the compound prepared according to the process described in step (i), 20ml of DMSO, 10ml of water, and lOgr of potassium hydroxide flakes. The reaction mixture was heated to 100°C and maintained for 5hrs. The reaction mixture was cooled to RT and diluted with 100ml of water. Product was extracted into toluene (2 x 50ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude compound of the formula-XIII (X = OMe). The crude compound was crystallized from isopropyl ether to get white crystalline solid (3.0gr).

Example 11 Preparation of N-methyl-N-[3-hydroxy-3-(4-methoxyphenyl)]propylamine of formula-xm (X = OMe)
(i) Preparation of N-Methyl-N-carbophenoxy-N-[3-hydroxy-3-(4-methoxyphenyl)]-propylamine of the formuIa-XX (X = OMe, R = phenyl)
Into a 500ml three-necked RB flask was charged 30gr of 4-methoxy-ot-(2-dimethyl-aminoethyl)benzyl alcohol, 200ml of chloroform, and 30gr of anhydrous powder potassium carbonate. To the reaction mixture phenyl chloroformate (50gr) was slowly at RT and heated to reflux temperature. After maintaining for 8hrs at reflux temperature, the reaction mixture was cooled to RT and water (200ml) added. Chloroform layer was separated and the aqueous layer extracted with 100ml of chloroform. The combined chloroform layer was washed with 5% aqueous acetic acid (150ml). Chloroform layer was dried over sodium sulfate and the solvent distilled off under vaccum to get the crude (12gr) compound of the formula-XX (X = OMe, R = phenyl). A small sample was purified over a column of silica gel to get analytically pure sample as syrup. IR (neat): 3378, 3065, 3044, 2937, 2838, 1720, 1610, 1593, 1513, 1493, 1458, 1400, 1302, 1248, 1207, 1182, 1162, 1122, 1071, 1032, 1006, 915, 855, 836, 747, 689, 580, and 500cm-1. (ii) Preparation of N-methyI-N-[3-hydroxy-3-(4-methoxyphenyl)] propylamine of the formuIa-XIII (X = OMe)
Into a 500ml three-necked RB flask was charged lOgr of the compound prepared according to the process described in step (i), 20ml of DMSO, 10ml of water, and lOgr of potassium hydroxide flakes. The reaction mixture was heated to 100°C and maintained for 5hrs. The reaction mixture was cooled to RT and diluted with 100ml of water. Product was extracted into toluene (2 x 50ml). The combined toluene layer was washed with water, dried and the solvent distilled off under vaccum to get the crude compound of the formula-XIII (X = OMe). The crude compound was crystallized from isopropyl ether to get white crystalline solid (3.0gr). M. P. 114-115°C.

Example 12 Preparation of N-methyI-N-[3-hydroxy-3-(4-methoxyphenyl)] propylamine of the formula-XIII (X = OMe)
(i) Preparation of 4-methoxy-3'-(N-benzyl-N-methyIamino)propiophenone hydrochloride of the formula-XXI (X = OMe)
Into a 2L three-necked RB flask was charged isopropanol (200ml) and N-methylbenzylamine (161.5gr). The reaction mixture was cooled to 15-20°C and treated with IPA-HC1 (406gr, 13.9% HC1 content). After maintaining for lhr, p-methoxycetophenone (200gr), and paraformaldehyde (63.4gr) were added. Slowly the reaction mixture was heated to reflux temperature and maintained for 8hrs. The reaction mixture was cooled to 40°C and filtered while hot. The wet cake was washed with 200ml of acetone. The wet cake thus obtained was suspended in acetone (600ml) and heated to reflux. After maintaining for 15min, reaction mixture was cooled to RT and then to 50-10°C. The reaction mixture was filtered and washed with 100ml of chilled acetone. Finally, drying of the salt at 50-60°C gave white crystalline solid (298gr) of the compound of the formula-XXI (X = OMe). M. P. 165-7°C. IR (KBr): 3061, 2991, 2969, 2902, 2839, 2548, 2463, 1671, 1605, 1576, 1512, 1456, 1420, 1372, 1322, 1266, 1236, 1219, 1173, 1030, 995, 934, 921, 844, 803, 740, 699, and 600 cm"1. JH-NMR (300MHz, DMSO-d6): 11.13 (br. s, exch. with D20, 1H, NH+); 7.98 (d, J = 8.79Hz, 2H, ar. H); 7.63-7.67 (m, 2H, ar. H); 7.43-7.46 (m, 3H, ar. H); 7.07 (d, J = 8.79Hz, 2H, ar. H); 4.24-4.50 (m, 2H, -CH2-), 3.84 (s, 3H, -OCH3); 3.63-3.72 (m, 2H, -CH2-); 3.35 (s, 3H, -NCH3); 2.67 (d, J = 4.00Hz, 2H, PhCH2).
(ii) Preparation of N-benzyl-N-methyl-N-[3-hydroxy-3-(4-methoxyphenyI)]propylamine of the formula-XXII (X = OMe)
Into a 1L three-necked RB flask was charged 600ml of methanol and 24gr of sodium hydroxide. The reaction mixture was heated to 50-55°C to get a clear solution. The solution was cooled to 10°C and added solid salt (150gr) obtained in step (i) above. After maintaining for lhr, sodium borohydride (9.0gr) was slowly added in lots keeping the temperature below 10°C. Slowly the reaction mixture was allowed to reach RT and left for 2hrs. The reaction mixture was filtered and the solvent distilled off from filtrate under vaccum. The residue was dissolved in toluene (200ml) and washed with water (200ml).

Aqueous layer was extracted with 100ml of toluene. Combined toluene layer was washed with 100ml of water and the solvent distilled off under vaccum to get the compound of the formula-XXII (X = OMe) as colorless syrup (1355gr). IR (neat): 3242, 3062, 3028, 2950, 2834, 2800, 1612, 1586, 1513, 1496, 1454, 1344, 1302, 1246, 1174, 1129, 1077, 1036, 833, 739, and 700 cm"1. 'H-NMR (300MHz, CDC13): 7.21-7.31 (m, 7H, ar.H); 6.79-6.84 (m, 2H, ar.H); 4.80 9dd, J = 3.66Hz, 8.06Hz, 1H, -CH(OH)-); 3.70 (s, 3H, -OCH3); 3.48 (dd, J = 2.82, 36.26, 2H, PhCH2); 2.67-2.73 (m, 1H, -NCH2CH2); 2.47-2.56 (m, 1H, -NCH2CH2); 2.19 (s, 3H, -NCH3); 1.76-1.85 (m, 2H, -CH(OH)CH2-). (iii) Preparation of N-methyl-N-[3-hydroxy-3-(4-methoxyphenyl)] propylamine of the formula-XHI (X = OMe)
Into a 1L stainless steel hydrogenation kettle was charged 1350ml of methanol, 135gr of the compound of the formula-XXII (X = OMe) obtained in step (ii), and 8.5gr of palladium-on-carbon (5% w/w, 50% wet). The reaction mixture was pressurized with hydrogen and shaken under hydrogen pressure (40-60psi) for 8hr at RT. After releasing the hydrogen pressure, the reaction mixture was filtered and the filtrate was taken into a 2L RB flask. Solvent was removed under vaccum below 50°C and the residue thus obtained was dissolved in 150ml of hexane and kept under stirring for 2hr at 0-5°C. The crystallized product was filtered and washed with 50ml of chilled hexane to get white crystalline solid (75gr) of the formula-XIII (X - OMe). M. P. 114-115°C.
Example 13 Preparation of (±)-trans-4-phenyl-3-hydroxymethyl-l-methyIpiperidine of the formula-I (X = H)
(i) Preparation of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]amino-propionate of the formula-XIV (X = H, R = Me)
Into a 1L three-necked RB flask was charged lOOgr of N-methyl-N-(3-hydroxy-3-phenyl)propylamine and 300ml of toluene. Methyl acrylate (57gr) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65°C and maintained for 7hrs. The reaction mixture was cooled to 40°C and toluene distilled off under vaccum. The residue was dissolved in isopropyl ether (150ml) and stirred for lhr, filtered off the crystals to get 140gr (92%) of white crystalline solid of the formula-XIV (X = H, R = Me). M. P. 41-42°C. IR (KBr): 3125, 2946, 2967, 1734, 1437, 1373, 1325, 1202, 1182,

1142, 1066, 1016, 943, 859, 800, 768, and 703cm*1. !H-NMR (300MHz, CDC13): 7.23-7.40 (m, 5H, ar.H); 6.10 (br.s, exch. with D20, 1H, -CH(OH)-); 4.90 (t, J = 5.90Hz, 1H, -CH(OH)-); 3.71 (s, 3H, -CO2CH3); 2.50-2.53 (m, 6H, 3 x -CH2-); 2.31 (s, 3H, -NCH3); 1.79-1.88 (m, 2H,-CH2-).
(ii) Preparation of (±) methyl 3-[N-methyl-N-(3-methanesuIfonyloxy-3-phenyl-propyI)aminopropionate of the formula-XV (X = H, X' = OMs, R = Me) Into a 2L three-necked RB flask was charged 300ml of methylene chloride and 30gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate obtained above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and triethylamine (16.7gr) was added. A solution of methanesulfonyl chloride (16.7gr) in methylene chloride (50ml) was added to the reaction mixture slowly over a period of 4-5hrs and kept under maintenance for additional lOhrs. The reaction mixture was poured into 200ml of chilled water and extracted the product into methylene chloride. Aqueous layer was extracted with 2 x 50ml of methylene chloride. Combined methylene chloride layer was washed with water (2 x 80ml) and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound (26.5gr) of the formula-XV (X = H, X' = OMs, R = Me) as syrup. This was found to be sufficiently pure enough for further conversion. IR (neat): 2952, 2843, 2801, 1739, 1494, 1454, 1436, 1357, 1205, 1166, 1124, 1044, 760, and 699cm"1. !H-NMR (300MHz, CDCI3): 7.26-7.42 (m, 5H, ar.H); 5.00 (dd, J = 6.20Hz, 8.40Hz, 1H, -CH(OMs)-); 3.68 (s, 3H, -C02CH3), 2.65-2.72 (m, 2H, -CH2-); 2.34-2.56 (m, 4H, 2 x -CH2-); 2.11-2.26 (m, 2H, -CH2-); 2.22 (s, 3H, -NCH3).
(iii) Preparation of (±)-trans-3-carbomethoxy-4-phenyl-N-methylpiperidine of the formuIa-XVI (X = H, R = Me)
Into a 1L three-necked RB flask was charged 130ml of dry DMF and 20gr of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and added sodium hydride (3.5gr, 55%) in lots over a period of lhr. The reaction mixture was maintained at same temperature for 3hrs and slowly allowed to reach 25°C over a period of 5-6hrs. The reaction mixture was maintained at RT for 12hrs and found to be over by TLC. The reaction mixture was cooled to 5-10°C and quenched with methanol (5ml). The reaction mixture was poured into 500ml of chilled water.

Toluene (250ml) was added to the reaction mixture and stirred for lhr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 75ml). The combined organic layer was washed with water and product extracted into 5% aqueous acetic acid (150ml). Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (2 x 100ml). Toluene was distilled off from the organic layer to leave the compound (1 lgr) of the formula-XVI (X = H, R = Me) as syrup. IR (neat): 3028, 2940, 2843, 2787, 1738, 1603, 1495, 1453, 1435, 1380, 1317, 1192, 1159, 1138, 1081, 1062, 760, 732, and 700cm-1. *H-NMR (300MHz, CDC13): 7.14-7.40 (m, 5H, ar.H); 3.41 (s, 3H, -CO2CH3); 2.69-3.14 (m, 4H); 2.34 (s, 3H, -NCH3); 2.04-2.30 (m, 2H); 1.79-1.90 (m, 2H).
(iv) Preparation of (±)-trans-4-phenyI-3-hydroxymethyl-l-methyIpiperidine of the formula-I (X = H)
Into a 1L three-necked RB flask was charged lOgr of the crude compound obtained according to step (iii) above and t-butanol (60ml). Sodium borohydride (3gr) was added to the reaction mixture and heated to reflux temperature. Methanol (10ml) was added in lots to the reaction mixture over a period of 4hr. After the last lot addition reaction mixture was maintained at reflux for 2hrs and checked the TLC. Reaction mixture was quenched with 2ml of acetic acid. Solvent was removed from the reaction mixture under vaccum and water (100ml) added to the reaction mass. Compound was extracted into toluene (2 x 75ml). Toluene layer was dried and distilled under vaccum to get the crude product which was crystallized from hexane/toluene to get the title compound as off white solid. M. P. 107-8°C. IR (KBr): 3168, 3026, 2937, 2802, 1600, 1493, 1467, 1449, 1358, 1250, 1137, 1121, 1087, 1067, 994, 855, 761, 700, 628, and 542cm-1. *H-NMR (300MHz, CDCI3): 7.16-7.34 (m, 5H, ar. H); 3.40 (dd, J = 3.3Hz, 11.0Hz, 1H); 3.18-3.23 (m, 2H), 2.90-2.95 (m, 1H); 2.31 (s, 3H, -NCH3); 2.21-2.43 (m, 2H); 1.78-2.13 (m, 4H).
Example 14 Preparation of (±)-trans-3-carbomethoxy-4-phenyl-N-methylpiperidine of the formula-XVI (X = H, R = Me)
Into 500ml three-necked RB flask was charged 20gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate and 100ml of dry THF. The reaction mixture was cooled to -15°C and charged triethylamine (12gr). A solution of benzenesulfonyl

chloride (17.6gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -15°C. The reaction mixture maintained at same temperature for 4hrs. Sodium hydride (6.5gr, 50%) was added to the reaction mixture in lots over a period of lhr at -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 10ml of methanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 100ml). Toluene was distilled off under vaccum to get the crude compound (12gr) of the formula-XVI (X = H, R = Me) as syrup.
Example IS Preparation of (±)-trans-3-carbomethoxy-4-phenyl-N-methylpiperidine of the formula-XVI (X = H, R = Me)
Into 500ml three-necked RB flask was charged 20gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate and 100ml of dry THF. The reaction mixture was cooled to -15°C and charged triethylamine (12gr). A solution of p-toluenesulfonyl chloride (19gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -15°C. The reaction mixture maintained at same temperature for 4hrs. Sodium hydride (6.5gr, 50%) was added to the reaction mixture in lots over a period of lhr at -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 10ml of methanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 100ml). Toluene was distilled off under vaccum to get the crude compound (10gr) of the formula-XVI (X = H, R = Me) as syrup.
Example 16 Preparation of (±)-trans-3-carboethoxy-4-phenyl-N-methylpiperidine of the formula-XVI (X = H, R = Et)
(i) Preparation of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-phenyIpropyI)amino-propionate of the formula-XIV (X = H, R = Et)

Into a 1L three-necked RB flask was charged lOOgr of N-methyl-N-(3-hydroxy-3-phenyl)propylamine and 300ml of toluene. Ethyl aery late (62gr) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65°C and maintained for 7hrs. The reaction mixture was cooled to 40°C and toluene distilled off under vaccum to get the title compound (160gr) of formula-XIV (X = H, R = Et) as syrup. IR (neat): 3243, 3062, 3028, 2980, 2953, 2846, 2808, 1730, 1453, 1371, 1322, 1199, 1127, 1093, 1043, 763, and 702cm*1. ^-NMR (300MHz, CDC13): 7.18-7.40 (m, 5H, ar.H); 6.14 (br.s, 1H, exch. with D20, -CH(OH)-); 4.89 (t, J = 5.9Hz, 1H, -CH(OH)-); 4.16 (q, J = 7.0Hz, 2H, -OCH2CH3); 2.47-2.84 (m, 6H, 3 x -CH2-); 2.30 (s, 3H, -NCH3); 1.78-1.87 (m, 2H, -CH2-); 1.26 (t, J = 7.3Hz, 3H, -OCH2CH3).
(ii) Preparation of (±) ethyl 3-[N-methyI-N-(3-methanesulfonyloxy-3-phenyl-propyI)aminopropionate of the formula-XIV (X = H, X' = OMs, R= Et) Into a 2L three-necked RB flask was charged 500ml of methylene chloride and 50gr of (±) ethyl 3-[N-ethyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and triethylamine (24.8gr) was added. A solution of methanesulfonyl chloride (24.5gr) in methylene chloride (50ml) was added to the reaction mixture slowly over a period of 4-5hrs and kept under maintenance for additional lOhrs. The reaction mixture was poured into 500ml of chilled water and extracted the product into methylene chloride. Aqueous layer was extracted with 2 x 100ml of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound (50gr) of the formula-XV (X = H, X' = OMs, R = Et) as syrup. This was found to be sufficiently pure enough for further conversion. IR (neat): 3031, 2979, 2801, 1734.7, 1493, 1454, 1370, 1297, 1199, 1124, 1043, 759, and 699 cm"1. XH-NMR (300MHz, CDCI3): 7.28-7.42 (m, 5H, ar.H); 5.01 (dd, J = 5.86Hz, 8.42Hz, 1H, -CH(OMs)-); 4.14 (q, J = 6.96Hz, 2H, -OCH2CH3); 2.65-2.72 (m, 2H, -CH2-); 2.40-2.56 (m, 4H, 2 x -CH2-); 2.22 (s, 3H, -NCH3-); 2.11-2.26 (m, 2H, -CH2-); 1.25 (t, J = 7.00Hz, 3H, -OCH2CH3).
(iii) Preparation of (±)-trans-3-carboethoxy-4-phenyl-N-methylpiperidine of the formuIa-XVI (X = H, R = Et)

Into a 1L three-necked RB flask was charged 200ml of dry DMF and 30gr of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and added sodium hydride (5.3gr, 55%) in lots over a period of lhr. The reaction mixture was maintained at same temperature for 3hrs and slowly allowed to reach 25°C over a period of 5-6hrs. The reaction mixture was maintained at RT for 12hrs and found to be over by TLC. The reaction mixture was cooled to 5-10°C and quenched with ethanol (5ml). The reaction mixture was poured into 5001 of chilled water. Toluene (150ml) was added to the reaction mixture and stirred for lhr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 75ml). The combined organic layer was washed with water and product extracted into 5% aqueous acetic acid (200ml). Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (2 x 100ml). Toluene was distilled off from the organic layer to leave the compound (20gr) of the formula-XVI (X = H, R = Et) as syrup. IR (neat): 3029, 2938, 2844, 2786, 1731, 1603, 1495, 1455, 1454, 1380, 1319, 1240, 1180, 1157, 1138, 1083, 1061, 1029, 760, and 700cm-1. !H-NMR (300MHz, CDC13): 7.14-7.31 (m, 5H, ar.H); 3.87 (q, J = 7.00Hz, 2H, -OCH2CH3); 2.73-3.13 (m, 4H); 2.35 (s, 3H, -NCH3); 2.10-2.33 (m, 2H); 1.80-2.04 (m, 2H); 0.93 (t, J - 7.00Hz, 3H, -OCH2CH3).
Example 17 Preparation of (±)-trans-3-carboethoxy-4-phenyI-N-methylpiperidine of the formula-XVI (X = H, R = Et)
Into 250ml three-necked RB flask was charged 20gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate and 50ml of dry THF. The reaction mixture was cooled to -5°C and charged triethylamine (12gr). A solution of benzenesulfonyl chloride (16.6gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -5°C. The reaction mixture was maintained at same temperature for 4hrs. Sodium hydride (12gr, 50%) was added to the reaction mixture in lots over a period of lhr at -10°C to -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5ml of ethanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml).

Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml). Toluene was distilled off under vaccum to get the compound (1 lgr) of the formula-XVI (X = H, R = Et) as syrup.
Example 18 Preparation of (±)-trans-3-carboethoxy-4-phenyI-N-methyIpiperidine of the formula-XVI (X = H, R = Et)
Into 250ml three-necked RB flask was charged 20gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate and 50ml of dry THF. The reaction mixture was cooled to -5°C and charged triethylamine (12gr). A solution of p-toluenesulfonyl chloride (19gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -5°C. The reaction mixture was maintained at same temperature for 4hrs. Sodium hydride (12gr, 50%) was added to the reaction mixture in lots over a period of lhr at -10°C to -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5ml of ethanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml). Toluene was distilled off under vaccum to get the compound (8gr) of the formula-XVT (X = H, R = Et) as syrup.
Example 19 Preparation of (±)-trans-3-carboethoxy-4-phenyl-N-methylpiperidine of the formula-XVI (X = H, R = Et)
Into 250ml three-necked RB flask was charged 100ml of dry toluene and 13.5gr of thionyl chloride. A solution of 20gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate in toluene (40ml) was added to the reaction mixture at 25°C over a period of lhr. The reaction mixture was maintained for 2hrs at RT and excess thionyl chloride and toluene were distilled off from the reaction mixture below 40°C. The residue was dissolved in dry DMF (75ml) and cooled to -15°C under nitrogen atmosphere. Sodium hydride (13gr, 50%) was added to the reaction mass in lots over a period of lhr. Slowly the reaction mass temperature was brought to 25°C and maintained

for lOhr before quenching with ethanol (10ml). The reaction mass poured into 250ml of water and the product extracted into toluene (2 x 150ml). Toluene layer was treated with 10% aqueous acetic acid (200ml). Acetic acid layer was treated with carbon, filtered and the pH of filtrate adjusted to 9.0 with sodium carbonate. Product was extracted into toluene (2 x 150ml). Toluene layer dried over sodium sulfate, distilled under vaccum and the crude compound was purified over a column of silica gel to get 2gr of the compound of formula-XVI (X = H, R = Et) as liquid.
Example 20 Preparation of (±) methyl 3-[N-methyl-N-(3-acetoxy-3-phenylpropyl)amino-propionate of the formula-XIV (X = H, X' = OAc, R = Me)
Into a 250ml three-necked RB flask was charged 5gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate and 50ml of dry methylene chloride. Acetic anhydride (2.5gr) was added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 3gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave 4.5gr of the title compound as syrup. IR (neat): 2953, 2845, 2802, 1739, 1456, 1437, 1372, 1238, 1171, 1128, 1024, 762, and 701cm"1. *H-NMR (300MHz, CDC13): 7.26-7.35 (m, 5H, ar. H); 5.68 (dd, J = 6.23Hz, 7.69Hz, 1H, -CH(OAc)); 3.68 (s, 3H, -COOCH3); 2.66 (t, J = 8.06Hz, 2H, -CH2); 2.43 (t, J - 6.96Hz, 2H, -CH2); 2.34 (t, J = 6.96Hz, 2H, -CH2); 2.21 (s, 3H, -NCH3); 2.06 (s, 3H, -OCOCH3); 1.87-2.19 (m, 2H, -CH2).
Example 21 Preparation of (±) ethyl 3-[N-methyl-N-(3-acetoxy-3-phenylpropyl)amino-propionate of the formula-XIV (X = H, X' = OAc, R = Et)
Into a 250ml three-necked RB flask was charged 3gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-phenylpropyl)]aminopropionate and 40ml of dry methylene chloride. Acetic anhydride (1.4gr) and 4-dimethylaminopyridine (0.1 gr) were added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 2gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave 3gr of the title compound as syrup. IR(neat): 2980, 2846, 2801, 1736, 1495, 1456, 1371, 1238, 1177, 1127, 1027, 952, 762, and 701cm"1. *H-NMR (300MHz, CDC13): 7.21-7.35 (m, 5H, ar. H); 5.79 (dd, J =

6.23Hz, 7.69Hz, 1H, -CH(OAc)); 4.13 (q, J = 7.32Hz, 2H, -OCH2CH3); 2.66 (t, J = 6.96Hz, 2H, -CH2); 2.43 (t, J = 3.66Hz, 2H, -CH2); 2.34 (t, J = 7.32Hz, 2H, -CH2); 2.21 (s, 3H, -NCH3); 2.06 (s, 3H, -OCOCH3); 1.85-2.18 (m, 2H, -CH2), 1.25 (t, J - 7.00Hz, 3H, -OCH2CH3).
Example 22 Preparation of (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-l-methyIpiperidine of the formula-I (X = F)
(i) Preparation of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenyl)propyl)]-aminopropionate of the formula-XIV (X = F, R = Me)
Into a 1L three-necked RB flask was charged lOOgr of N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine and 300ml of toluene. Methyl acrylate (48gr) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65°C and maintained for 7hrs. The reaction mixture was cooled to 40°C and toluene distilled off under vaccum. The residue was dissolved in isopropyl ether (150ml) and stirred for lhr, filtered off the crystals to get 140gr of white crystalline solid of the formula-XIV (X = F, R = Me). M. P. 64-65 °C. IR(KBr): 3111, 3006, 2958, 2819, 1730, 1601, 1508, 1460, 1435, 1372, 1323, 1215, 1175, 1067, 1014, 944, 904, and 845 cm"1. *H-NMR (300MHz, CDCI3): 7.27-7.37 (m, 2H, ar.H); 6.97-7.06 (m2H, ar.H); 4.89 (t, J = 5.86Hz, 1H, -CH(OH)-); 3.72 (s, 3H, -C02CH3); 2.50-2.87 (m, 6H, -CH2C02CH3, 2 x -NCH2-); 2.32 (s, 3H, -NCH3); 1.76-1.85 (m, 2H, -CH(OH)CH2CH2-).
(ii) Preparation of (±) methyl 3-[N-methyl-N-(3-methanesulfonyloxy-3-(4-fluoro-phenyl)propyl)]aminopropionate of the formula-XV (X = F, X' = OMs, R = Me) Into a 5L three-necked RB flask was charged 2.8L of methylene chloride and 280gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenyl)propyl)]aminopropionate under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and triethylamine (162gr) was added. A solution of methanesulfonyl chloride (162gr) in methylene chloride (300ml) was added to the reaction mixture slowly over a period of 4-5hrs and kept under maintenance for additional lOhrs. The reaction mixture was poured into 1000ml of chilled water and extracted the product into methylene chloride. Aqueous layer was extracted with 2 x 150ml of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave

the crude compound (270gr) of the formula-XV (X = F, X' = OMs, R = Me) as syrup. This was found to be sufficiently pure enough for further conversion. IR (neat): 2953, 2845, 2803, 1738, 1605, 1511, 1461, 1437, 1358, 1330, 1297, 1263, 1160, 1125, 1045, and 839cm"1. !H-NMR (300MHz, CDC13): 7.25-7.39 (m, 2H, ar.H); 6.97-7.06 (m, 2H, ar.H); 4.99 (dd, J = 6.2Hz, 8.4Hz, 1H, -CH(OMs)-); 3.67 (s, 3H, -CO2CH3); 2.62-2.70 (m, 2H, -CH2-); 2.23-2.53 (m, 4H, -CH2CH2-); 2.20 (s, 3H, -NCH3); 1.10-2.19 (m, 2H, -
CH2-).
(iii) Preparation of (±)-trans-3-carbomethoxy-4-(4-fluorophenyl)-N-methyl-
piperidine of the formula-XVI (X = F, R = Me)
Into a 1L three-necked RB flask was charged 640ml of dry DMF and 11 lgr of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and added sodium hydride (20gr, 55%) in lots over a period of lhr. The reaction mixture was maintained at same temperature for 3hrs and slowly allowed to reach 25°C over a period of 5-6hrs. The reaction mixture was maintained at RT for 12hrs and found to be over by TLC. The reaction mixture was cooled to 5-10°C and quenched with methanol (25ml). The reaction mixture was poured into 3000ml of chilled water. Toluene (900ml) was added to the reaction mixture and stirred for lhr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 150ml). The combined organic layer was washed with water and product extracted into 5% aqueous acetic acid (1000ml). Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (2 x 500ml). Toluene was distilled off from the organic layer to leave 70gr of compound of the formula-XVI (X = F, R = Me) as syrup. IR (neat): 2942, 2846, 2788, 1738, 1603, 1511, 1436, 1380, 1317, 1224, 1199, 1161, 1137, and 833 cm"1. XH-NMR (300MHz, CDCI3): 7.10-7.29 (m, 2H, ar.H); 6.92-7.00 (m, 2H, ar.H); 3.44 (s, 3H, -C02CH3); 2.68-3.14 (m, 4H), 2.35 (s, 3H, -NCH3); 2.04-2.29 (m, 2H, -NCH2-); 1.76-1.82 (m, 2H, -NCH2-). (iv) Preparation of (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-l-methyI-piperidine of the formula-I (X = F)
Into a 1L three-necked RB flask was charged 50gr of the crude compound obtained in step (iii) above and t-butanol (300ml). Sodium borohydride (10gr) was added to the reaction mixture and heated to reflux temperature. Methanol (50ml) was added in lots to

the reaction mixture over a period of 6hr. After the last lot addition reaction mixture was maintained at reflux for 2hrs and checked the TLC. Reaction mixture was quenched with 5 ml of acetic acid. Solvent was removed from the reaction mixture under vaccum and water (200ml) added to the reaction mass. Compound was extracted into toluene (2 x 100ml). Toluene layer was dried and distilled under vaccum to get the crude product which was crystallized from hexane/toluene to get the compound of the formula-I (X = F) as off white solid (30gr). Purity by HPLC is 98.5%. Melting point is 123-124°C. IR (KBr): 3158, 3046, 2977, 2947, 2923, 2890, 2807, 1599, 1509, 1488, 1467, 1449, 1437, 1421, 1362, 1348, 1288, 1252, 1222, 1194, 1159, 1138, 1133, 1066, 1056, 994, 863, 835, 824, 792, 771, 626, 589, and 547cm'1. lH-NMR (300MHz, CDC13): 7.11-7.18 (m, 2H, ar. H); 6.93-7.01 (m, 2H, ar.H); 3.37 (dd, J = 2.93Hz, 11.00Hz, 1H); 3.13-3.22 (m, 2H); 2.89-2.94 (m, 1H), 2.46 (br. s, exch. with D20, 1H, -OH); 2.30 (s, 3H, -NCH3); 2.20-2.27 (m, 1H); 1.74-2.07 (m,5H).
Example 23 Preparation of (±)-trans-4-(4-fluorophenyI)-3-hydroxymethyI-l-methyl-piperidine of the formula-I (X = F)
(i) Preparation of (±)-trans-3-carbomethoxy-4-(4-fluorophenyl)-N-methylpiperidine of the formuIa-XVI (X = F, R = Me)
Into 500ml three-necked RB flask was charged 20gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenyl)propyl)]aminopropionate and 100ml of dry THF. The reaction mixture was cooled to -15°C and charged triethylamine (llgr). A solution of benzenesulfonyl chloride (16gr) in THF (30ml) was added to the reaction mixture slowly over a period of 2hrs at -15°C. The reaction mixture maintained at same temperature for lOhrs. Sodium hydride (10gr, 50%) was added to the reaction mixture in lots over a period of lhr at -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 10ml of methanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 75ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 100ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 50ml). Toluene was distilled off under vaccum

to get the crude compound, which was purified over a column of silica gel to get the compound (6gr) of the formula-XVI (X = F, R - Me) as syrup.
(ii) Preparation of (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-l-methyI-piperidine of the formula-I (X = F)
Into a 250ml three-necked RB flask was charged 50ml of dry THF under nitrogen atmosphere. The flask was cooled to 0°C and LAH (1.5gr) added. The reaction mixture was cooled to -30°C and added a solution of the above step (i) compound (6gr) in THF (15ml) over a period of 30min. After maintaining at same temperature for lhr, reaction was quenched with 1ml of water. The reaction mixture was slowly warmed to RT and maintained for 2hrs. The reaction mass was filtered and washed with 25 ml of ethyl acetate. Solvent was distilled off from the filtrate and the residue dissolved in toluene (50ml). Toluene solution was washed with water, dried, and evaporated to get the crude compound (5.0gr), which was crystallized from toluene/hexane to get white crystalline solid (4.5gr) of formula-I (X = F).
Example 24 Preparation of (±)-trans-3-carbomethoxy-4-(4-fluorophenyl)-N-methylpiperidine of the formula-XVI (X = F, R = Me)
Into 500ml three-necked RB flask was charged lOgr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenyl)propyl)]aminopropionate and 100ml of dry THF. The reaction mixture was cooled to -15°C and charged triethylamine (5.6gr). A solution of p-toluenesulfonyl chloride (8.9gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -15°C. The reaction mixture maintained at same temperature for 4hrs. Sodium hydride (5gr, 50%) was added to the reaction mixture in lots over a period of lhr at -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 10ml of methanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 75ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 100ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 50ml). Toluene was distilled off under vaccum to get the crude compound, which was purified over a column of silica gel to get the compound (3.5gr) of the formula-XVI (X = F, R = Me) as syrup.

Example 25 Preparation of (±)-trans-3-carboethoxy-4-(4-fluorophenyl)-N-methylpiperidine of the formula-XVI (X = F, R = Et)
(i) Preparation of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenyI)propyI)]-aminopropionate of the formula-XIV (X = F, R = Et)
Into a 1L three-necked RB flask was charged 150gr of N-methyl-N-[3-hydroxy-3-(4-fluorophenyl)]propylamine and 450ml of toluene. Ethyl acrylate (83.2gr) was added to the reaction mixture. The reaction mixture was slowly heated to 60-65°C and maintained for 7hrs. The reaction mixture was cooled to 40°C and toluene distilled off under vaccum to leave the title compound (232gr) of formula-XIV (X = F, R = Et) as syrup. IR (neat): 3239, 2981, 2847, 1734, 1604, 1509, 1467, 1372, 1210, 1128, 1044, and 838 cm-1. 1H-NMR (300MHz, CDC13): 7.27-7.37 (m, 2H, ar. H); 6.97-7.07 (m, 2H, ar. H); 6.30 (br.s, exch. with D20, 1H, -CH(OH)-); 4.88 (t, J = 5.5Hz, 1H, -CH(OH)-); 4.17 (q, J = 7.00Hz, 2H, -CO2CH2CH3); 2.65-2.90 (m, 2H, -CH2-); 2.40-2.61 (m, 2H, -CH2-); 2.31 (s, 3H, -NCH3); 1.76-1.84 (m, 2H, -CH2-); 1.27 (t, J = 7.4Hz, 3H, -C02CH2CH3). (ii) Preparation of (±)-trans-3-carboethoxy-4-(4-fluorophenyl)-N-methylpiperidine of the formula-XVI (X = F, R = Et)
Into 250ml three-necked RB flask was charged 20gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenylpropyl))]aminopropionate and 50ml of dry THF. The reaction mixture was cooled to -5°C and charged triethylamine (12gr). A solution of methane sulfonyl chloride (10gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -5°C. The reaction mixture was maintained at same temperature for 4hrs. Sodium hydride (llgr, 50%) was added to the reaction mixture in lots over a period of lhr at -10°C to -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5ml of ethanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml). Toluene was distilled off under vaccum to get the compound (10gr) of the formula-XVI (X = F, R = Et) as syrup. IR (neat): 2977, 2939, 2848, 2788, 1726, 1603, 1512, 1466, 1449, 1380, 1318, 1225, 1199,

1182, 1160, 1137, 1099, 1029, 832, 795, and 543cm"1. 'H-NMR (300MHZ, CDC13): 7.12-7.21 (m, 2H, ar. H); 6.91-7.01 (m, 2H, ar. H); 3.89 (q, J = 7.00Hz, 2H, -OCH2CH3); 2.67-3.13 (m, 4H); 2.35 (s, 3H, «NCH3); 2.04-2.32 (m, 2H, -NCH2); 1.76-1.86 (m, 2H, -NCH2); 0.97 (t, J = 7.00Hz, 3H, -OCH2CH3).
Example 26 Preparation of (±)-trans-3-carboethoxy-4-(4-fluorophenyl)-N-methylpiperidine of the formula-XVI (X = F, R = Et)
Into 250ml three-necked RB flask was charged 20gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenylpropyl))]aminopropionate and 50ml of dry THF. The reaction mixture was cooled to -5°C and charged triethylamine (12gr). A solution of benzenesulfonyl chloride (15.5gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -5°C. The reaction mixture was maintained at same temperature for 4hrs. Sodium hydride (llgr, 50%) was added to the reaction mixture in lots over a period of lhr at -10°C to -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5 ml of ethanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml). Toluene was distilled off under vaccum to get the crude compound (llgr), which was purified over a column of silica gel to get the compound (6gr) of formula-XVI (X = F, R = Et) as syrup.
Example 27 Preparation of (±)-trans-3-carboethoxy-4-(4-fluorophenyl)-N-methyIpiperidine of the formula-XVI (X = F, R = Et)
Into 250ml three-necked RB flask was charged 20gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenylpropyl))]aminopropionate and 50ml of dry THF. The reaction mixture was cooled to -5°C and charged triethylamine (12gr). A solution of p-toluenesulfonyl chloride (16.8gr) in THF (20ml) was added to the reaction mixture slowly over a period of 2hrs at -5°C. The reaction mixture was maintained at same temperature for 4hrs. Sodium hydride (llgr, 50%) was added to the reaction mixture in

lots over a period of lhr at -10°C to -15°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5ml of ethanol. The reaction mass was poured into ice water and the product extracted toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 150ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml). Toluene was distilled off under vaccum to get the crude compound, which was purified over a column of silica gel to get the compound (8gr) of the formula-XVI (X = F, R = Et) as syrup.
Example 28 Preparation of (+) methyl 3-[N-methyl-N-(3-chloro-3-(4-fluorophenyl)propyl)]-aminopropionate hydrochloride of the formula-XV (X = F, X' = CI, R = Me) Into 250ml three-necked RB flask was charged 100ml of dry toluene and 11.5gr of thionyl chloride. A solution of 20gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluorophenyl)propyl)]aminopropionate in toluene (40ml) was added to the reaction mixture at 25°C over a period of lhr. The reaction mixture was maintained for 2hrs at RT and excess thionyl chloride and toluene were distilled off from the reaction mixture below 40°C. The residue was suspended in toluene (50ml) and stirred for lhr. The reaction mixture was filtered and the wet cake washed with toluene, dried under vaccum to get the compound (18gr) of formula-XV (X = F, X' = CI, R == Me) as white solid. M.P. 117-118°C. IR (KBr): 2994, 2947, 2579, 2552, 2508, 2414, 1734, 1604, 1514, 1472, 1437, 1414, 1387, 1359, 1245, 1204, 1185, 1159, 989, 843, 810, and 619cm*1.
Example 29 Preparation of (±) ethyl 3-[N-methyl-N-(3-chloro-3-(4-fluorophenyl)propyl)]-aminopropionate hydrochloride of the formula-XV (X = F, X' = CI, R = ethyl) Into 250ml three-necked RB flask was charged 50ml of dry toluene and 4gr of thionyl chloride. A solution of 5gr of (±) ethyl 3-pST-methyl-N-(3-hydroxy-3-(4-fluorophenyl)propyl)]aminopropionate in toluene (10ml) was added to the reaction mixture at 25°C over a period of lhr. The reaction mixture was maintained for 2hrs at RT and excess thionyl chloride and toluene were distilled off from the reaction mixture below 40°C. The residue was suspended in diisopropyl ether (10ml) and stirred for lhr.

The reaction mixture was filtered and the wet cake washed with toluene, dried under vaccum to get the compound (5gr) of formula-XV (X = F, X' = CI, R = Me) as white solid. M.P. 122-124°C. IR(KBr): 3422, 2949, 2537, 2501, 1732, 1613, 1516, 1473, 1436, 1417, 1360, 1242, 1206, 1186, 993, 804, 756, 721, 646, and 624cm-1.
Example 30 Preparation of (±) methyl 3-[N-methyl-N-(3-acetoxy-3-(4-fluorophenyI)propyI)]-aminopropionate of the formula-XV (X = F, X' = OAc, R = Me) Into a 250ml three-necked RB flask was charged lOgr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluoropheny)lpropyl)]aminopropionate and 100ml of dry methylene chloride. Acetic anhydride (5gr) and 4-dimethylaminopyridien (O.lgr) were added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 6gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave lOgr of the title compound as syrup. IR (neat): 2954, 2847, 2802, 1740, 1607, 1513, 1438, 1372, 1225, 1160, 1023, and 837cm"1. *H-NMR (300MHz, CDC13): 7.27-7.35 (m, 2H, ar. H); 6.98-7.08 (m, 2H, ar. H); 5.76 (t, J = 7.32Hz, 1H, -CH(OAc)); 3.68 (s, 3H, -COOCH3); 2.62-2.70 (m, 2H); 2.38-2.47 (m, 2H, -CH2); 2.25-2.36 (m, 2H, -CH2); 2.20 (s, 3H, -NCH3); 2.06 (s, 3H, -OCOCH3); 1.79-2.18 (m, 2H, -CH2).
Example 31 Preparation of (±) ethyl 3-[N-methyl-N-(3-acetoxy-3-(4-fluorophenyl)propyl)]-aminopropionate of the formula-XV (X = F, X' = OAc, R = Et) Into a 250ml three-necked RB flask was charged 5gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-fluoropheny)lpropyl)]aminopropionate and 50ml of dry methylene chloride. Acetic anhydride (3gr) and 4-dimethylaminopyridien (O.lgr) were added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 4gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave 4.5gr of the title compound as syrup. IR (neat): 2980, 2803, 1734, 1607, 1465, 1371, 1225, 1160, 1127, 1026, 951, and 837cm"1. XH-NMR (300MHz, CDCI3): 7.27-7.36 (m, 2H, ar. H); 6.98-7.07 (m, 2H, ar. H); 5.76 (t, J = 7.33Hz, 1H, -CH(OAc)); 4.14 (q, J = 7.30Hz, 2H, -OCH2CH3); 2.66 (t, J = 7.00Hz, 2H, -CH2); 2.42 (t, J = 7.30Hz, 2H, -CH2); 2.33 (t, J = 7.00Hz, 2H, -CH2);

2.21 (s, 3H, -NCH3); 2.06 (s, 3H, ArCH3); 2.02-2.11 (m, 1H); 1.85-2.00 (m, 1H); 1.26 (t, J - 7.00Hz, 3H, -OCH2CH3).
Example 32 Preparation of (±)-trans-4-(4-methylphenyl)-3-hydroxymethyI-l-methylpiperidine of the formula-I (X = Me)
(i) Preparation of methyl (±)-3-[N-methyl-N-(3-hydroxy-3-(4-methylphenyl)-propyl)]aminopropionate of the formula-XIV (X = R = Me)
Into a 500ml three-necked RB flask were charged 30gr of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propylamine, 90ml of toluene, and 16gr of methyl acrylate. The reaction mixture was heated to 60-65°C and maintained for 7hrs. Toluene was removed from the reaction mixture under vaccum and diisopropyl ether added to the residue. After stirring for 30min solid formed. The reaction mass was cooled to 0-5°C and filtered the solid to get 40gr of the compound of the formula-XIV (X = R = Me) as white crystalline solid. M. P. 46-47°C. IR (KBr): 3126, 3026, 2946, 2858, 2814, 2731, 1732, 1516, 1471, 1458, 1435, 1416, 1402, 1372, 1324, 1199, 1174, 1144, 1109, 1067, 1015, 942, 904, 862, 825, 798, 761, 723, 704, and 562cm-1. 'H-NMR (300MHz, CDCI3): 7.11-7.27 (m, 4H, ar.H); 5.30 (br.s, exch. with D20, 1H, -CH(OH)-); 4.85 (t, J = 5.2Hz, 1H, -CH(OH)-); 3.70 (s, 3H, -COOCH3); 2.63-2.78 (m, 4H, 2 x -CH2-); 2.48-2.57 (m, 2H, -CH2-); 2.33 (s, 3H, -NCH3); 2.30 (s, 3H, ArCH3); 1.76-1.88 (m, 2H, -CH2-).
(ii) Preparation of (±)- methyl 3-[N-methyl-N-(3-methanesulfonyIoxy-3-(4-methyl-phenyl)propyl)]aminopropionate of the formula-XV (X = Me, X' = OMs, R = Me) Into a 250ml three-necked RB flask was charged 50ml of methylene chloride and lOgr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylphenyl)propyl)]aminopropionate obtained above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and triethylamine (7.2gr) was added. A solution of methanesulfonyl chloride (5.6gr) in methylene chloride (25ml) was added to the reaction mixture slowly over a period of lhr and kept under maintenance for additional 6hrs. The reaction mixture was poured into 50ml of chilled water and extracted product into methylene chloride. Aqueous layer was extracted with 2 x 50ml of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound of the formula-XV as syrup (6gr). This was found to be sufficiently

pure enough for further conversion. IR (neat): 2952, 2803, 1737, 1614, 1514, 1436, 1357, 1324, 1206, 1173, 1126, 1042, 816, 761, 626, and 522 cm"1. !H-NMR (300MHz, CDC13): 7.26-7.30 (m, 2H, ar.H); 7.13-7.17 (m, 2H, ar.H); 4.98 (dd, J = 6.2Hz, 8.4Hz, 1H, -CH(OMs)-); 3.68 (s, 3H, -COOCH3); 2.34 (s, 3H, -NCH3); 2.24 (s, 3H, ArCH3); 2.16-2.89 (m, 8H).
(iii) Preparation of (±)-trans-3-carbomethoxy-4-(4-methylphenyI)-N-methyl-piperidine of the formula-XVI (X = R = Me)
Into a 250ml three-necked RB flask was charged 30ml of dry DMF and 5gr of compound obtained in step (ii) above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C and added sodium hydride (1.2gr, 55%) in lots over a period of lhr. The reaction mixture was maintained at same temperature for 3hrs and slowly allowed to reach 25°C over a period of 5-6hrs. The reaction mixture was maintained at RT for 12hrs and found to be over by TLC. The reaction mixture was cooled to 5-10°C and quenched with methanol (2ml). The reaction mixture was poured into 150ml of chilled water. Toluene (50ml) was added to the reaction mixture and stirred for lhr. Toluene layer was separated and the aqueous layer extracted with toluene (2 x 50ml). The combined organic layer was washed with water and product extracted into 5% aqueous acetic acid (50ml). Aqueous acetic acid layer was treated with carbon and neutralized with sodium bicarbonate. The product thus obtained was extracted into toluene (2 x 50ml). Toluene was distilled off from the organic layer to leave the compound (2.5gr) of the formula-XVI (X = R = Me) as syrup. IR (neat): 2937, 2824, 1736, 1515, 1447, 1380, 1304, 1288, 1243, 1222, 1180, 1159, 1138, 1112, 1074, 1059, 1030, 964, 814, 786, 746, 539, and 524cm"1. *H-NMR (300MHz, CDC13): 7.08 (s, 4H, ar. H); 3.44 (s, 3H, -COOMe); 2.61-3.14 (m, 4H); 2.34 (s, 3H, NCH3); 2.30 (s, 3H, ArCH3); 2.04-2.32 (m, 2H); 1.78-1.89 (m, 2H).
(iv) Preparation of (±)-trans-4-(4-methylphenyI)-3-hydroxymethyl-l-methyl-piperidine of the formula-I (X = Me)
Into 250ml three-necked RB flask was charged tetrahydrofuran (20ml) under nitrogen. The flask was cooled to 0°C and lithium aluminum hydride (0.5gr) was added to the reaction flask. The ester compound (2.0gr) obtained in step (iii) was dissolved in tetrahydrofuran (10ml) and added to the reaction mixture slowly over a period of 15min.

The reaction mixture was maintained for Ihr and found to be over by TLC. Water (0.2ml) was slowly added to the reaction and stirred for 2hr. The reaction mixture was filtered and the solvent distilled off to get the crude compound. The crude compound of the formula-I (X = Me) was crystallized from hexane/diisopropyl ether to get crystalline compound (0.9gr) of formula-I (X = Me). M. P. 101°C. IR (KBr): 3176, 2923, 2845, 2781, 1514, 1450, 1378, 1276, 1134, 1072, 1025, 993, 881, 808, 720, 552, and 531cm*1. 'H-NMR (300MHz, CDC13): 7.10 (s, 4H, ar. H); 3.64 (s, 1H, OH); 3.41 (dd, J - 3.66Hz, 11.00Hz, 1H); 3.12-3.25 (m, 2H); 2.91-2.96 (m, 1H), 2.32 (s, 3H, NCH3); 2.31 (s, 3H, ArCH3); 1.76-2.43 (m, 6H). 13C-NMR (75MHz, CDCI3): 141.00, 135.61, 129.04, 127.13, 63.28, 59.54, 56.11, 46.21, 44.01, 34.12, and 20.89
Example 33 Preparation of (±)-trans-3-carboethoxy-4-(4-methylphenyl)-N-methylpiperidine of the formula-XVI (X = Me, R = Et)
(i) Preparation of ethyl (±)-3-[N-methyl-N-(3-hydroxy-3-(4-methyl-phenyl)-propyl)]aminopropionate of the formula-XIV (X = Me, R = Et) Into a 500ml three-necked RB flask were charged 30gr of N-methyl-N-[3-hydroxy-3-(4-methylphenyl)]propylamine, 90ml of toluene, and 13gr of ethyl acrylate. The reaction mixture was heated to 60-65°C and maintained for 7hrs. Toluene was removed from the reaction mixture under vaccum to get the crude product (41gr) of formula-XIV (X = Me, R = Et) as syrup. This was found to be sufficiently pure for further reaction. IR (neat): 3314, 2980, 2949, 2850, 1734, 1514, 1465, 1371, 1322, 1198, 1128, 1043, and 819cm"1. 'H-NMR (300MHz, CDCI3): 7.23-7.27 (m, 2H, ar. H); 7.11-7.15 (m, 2H, ar. H); 5.80 (br. s, exch. with D20, 1H, -CH(OH)-); 4.86 (t, J = 5.86Hz, 1H, -CH(OH)-); 4.16 (q, J = 7.33Hz, 2H, OCH2CH3); 2.63-2.81 (m, 2H, -CHr); 2.47-2.60 (m, 4H, 2 x -CH2-); 2.33 (s, 3H, -CH3); 2.30 (s, 3H, -CH3), 1.77-1.84 (m, 2H, -CH2-); 1.26 (t, J = 7.00Hz, -OCH2CH3).
(ii) Preparation of (±)- ethyl 3-[N-methyI-N-(3-methanesuIfonyIoxy-3-(4-methyl-phenyl)propyl)]aminopropionate of the formula-XV (X = Me, X' = OMs, R = Et) Into a 250ml three-necked RB flask was charged 50ml of methylene chloride and 7.5gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylphenyl)propyl)]aminopropionate obtained above under nitrogen atmosphere. The reaction mixture was cooled to -5 to 0°C

and triethylamine (5gr) was added. A solution of methanesulfonyl chloride (4gr) in methylene chloride (15ml) was added to the reaction mixture slowly over a period of lhr and kept under maintenance for additional 6hrs. The reaction mixture was poured into 50ml of chilled water and extracted product into methylene chloride. Aqueous layer was extracted with 2 x 50ml of methylene chloride. Combined methylene chloride layer was washed with water and dried over sodium sulfate. Distillation of methylene chloride gave the crude compound of the formula-XV as syrup (7gr). This was found to be sufficiently pure enough for further conversion. IR (neat): 2974, 2846, 2801, 1734, 1516, 1463, 1370, 1335, 1194, 1125, 1045, 965, and 814cm"1. *H-NMR (300MHz, CDC13): 7.26-7.30 (m, 2H, ar. H); 7.17-7.22 (m, 2H, ar. H); 5.98 (dd, J = 6.20Hz, 8.40Hz, 1H, -CH(OMs)); 4.14 (q, J = 7.00Hz, 2H, -OCH2CH3); 2.37 (s, 3H, -NCH3); 2.23 (s, 3H, ArCH3); 2.09-2.88 (m, 8H); 1.26 (t, J = 7.20Hz, 3H, -OCH2CH3).
(ii) Preparation of (±)-trans-3-carboethoxy-4-(4-methylphenyl)-N-methylpiperidine of the formula-XVI (X = Me, R = Et)
Into a 250ml three-necked RB flask was charged 7gr of ethyl (±)-3-[N-methyl-N-(3-methanesulfonyloxy-3-(4-methylphenyl)propyl)]aminopropionate obtained in step (ii) above and dry DMF (20ml). The reaction mixture was cooled to -5°C and added sodium hydride (3gr, 50%) in lots over a period of 30min. The reaction mixture was slowly warmed to 25°C and maintained for overnight. The reaction mixture was quenched with ethanol (5 ml) and poured into water (100ml). Product was extracted into toluene (2 x 50ml). Toluene layer was washed with aqueous acetic acid (5%, 2 x 50ml), and treated with carbon. pH of the aqueous acetic acid layer was adjusted to 8.0 with solid sodium bicarbonate and extracted with toluene (2 x 50ml). Toluene layer was dried, evaporated and the crude thus obtained was purified over a column of silica gel to get l.Ogr of the compound of formula-XVI (X = Me, R = Et). IR (neat): 2939, 2848, 2788, 1731, 1515, 1465, 1447, 1379, 1320, 1289, 1258, 1181, 1158, 1137, 1029, and 814cm"1. *H-NMR (300MHz, CDC13): 7.09 (s, 4H, ar. H); 3.89 (q, J = 7.00HZ, 2H, -OCH2CH3); 3.12 (ddd, J = 1.47Hz, 3.66Hz, 11.00Hz, 1H); 2.97-3.03 (m, 1H); 2.89 (dd, J = 3.66Hz, 11.35Hz, 1H); 2.65-2.79 (m, 1H); 2.36 (s, 3H, -NCH3); 2.30 (s, 3H, ArCH3); 2.21-2.41 (m, 2H); 1.80-2.18 (m, 2H); 0.96 (t, J = 7.30Hz, 3H, -OCH2CH3).

Example 34 Preparation of (±)- methyl 3-[N-methyl-N-(3-acetoxy-3-(4-methylphenyl)propyl)]-aminopropionate of the formuIa-XV (X = Me, X' = OAc, R = Me)
Into a 250ml three-necked RB flask was charged 4gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylpheny)lpropyl)]aminopropionate and 50ml of dry methylene chloride. Acetic anhydride (1.9gr) and 4-dimethylaminopyridien (0.05gr) were added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 4gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave 3.4gr of the title compound as syrup. IR (neat): 2953, 2845, 2801, 1737, 1516, 1438, 1371, 1339, 1170, 1128, 1020, 950, and 817cm'1. XH-NMR (300MHz, CDC13): 7.12-7.25 (m, 4H, ar. H); 5.75 (t, J = 6.60Hz, 1H, -CH(OAc)); 3.68 (s, 3H, -COOMe); 2.66 (t, J - 6.60Hz, 2H); 2.30-2.54 (m, 2H); 2.33 (s, 3H, -NCH3); 2.21 (s, 3H, ArCH3); 1.81-2.18 (m, 4H); 2.05 (s, 3H, OCOCH3).
Example 35 Preparation of (±)- ethyl 3-[N-methyl-N-(3-acetoxy-3-(4-methylphenyI)propyl)]-aminopropionate of the formula-XV (X = Me, X' = OAc, R = Et) Into a 250ml three-necked RB flask was charged 5gr of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylpheny)lpropyl)]aminopropionate and 50ml of dry methylene chloride. Acetic anhydride (2.3gr) and 4-dimethylaminopyridien (O.Olgr) were added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 4gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave 5gr of the title compound as syrup. IR (neat): 2979, 2801, 1736, 1516, 1464, 1371, 1239, 1182, 1127, 1021,949, and 817cm*1.
Example 36 Preparation of (±)-methyl 3-[N-methyl-N-(3-chloro-3-(4-methyIphenyl)propyl)]-aminopropionate hydrochloride of the formula-XV (X = Me, X' = CI, R = Me) Into a 250ml three-necked RB flask was charged 30ml of dry toluene and 2gr of thionyl chloride. A solution of (±)-methyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylphenyl)-propyl)]aminopropionate (3gr) in toluene (10ml) was slowly added to the reaction

mixture at RT. The reaction mixture was stirred at RT for 2hrs and the solvent along with excess thionyl chloride were distilled off from the reaction mixture under vaccum keeping the temperature below 50°C. The residue was suspended in toluene and filtered to get the title compound (2gr) and white solid. M. P. 110-112°C. IR (KBr): 2949, 2537, 2503, 2413, 1732, 1516, 1473, 1437, 1418, 1361, 1248, 1206, 1188, 1162, 995, 985, 805, 722, and 624cm'1.
Example 37 Preparation of (±)-ethyI 3-[N-methyl-N-(3-chloro-3-(4-methylphenyl)-propyl)]-aminopropionate hydrochloride of the formula-XV (X = Me, X' = CI, R = Et) Into a 250ml three-necked RB flask was charged 80ml of dry toluene and 6gr of thionyl chloride. A solution of (±)-ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-methylphenyl)-propyl)]aminopropionate (10gr) in toluene (20ml) was slowly added to the reaction mixture at RT. The reaction mixture was stirred at RT for 2hrs and the solvent along with excess thionyl chloride were distilled off from the reaction mixture under vaccum keeping the temperature below 50°C. The residue was suspended in toluene and filtered to get the title compound (8gr) and white solid. M. P. 118-119°C. IR (KBr): 2982, 2941, 2536, 2422, 1516, 1473, 1471, 1242, 1195, 1008, 983, 804, 721, and 624cm"1. ^-NMR (300MHz, DMSO-d6): 11.14 (br s, exch. with D20, 1H, -NH+); 7.37 (d, J = 8.06Hz, 2H, ar. H); 7.21 (d, J = 8.06Hz, 2H, ar. H); 5.24-5.26 (m, 1H, -CHC1); 4.09 (q, J = 7.3Hz, 2H, ^OCH2CH3), 3.75 (s, 3H, -NCH3); 3.16-3.46 (m, 2H, -CH2); 2.87-2.92 (m, 2H, -CH2), 2.73 (d, J = 3.30Hz, 2H, -CH2); 2.42-2.61 (m, 2H, -CH2); 2.30 (s, 3H, ArCH3); 1.19 (t, J - 7.30Hz, 3H, -OCH2CH3).
Example 38 Preparation of (±)-trans-4-(4-methoxyphenyI)-3-hydroxymethyl-l-methylpiperidine Of the formula-I (X = OMe)
(i) Preparation of methyl (±)-3-[N-methyl-N-(3-hydroxy-3-(4-methoxyphenyl)-propyI)]aminopropionate of the formula-XIV (X = OMe, R = methyl) Into a 500ml three-necked RB flask was charged 30gr of N-methyl-N-[3-hydroxy-3-(4-methoxyphenyl)]propylamine, toluene (90ml), and 14gr of methyl acrylate. The reaction mixture was heated to 60-65°C and maintained for 7hrs. Toluene was removed from the reaction mixture under vaccum to get 44gr of the compound of the formula-XIV (X =

OMe, R = Me) as colorless syrup. IR (neat): 3377, 2592, 2837, 1737, 1612, 1513, 1465, 1439, 1301, 1246, 1205, 1174, 1036, and 835cm-1. lH-NMR (300MHz, CDC13): 7.21-7.28 (m, 2H, ar.H); 6.79-6.86 (m, 2H, ar.H); 5.60 (br.s., 1H, exch. with D20, -CH(OH)-); 4.79 (dd = 4.76Hz, 7.76Hz, 1H, -CH(OH)-); 3,75 (s, 3H, -C02Me); 3.66 (s, 3H, -OMe); 2.45-2.81 (m, 6H, -CH2N(CH3)CH2CH2-); 2.26 9s, 3H, -NCH3); 1.72-1.82 (m, 2H, -CH(OH)CH2-)
(ii) Preparation of (±)-trans-3-carbomethoxy-4-(4-methoxyphenyl)-N-methyl-piperidine of the formula-XVI (X = OMe, R = Me)
Into 250ml three-necked RB flask was charged 20gr of (+/-) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-methoxyphenyl)propyl)]aminopropionate and 50ml of dry THF. The reaction mixture was cooled to -15°C and charged triethylamine (10.8gr). Methanesulfonyl chloride (10.2gr) was added to the reaction mixture slowly over a period of 2hrs at -15°C. The reaction mixture was maintained at same temperature for lhrs. Sodium hydride (9.3gr, 50%) was added to the reaction mixture in lots over a period of lhr at -10°C to -5°C. Slowly the reaction mixture was allowed to reach 25°C and maintained for lOhrs at this temperature. Reaction was quenched with 5ml of methanol. The reaction mass was poured into ice water and the product extracted into toluene (2 x 100ml). Product was extracted from toluene layer into aqueous acetic acid (10%, 100ml). Aqueous acetic acid layer was treated with carbon, neutralized to pH 9.0 with sodium carbonate, and extracted into toluene (2x 75ml). Toluene was distilled off under vaccum to get the crude compound (5gr) of the formula-XVI (X = OMe, R = Me) as syrup. IR(neat): 2952,2837,1737,1609,1512,1460,1439,1302,1250,1175,1037, and 836cm'1 '
(iii) Preparation of (±)-trans-4-(4-methoxyphenyl)-3-hydroxymethyl-l-methyI-piperidine of the formula-l (X = OMe)
Into a 250ml three-necked RB flask was charged 50ml of dry THF under nitrogen. The flask was cooled to 0C and LAH (1.3gr) added. A solution of above step (ii) compound (5gr) in THF was added to the reaction mixture slowly over a period of lhr. After maintaining for lhr, the reaction mixture was quenched with water, filtered and washed the solids with ethyl acetate. Solvent was evaporated from the filtrate. The residue was dissolved in toluene, washed with water, dried over sodium sulfate, and distilled off solvent under vaccum to get the crude compound, which was crystallized from

hexane/toluene to get white crystals of compound of formula-I (X = OMe). Melting point is 113-114°C. IR (KBr): 3131, 2948, 2893, 2831, 2790, 1614, 1583, 1514, 1463, 1441, 1376, 1322, 1280, 1248, 1171, 1132, 1106, 1072, 1027, 994, 880, 821, 785, 766, 598, and 556cm'1.
Example 39 Preparation of (±) ethyl 3-[N-methyl-N-(3-hydroxy-3-(4-methoxyphenyl)propyl)]-aminopropionate of the formula-XIV (X = OMe, R = Et)
Into a 500ml three-necked RB flask was charged 74gr of N-methyl-N-[3-hydroxy-3-(4-methoxyphenyl)]propylamine, toluene (180ml), and 40gr of ethyl acrylate. The reaction mixture was heated to 60-65°C and maintained for 7hrs. Toluene was removed from the reaction mixture under vaccum to get 88gr of the compound of the formula-XIV (X = OMe, R = Et) as colorless syrup. IR (neat): 3384, 2954, 2837, 1733, 1612, 1513, 1466, 1371, 1302, 1246, 1176, 1127, 1035, and 834cm-1. !H-NMR (300MHz, CDC13): 7.28-7.32 (m, 2H, ar.H); 6.86-6.90(m, 2H, ar.H); 4.86 (dd, J = 4.4Hz, 7.0Hz, 1H, -CH(OH)-); 4.17 (q, J = 7.0Hz, 2H, -OCH2CH3); 3.80 (s, 3H, ArOCH3); 2.49-3.45 (m, 4H, 2 x -CH2-); 2.32 (s, 3H, -NCH3); 1.77-1.85 (m, 2H, -CH2-); 1.28 (t, J = 7.3Hz, 3H, -OCH2CH3).
Example 40 Preparation of methyl (±)-3-[N-methyl-N-(3-acetyloxy-3-(4-methoxyphenyl)-propyl)]aminopropionate of the formula-XV (X = OMe, X' = OAc, R = methyl) Into a 250ml three-necked RB flask was charged 5gr of (±) methyl 3-[N-methyl-N-(3-hydroxy-3-(4-methoxypheny)lpropyl)]aminopropionate and 50ml of dry methylene chloride. Acetic anhydride (2.3gr) and 4-dimethylaminopyridien (O.Olgr) were added to the reaction mixture and kept under stirring for overnight. The reaction mixture was poured into ice-water and neutralized with 4gr of solid sodium bicarbonate. Organic layer was separated and washed with water. Distillation of solvent gave 5gr of the title compound as syrup. IR (neat): 2954,2847,2802,1740,1607, 1512,1437,1372,1225,1160, 1128,1022, and 837cm'1. *H-NMR (300MHz, CDC13): 7.28 (d, J = 8.80Hz, 2H, ar. H); 6.87 (d, J = 8.80Hz, 2H, ar. H); 5.74 (t, J = 7.00Hz, -CH(OAc)); 3.80 (s, 3H, -OCH3); 3.68 (s, 3H, -COOCH3); 2.66 (t, J = 6.96Hz, 2H, -CH2); 2.43 (t, J = 7.00Hz, 2H, -CH2); 2.32 (t, J = 7.00Hz, 2H, -CH2); 2.20 (s, 3H, -NCH3); 2.04 (s, 3H, -OCOCH3); 1.86-2.15 (m, 2H, -CH2).

Example 41 Preparation of ethyl (±)-3-[N-methyl-N-(3-acetyloxy-3-(4-methoxyphenyl)propyl)]-aminopropionate of the formula-XV (X = OMe, X' = OAc, R = ethyl)
Into a 250ml three-necked RB flask was charged 5gr of ethyl (±)-3-[N-methyl-N-(3-hydroxy-3-(4-methoxyphenyl)propyl)]aminopropionate of the formula-XIV (X = OMe, R = ethyl), 50ml of methylene chloride. Acetic anhydride (2.5gr) and 4-dimethylamino-pyridine (0.1 gr) were added to the reaction mixture. The reaction mixture was stirred at RT for lOhrs and quenched with water. pH of the reaction mass was adjusted to 8.0 with sodium bicarbonate. Product was extracted into methylene chloride. Methylene chloride layer was washed with water, dried over sodium sulfate. Evaporation of the solvent gave 4.5gr of colorless syrup of formula-XV (X = OMe, X*= OAc, R = Et). IR (neat): 2958, 2839, 2802, 1736, 1613, 1515, 1465, 1372, 1302, 1241, 1177, 1127, 1034, 950, and 832cm-1. *H-NMR (300MHz, CDC13): 7.24-7.30 (m, 2H, ar. H); 6.84-6.90 (m, 2H, ar. H); 5.74 (t, J = 7.00Hz, 1H, -CH(OAc)); 4.13 (q, J = 7.32Hz, 2H, -OCH2CH3); 3.80 (s, 3H, -COOCH3); 2.66 (t, J = 6.60Hz, 2H, -CH2); 2.41 (t, J = 7.20Hz, 2H, -CH2); 2.32 (t, J = 7.20Hz, 2H, -CH2); 2.21 (s, 3H, -NCH3); 2.04 (s, 3H, -OCOCH3); 1.79-2.15 (m, 2H, -CH2), 1-25 (t, J = 7.30Hz, 3H, -OCH2CH3).
Example 42 Preparation of methyl (±)-3-[N-methyl-N-(3-chloro-3-(4-methoxyphenyl)propyl)]-aminopropionate hydrochloride of the formula-XV (X = OMe, X' = CI, R = Me) Into a 250ml three-necked RB flask was charged 50ml of dry toluene, and 4gr of thionyl chloride. A solution of 5gr of methyl (±)-3-[N-methyl-N-(3-hydroxy-3-(4-methoxyphenyl)propyl)]aminopropionate of formula-XIV (X = OMe, R = Me) in toluene (10ml) was added to the reaction mixture slowly over a period of 30min. The reaction mixture was stirred at 40°C for lhr and the solvent distilled off under vaccum keeping the mass temperature below 40°C to get the compound (5gr) of the formula-XV (X = OMe, X5 = CI, R = Et) as syrup. IR (neat): 3384, 2957, 2840, 2648, 1735, 1607, 1513, 1460, 1440, 1306, 1253, 1180, 1130, 1028, 986, and 837cm"1.

Example 43 Preparation of ethyl (±)-3-[N-methyl-N-(3-chloro-3-(4-methoxyphenyl)propyl)]-aminopropionate hydrochloride of the formula-XV (X = OMe, X' = CI, R = ethyl)
Into a 250ml three-necked RB flask was charged 50ml of dry toluene, and 6gr of thionyl chloride. A solution of lOgr of ethyl (±)-3-[N-methyl-N-(3-hydroxy-3-(4-methoxy-phenyl)propyl)]aminopropionate of formula-XIV (X = OMe, R = Et) in toluene (20ml) was added to the reaction mixture slowly over a period of 30min. The reaction mixture was stirred at 40°C for lhr and the solvent distilled off under vaccum keeping the mass temperature below 40°C to get the compound (1 lgr) of the formula-XV (X - OMe, X' = CI, R = Et) as syrup. IR (neat): 3396, 2966, 2839, 2635, 1731, 1654, 1608, 1514, 1466, 1252, 1205, 1178, 1027, 980, 943, and 842cm'1.
Advantages of the present invention:
The process of the present invention has the advantages over the processes of the prior art that the piperidine ring is formed without involving any piperidone derivative, and no lithium aluminum hydride is used. No hazardous reactions are involved in the synthesis Therefore, the process simple, cheap, safe and environmentally friendly. In addition the raw materials employed are readily available.


We claim
1. Novel compounds of the formula-XX

Wherein X = F, Me, OMe
with an alkyl or aryl chloroformate in the presence of a base to get the novel urethane
derivative of the formula-XX.
3. A process as claimed in claims 2 wherein the alkyl or aryl chloroformate used for the
N-demethylation of the compound of the formula-XIX is selected from methyl, ethyl,
phenyl chloroformate.
4. A process as claimed in claims 2 and 3 wherein solvents like chloroform, methylene
chloride, dichloroethane, preferably chloroform is used in N-demethylation.

5. A process as claimed in claim 2 to 4 wherein the base used in the reaction is selected from sodium or potassium carbonate, or bicarbonate, preferably potassium carbonate.


wherein R and X are as defined above
(ii) Hydrolysis of the novel urethane derivative with an alkali to get the novel secondary
amine of formula-XIII
8. A process as claimed in claims 7 wherein the alkyl or aryl chloroformate used for the
N-demethylation of the compound of the formula-XIX in step (i) is selected from methyl,
ethyl or phenyl chloroformate.
9. A process as claimed in claim 7 and 8 wherein the base used in the reaction is selected
from sodium or potassium carbonate, or bicarbonate, preferably potassium carbonate.
10. A process as claimed in claims 7 to 9 wherein the alkali used in step (ii) is selected
from sodium or potassium hydroxide preferably potassium hydroxide in aqueous DMSO
at 60-140°C, preferably at 100-120°C.

wherein X = Me, OMe; HX' is inorganic or organic acid
which comprises a Mannich reaction on known compound of formula-XVII,


with formaldehyde (paraformaldehyde or aqueous formaldehyde) and N-methylbenzylamine, or its addition salts with inorganic or organic acids, in a polar solvent to get the compound of formula-XXI.
13. A process according to claim 12 wherein the inorganic acid is hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid, preferably hydrochloric acid.
14. A process according to claim 12 and 13 wherein the organic acid used is acetic acid,
propionic acid, oxalic acid, benzoic acid, preferably, acetic acid, or oxalic acid.
15. A process according to claim 12 to 14 wherein the alcoholic solvent employed in the
reaction is methanol, ethanol, isopropanol, sec-butanol, preferably methanol or
isoproanol.

wherein X = F, Me, OMe and its acid addition salts.
17. A process for the preparation of novel compounds of the formula-XXII,


18. A process as claimed in claim 17 wherein the base used in step (i) is selected from sodium or potassium hydroxide, carbonate, bicarbonate and the like.
19. A process as claimed in claims 17 and 18 wherein the alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol, isopropanol, sec-butanol, t-butanol, preferably methanol, ethanol or isopropanol is used.

20. A process as claimed in claims 17 to 19 wherein the temperature at which the reaction in step (ii) is effected is in the range of ~10°C to 25°C, preferably at 0-10°C.

(iii) N-Debenzylation of the hydroxy compound of the formula-XXII under heterogeneous hydrogenation conditions using a metal catalyst to get the novel N-debenzylated compound of formula-XIII.
22. A process as claimed in claim 21 wherein the base used in step (i) is selected from sodium or potassium hydroxide, carbonate, bicarbonate and the like.

23. A process as claimed in claims 21 and 22 wherein the alcoholic solvents such as
methanol, ethanol, isopropanol, n-butanol, isopropanol, sec-butanol, t-butanol, preferably
methanol, ethanol or isopropanol is used.
24. A process as claimed in claims 21 to 23 wherein the temperature at which the reaction
in step (ii) is effected is in the range of -10°C to 25°C, preferably at 0-10°C.

Wherein X = H, F, Me, OMe; R = Me, Et
which comprises:
Reacting the compound of the formula-XIII,


with an acrylate ester in the presence of a solvent at elevated temperature to get the Michael addition product of the formula-XIV.
27. A process as claimed in claim 26 wherein the solvent employed in the reaction is selected from benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, THF, preferably toluene, cyclohexane or heptane.
28. A process as claimed in claims 26 and 27 wherein the temperature of the reaction is in the range of 25-100°C, preferably 40-70°C.

Wherein X = H, X' = OMs, OBs, OTs, OAc; R = Me, Et
X = F, X' - OMs, OBs, OTs, OAc; CI, R = Me, Et
X = Me, X5 = OMs, OBs, OTs, OAc; CI, R = Me, Et
X = OMe, X5 = OMs, CI, R = Me, Et and its acid addition salts 30. A process for the preparation of novel compounds of the formula-XV,


Wherein X = H, X5 = OMs, OBs, OTs, OAc; R = Me, Et
X = F, X' = OMs, OBs, OTs, OAc; CI, R = Me, Et
X = Me, X' = OMs, OBs, OTs, OAc; CI, R - Me, Et
X = OMe, X' = OMs, CI, R = Me, Et and its acid addition salts which comprises:

with an acrylate ester in the presence of a solvent at an elevated temperature to get the Michael addition product of the formula-XIV,


Wherein X and R are as defined above
(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X5 with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.
31. A process as claimed in claim 30 wherein the acrylate ester used in step (i) is selected from methyl or ethyl acrylate.
32. A process as claimed in claims 30 and 31 wherein the step (i) is effected in the presence of solvent such as benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, preferably toluene, cyclohexane, heptane.
.33. A process as claimed in claims 30 to 32 wherein the step (i) is effected at a temperature in the range of 25-100°C, preferably 40-70°C.
34. A process as claimed in claims 30 to 33 wherein the reagents used in step (ii) for sulfonate esters (X' = OMs, OBs, OTs) are methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, respectively.
35. A process as claimed in claim 30 to 34 wherein the reagents used in step (ii) for the acetate (X* = OAc) is selected from acetyl cloride or acetic anhydride.
36. A process as claimed in claim 30 to 35 wherein the reagent used for chloride (X' = CI) is thionyl chloride
37. A process as claimed in claims 30 to 36 wherein the solvent employed in step (ii) is selected from hexane, heptane, cyclohexane, toluene, methylene chloride, chloroform, ethylene dichloride, diethyl ether, diisopropyl ether, THF, 1,4-dioxane, etc, preferably toluene, methylene chloride or THF.

38. A process as claimed in claims 30 to 37 wherein the base employed in step (ii) is
selected from pyridine, triethylamine, sodium or potassium carbonate, preferably
triethylamine or pyridine.
39. A process as claimed in claims 30 to 38 wherein the temperature of the reaction in
step (ii) for sulfonate esters (X' = OMs, OBs, OTs) is between -30 to 30°C, preferably -
10 to 25°C and for the acetates (X' = OAc) or chlorides (X' = CI) is between 15 to 80°C,
preferably 25-50°C.



with an acrylate ester in the presence of a solvent at an elevated temperature to get the Michael addition product of the formula-XIV

Wherein X - Me, R = Me, Et
(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X5 with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.
Wherein X = Me; X5 = OMs, OBs, OTs, OAc, OBz, CI; R - Me, Et

(iii) Reacting the compound of the formula-XV with a strong base in the presence of an ether or dipolar aprotic solvent at low temperature to get the cyclized compound of formula-XVI.
42. A process as claimed in claim 41 wherein the acrylate ester used in step (i) is selected
from methyl or ethyl acrylate.
43. A process as claimed in claims 41 & 42 wherein the step (i) is effected in the presence of solvent such as benzene, toluene, xylene, hexane, heptane, cyclohexane, methylene chloride, acetonitrile, preferably toluene, cyclohexane, heptane.
44. A process as claimed in claims 41 to 43 wherein the step (i) is effected at a temperature in the range of 25-100°C, preferably 40-70°C.
45. A process as claimed in claims 41 to 44 wherein the reagents used in step (ii) for the conversion of the hydroxy group are selected from thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, acetic anhydride, acetyl chloride, benzoyl chloride, etc., preferably thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride more preferably methanesulfonyl chloride or benzenesulfonyl chloride.
46. A process as claimed in claims 41 to 45 wherein the solvent used in step (ii) is methylene chloride, ethylene dichloride, toluene, cylcohexane, heptane, diethyl ether, THF, etc., preferably, methylene chloride, THF, toluene or heptane.
47. A process as claimed in claims 41 to 46 wherein the temperature of reaction in step (ii) is in the range of-20 to 25°C, preferably ~5 to 15°C.
48. A process as claimed in claims 41 to 47 wherein the base used in step (ii) is
triethylamine, pyridine, sodium or potassium carbonate, or bicarbonate, etc., preferably,
pyridine or triethylamine.

49. A process as claimed in claim 41 to 48 wherein the strong base used in step (iii) is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec-amyloxide, sodium amide, lithium amide, sodium methoxide, and the like, preferably sodium hydride lithium diisopropylamide.
50. A process as claimed in claim 41 to 49 wherein the ether solvent used in step (iii) is selected from tetrahydrofiiran, dioxane, diethyl ether, diisopropyl ether, preferably tetrahydrofiiran.
51. A process as claimed in claim 41 to 50 wherein the dipolar aprotic solvent used in
step (iii) is selected from N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulfoxide, preferably N,N-dimethylformamide.
52. The process as claimed in claim 41 to 51 wherein the temperature of reaction in step
(iii) is between -10 to 45°C, preferably -5 to 25°C.

Wherein X = methyl and its acid addition salts
54. A novel and improved process for the preparation of compounds of the formula-I


where X has the meanings given earlier or its acid addition salts which comprises:

with an acrylate ester in the presence of a solvent at elevated temperature to get the Michael addition product of the formula-XIV.


Wherein X = H, F, Me, OMe; R = Me, Et
(ii) Converting the hydroxy group present in the compound of the formula-XIV into a leaving group X' with appropriate reagent in a solvent medium with or without a base at low temperature or elevated temperature to get the compound of formula-XV.

Wherein X = H, F, Me, OMe; X' = OMs, OBs, OTs, CI, Br, OAc, OBz; R = Me, Et (iii) Reacting the compound of the formula-XV with a strong base in the presence of an ether or dipolar aprotic solvent at low temperature to get the cyclized compound of formula-XVI.

Wherein X = H, F, Me, OMe; R = Me, Et
(iv) Reducing the ester group present in the compound of the formula-XVI with a reducing agent to get the hydroxy compound of formula-I where X has the meanings given earlier.

55. A process as claimed in claim 54 wherein the acrylate ester used in step (i) is selected
from from methyl or ethyl acrylate and the like.
56. A process as claimed in claims 54 & 55 wherein the solvent such as toluene, cyclohexane, heptane, xylene, acetonitrile, and the like preferably, toluene or cyclohexaneis sued in step (i).
57. A process as claimed in claims 54 to 56 wherein the temperature employed in step (i) is in the range of 60 to70°C,
58. A process as claimed in claims 54 to 57 wherein the reagents used in step (ii) for the conversion of the hydroxy group are selected from thionyl chloride, thionyl bromide, phosphorous trichloride, phosphorous tribromide, hydrochloric acid, hydrobromic acid, methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, acetyl chloride, benzoyl chloride, trifluoromethnesulfonyl chloride, etc., preferably thionyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride or trifluoromethanesulfonyl chloride, more preferably thionyl chloride or methanesulfonyl chloride.
59. A process as claimed in claims 54 to 58 wherein the solvent used in step (ii) is methylene chloride, ethylene dichloride, toluene, cylcohexane, heptane, etc., preferably, methylene chloride, toluene or heptane.
60. A process as claimed in claims 54 to 59 wherein the temperature of reaction in step (ii) is in the range of-20 to 25°C, preferably -5 to 15°C.
61. A process as claimed in claims 54 to 60 wherein the base used in step (ii) is
triethylamine, pyridine, lutidine, sodium or potassium carbonate, or bicarbonate, etc.,
preferably, pyridine or triethylamine.

62. A process according to claims 54 to 61 wherein the step (ii) is carried out at a temperature in the range of 40-120C, preferably 60-80°C.
63. A process as claimed in claims 54 to 62 wherein the strong base used in step (iii) is selected from sodium hydride, butyl lithium, hexyl lithium, lithium diisopropylamide, sodium t-butoxide, potassium t-butoxide, sodium sec-amyloxide, sodium amide, lithium amide, sodium methoxide, and the like., preferably sodium hydride lithium diisopropylamide.
64. A process as claimed in claims 54 to 63 wherein the solvent used in step (iii) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, dimethylsulfoxide, tetrahydrofuran, dioxane, toluene, xylene, diisopropyl ether, etc., preferably N,N-dimethylformamide, dimethylsulfoxide, pyridine, tetrahydrofuran, more preferably N,N-dimethylformamide, tetrahydrofuran.
65. A process as claimed in claims 54 to 64 wherein the temperature of reaction in step (iii) is between -10°C to 45°C, preferably -5 to 25°C.
66. A process as claimed in claims 54 to 65 wherein the mole ratio of base to substrate in step (iii) is 1:1.1 to 1:2.0, preferably 1:1.25.
67. A process as claimed in claims 54 to 66 wherein the reducing agent used in step (iv) is selected from sodium borohydride/t-butanol/methanol, sodium borohydride in the presence of an acid catalyst like boron trifluoride-etherate, sulfuric acid, etc.; vitride, lithium aluminum hydride, lithium tris-(t-butoxy)aluminum hydride, sodium/ethanol, and the like, preferably, sodium borohydide/t-butanol/methanol, vitride, lithium aluminum hydride.
68. A process as claimed in claims 54 to 67 wherein the temperature of reaction in step (iv) is -50°C to 70°C, preferably -20°C to 20°C.

69. Novel compounds of the formulae XX, XXI, XXII, XIII, XIV, XV & XVI as defined above substantially as herein described with reference to the Examples.
70. A process for the preparation of novel compounds of the formulae XX, XXI, XXII, XIII, XIV, XV & XVI as defined above substantially as herein described with reference to the Examples.
71. An improved process for the preparation of compounds of the formula-I as defined earlier substantially as herein described with reference to the Examples.


Documents:

830-mas-2002-abstract.pdf

830-mas-2002-claims duplicate.pdf

830-mas-2002-claims original.pdf

830-mas-2002-correspondence others.pdf

830-mas-2002-correspondence po.pdf

830-mas-2002-description complete duplicate.pdf

830-mas-2002-description complete original.pdf

830-mas-2002-description provisional.pdf

830-mas-2002-form 1.pdf

830-mas-2002-form 19.pdf

830-mas-2002-form 3.pdf

830-mas-2002-form 5.pdf

830-mas-2002-pct.pdf

abs-830-mas-2002.jpg


Patent Number 208040
Indian Patent Application Number 830/MAS/2002
PG Journal Number 15/2008
Publication Date 11-Apr-2008
Grant Date 06-Jul-2007
Date of Filing 11-Nov-2002
Name of Patentee NATCO PHARMA LIMITED
Applicant Address NATCO PHARMA LTD NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 03 ANDHARA PRADESH, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 PULLA REDDY MUDDASANI NATCO PHARMA LTD NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 03 ANDHARA PRADESH, INDIA.
PCT International Classification Number A61K31/445
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA