Office de la Propriéts Canadian CA 2487957 At 2003/12/11 Intellectuelle Intellectual Property du Canada Office en 2 487 957 cae eure (i) DEMANDE DE BREVET CANADIEN a CANADIAN PATENT APPLICATION ayAt (86) Date de dépét PCTIPCT Filing Date: 2003/02/03. (61) Clint Ant. Cl’ CO7C 217/00 (67) Date publication PCT/PCT Publication Date: 2003/12/11 | (71) Demandeur/Applicant: (85) Entrée phase nationale/National Entry: 2004/11/30 TOS BE RA EMITED !" demande lication No. (72) Inventeurs/inventors: (@6) N° demande PCT/PCT Application No.: IN 2003/000016 Re ESS AGE eeaed (67) N° publication PCTIPCT Publication No.: 2003/101931 VENKAIAH, CHOWDARY NANNAPANENI, IN (20) Priorité/Priority: 2002/05/31 (411/MAS/02) IN (74) Agent: BERESKIN & PARR (64) Titre : PROCEDE AMELIORE POUR L'ELABORATION D'ACETALS DE 4-(N, N-AMINODISUBSTITUE) BUTYRALDEHYDE (4 Title: AN IMPROVED PROCESS FOR THE PREPARATION OF 4-(N, N-DISUBSTITUTEDAMINO) BUTYRALDEHYDE ACETALS. (67) Abrége/Abstract ‘The invention disclosed in this application relates to an improved process for the preparation of compounds of formula (I: R'R? NCH,CH,CH,CH(OR®),, wherein, R! = R? = C,-Cyg alkyl; C,-C, cycloalkyl; R' = C,-Cye alkyl; R? = C,-C, cycloalkyl, NRIR? pyrrolidine, piperidino, morpholino, thiomorpholino, R’ = C,-C, allyl; R? = ArCH,; Ar=4-R*-C,H,,, Ré= MeO, E10, Me, Et, NMe,, NEt,, SMe, SEt, etc; R°=C.-C, alkyl; C.-C, cycloalkyl which comprises: (i) Reacting 3(N, N- 1 rity ————» _ R'R’NCH,CH,CH2CH(OEt)) IV Scheme-I ‘The main disadvantage of this route is the preparation of starting acetal of formula-XIV. Preparation of this is extremely difficult on a commercial scale. It involves chromium oxidation and is not stable under normal conditions, Also, the step of high pressure hydrogenation is involved. Currently there are only three routes available in the hitherto reported literature for the preparation of compounds of the formula-I R'R’NCH;CH;CH;CH(OR’); I Wherein, R'= R? = Me, R’ = Me or Et In the first route, Keglevic (Croat. Chem. Acta, 36(3), 103-9, 1964) reported the synthesis ‘of compound of formula-V in 45% yield starting from 4-aminobutyraldehyde diethyl acetal of formula-VI (Scheme-II). Mel H,NCH,CH,CH,CH(OEt), ———e Me,NCH,CH,CH,CH(OEt), vl v Scheme-II Starting material used in this process (compound of formula-V1) is not commercially available and is prepared in three steps starting from acrolein (see Scheme-II1)10 1s 20 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 According to the literature (Manske, et al, Can. J. Research, 5, 598, 1931; Gribble, et al, J. Org. Chem. 1988, 53, 3164) acrolein is reacted with ethanol and HCI to give the chloroprionaldehyde diethyl acetal of formula-VIII. The acetal of formula-VIII is reacted with sodium or potassium cyanide to get the cyano compound of formula-IX. The overall yield of these two steps is 43%. Conversion of the cyano compound of formula-IX to the amino compound of formula-VI is reported by Burckhalter (J. Org, Chem., 23, 1278, 1958) in 91%. Therefore the overall yield of compound of formula-V is 18.5% starting from commercially available acrolein of formula-VII. EtOHHCI NaCN or KCN Cl,=cHHo———— CICH,CH,CH(OE), —————te-_NCCH, CH,CH(OE), vil vil x h ati vdrogenation _.H,NCH,CH,CH,CH(OED, vl Scheme-II Some of the main disadvantages in this route are i. Starting from commercially available acrolein the overall yield is only 18.5% ii. Process is involving four steps. iii, Basic raw material, acrolein is not widely available and requires special handling techniques due to its lachrimatory nature and polymerization property, iv. Requires handling of poisonous chemicals like sodium cyanide or potassium cyanide used in the second step (Scheme-III). v. Requires high pressure hydrogenation used in the third step (Scheme-II)cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 In the second route, reported by Takahara (JP 68 09529, CA: 68, P107070z) the compound of the formula-X was prepared in 57% yield starting from 4- aminobutyraldehyde dimethyl acetal of formula-XI (Scheme-IV) H,NCH,CH,CH,CH(OMe), —HeHOM, Me,NCH,CH,CH,CH(OMe), xi 10% PdIc. fa s- Scheme-IV 4-Aminobutyraldehyde dimethyl acetal of formula-XI was methylated using 37% formalin under hydrogen pressure (114kg"/em’) with 10% Pd/C to get the compound of 10 formula-X. The starting material used in this process (compound of formula-XI) is not commercially available. It is prepared in three steps starting from acrolein as per the procedure given in literature (Manske, et al, Can. J. Research, 5, 598, 1931; Gribble, et al, J. Org, Chem. 1988, 53, 3164; Burckhalter, et al, J. Org. Chem., 23, 1278, 1958) in less than 60% yield (Scheme-V) MeOHIHCI H.C=ClICHO ————m Ich, cH,cH(OMe), xil cich,cH,cHiome), N@CN°" KCN nccH.cH,cH(oMe), xi xii Hydrogenation NCCH,CH,CH(OMe),. ————>_H, NCH,CH,CH,CH(OMe), xill x! 15 Scheme-V In the second route main disadvantages are: i Requires very high pressure (114 kg 7/ cm?) hydrogenation, 20 ii Basic raw material (compound of formula-XI) required in the process is not commercially available and is prepared in three steps (Scheme-V)ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 In the third route, reported by Chen (J. Org. Chem. 59, 3738, 1994) the compound of formula-X was obtained in 66% yield in three steps starting from 4-chlorobutyryl chloride of formula-XIV (Scheme-VI). 4-Chlorobutyry! chloride was reduced under 5 Rosenmund reduction conditions (10% Pd/C, 2,6-lutidine, 40psi hydrogen pressure) to get the 4-chlorobutyraldehyde of formula-XV. This crude aldehyde thus obtained was further reacted with methanol and sulfuric acid to get the acetal of formula-XVI. The acetal of formula-XVI was reacted with large (7 fold) excess of dimethylamine to get the compound of formula-X. The starting material (4-chlorobutyryl chloride of formula-XIV) 10 used in the process is not commercially available. It is prepared from y-butyrolactone using excess thionyl chloride (Reppe, et al, Liebigs Ann. Chem. 596, 190, 1955) in 90% yield Rosenmund Reduction CICH,CH,CH,CHO CICH,CH,CH,COCI XIV xv MeOH/H,SO Aq. Me,NH ME OHI S04 CICH,CH,CH,CH(OMe)., —— > p= xvi Me,NCH,CH,CH,CH(OMe), x Scheme-VI In the third route although overall yield is good, the major disadvantages are: i, Preparation of 4-chlorobutyryl chloride involves corrosive chemistry (hydrogen chloride and sulfur dioxide are evolved in the process). 20 ii, Rosenmund reduction is involved in the first step (scheme-V1). This requires a special technique (hydrogenation under pressure) and the yields can fluctuate. iii, Large excess (7 fold) of dimethylamine is required in the last step10 1s 20 28 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Keeping in view of the difficulties in implementing the above routes for making compounds of formula-I, which have gained importance in the recent years, we directed our research work to develop a simple, convenient and economical process for the preparation of compounds of formula-I which process is also commercially viable. ‘The main objective of the present invention is, therefore, to provide an improved process for the preparation of compounds of the formula-I as defined above overcoming all the disadvantages present in the hitherto known processes, Another objective of the present invention is to provide an improved process for the preparation of compounds of the formula-I as defined above which is simple and economical. Yet another objective of the present invention is to provide an improved process for the preparation of compounds of the formula-I as defined above which does not require the step of high pressure hydrogenation due to which the process is safe. Still another objective of the present invention is to provide an improved process for the preparation of compounds of the formula I as defined above which does not involve rare, expensive, and dangerous starting materials Another objective of the present invention is to provide an improved process for the preparation of compounds of the formula-I as defined above which does not require special equipment or technique. Another objective of the present invention is to provide an improved process for the preparation of compounds of the formula-I as defined above in which the yield of the final product is fairly high (>70%) and better purity (>98%).10 15 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Another objective of the present invention is to provide an improved process for the preparation of compounds of the formula-I as defined above which process is generally and widely applicable for the commercial preparation, It is known from the literature (Stetter, Chem. Ber., 103, 643, 1970) that orthoformates of formula-XVII HC(OR*),(OR*) XVI Wherein R? = alkyl, R° = phenyl undergo Grignard reaction in aromatic solvent medium at the reflux temperature with alkylmagnesium halides to give one carbon extended acetals of formula-XVIII (Scheme-VII). RX + Mg ————* RMgx RMgX + HC(OR?),(OR) ————> RCH(OR®): XVIL XVoL Scheme-VII It is also known from the literature (Org. Synth. Coll, Vol, VI, p76, 1988) that 3- (dimethylamino)propyl chloride of formula-XIX forms a stable Grignard reagent of formula-XX when reacted with magnesium in an aromatic solvent or ether solvent at reflux temperature (Scheme-VIII) Me,NCH,CH,CH,CI + Mg ————™ Me,NCH,CH,CH,MgCl xix Xx Scheme-VIII10 15 20 25 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Based on the above mentioned information we directed our attention towards reacting orthoformates of the formula-XVII, HC(OR®),(OR*) XVII wherein R? and R° is same or different and represent C; to Ce alkyl, Cs to Cy cycloalkyl, OR R’ is as defined above and R° represents a phenyl radical with the Grignard reagents derived from the halides of the formula-XXI, R'R’NCH2CH;CH2 X XXI Wherein, R!, R? = as defined above, X = Cl or Br ‘Accordingly the present invention provides an improved process for the preparation of the compounds of the formula-I which comprises reacting the readily available 3-(N, N- disubstitutedamino)propyl halides of formula-XXI, R'R?NCH2CH2CH2 X XXL Wherein, R', R? = as defined above, X = Cl or Br, and orthoformates of formula-XVI, HC(OR’)(OR?)2 XVII wherein R? and R° is same or different and represent C, to Cs alkyl, C3 to C cycloalkyl, OR R’ is as defined above and R’ represents a phenyl radical using a Grignard reaction.10 4s 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 ‘Accordingly, the present invention provides an improved process for the preparation of compounds of formula-I iti R'R?NCH;CH3CH;CH(OR®)2 I Wherein, R! = R?= C1-Gig alkyl; Cs-Cy cycloalkyl; R! = Cy-Cig alkyl; R?= C3-Cy cycloalkyl; NR'R?= pyrrolidino, piperidino, morpholino, thiomorpholino, R' = Ci-Ce alkyl, R? = ArCHp; Ar = 4-R'-CekLy-, R* = MeO, EtO, Me, Et, NMe2, NEt;, SMe, SEt, ete; R= Ci-Ce alkyl; C3-C7 cycloalkyl which comprises: Reacting 3-(N, N-disubstitutedamino)propy! halide of formula-XXI, R'R?NCH,CH2CH2X XXI wherein R', R?, = as defined above, X = CI or Br, with magnesium in the presence of'a solvent to get the Grignard reagent, 3-(N, N-disubstitutedamino)- propylmagnesium halide Reacting the resulting 3-(N, N-disubstitutedamino)propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula-XVII, HC(OR*)(OR*) XVII Wherein, R* and R° is same or different and represent C; to Cg alkyl, C3 to C7 cycloalkyl, OR R? is as defined above and R’ represents a phenyl radical Filtering the resulting reaction mixture and distilling the filtrate to isolate compound of the formula-t10 1s 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 The 3-(N, N-disubstitutedamino)propyl halide used in step (i) may be selected from its chloride or bromide. The solvent used in step (i) may be selected from non-polar hydrocarbon, aromatic solvent, or ether solvent, etc. Thus the solvent may be selected from benzene, toluene, xylene, hexane, cyclohexane; heptane, etc. The trisubstituted orthoformate used in step (ii) may be selected from trialkyl (methyl, ethyl, etc) or phenyl dialkyl orthoformate. Ina preferred embodiment of the present invention, the molar ratio between the Grignard reagent and the othoformate used may be in the ratio of 1:1-3, preferably in the ratio of U12-1.5 ‘The details of the invention are described in 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 4-(N, N-dimethylamino)butyraldehyde dimethyl acetal of the formula-I where R! = R? = R® = Me using Benzene as solvent: Preparation of 3-(N, N-dimethylamino)propyl chloride solution in benzene: Commercially available aqueous 3-(N, N-dimethylamino)propy! chloride hydrochloride (230gr, 60% wiw) was taken into a IL three-necked round bottom flask and cooled to 15- 20°C. Aqueous sodium hydroxide (40gr in 60m! water) solution was slowly added to the above salt solution keeping the temperature below 20°C. After stirring for 30min, 300ml of benzene was added to the reaction mixture and stirred for 1Smin, The benzene layer was separated and the aqueous layer extracted with benzene (200ml). The combined benzene layer was taken into a clean and dry IL three-necked round bottom flask and 1010 15 20 25 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the benzene solution was cooled to 25°C and decanted the colorless supematant liquid into a 1L round bottom flask. Chemical assay of this benzene solution was 17% w/w. Preparation of the Grignard reagent and the compound of the formula-I wherein R’ =R=R = Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr) under Na atmosphere. Benzene (50ml), the above benzene solution (50m), trimethyl orthoformate (20gr), and a small crystal of iodine were added into the flask and heated to reflux temperature. Within 15-20min of reflux, vigorous reaction took place indicating the initiation of Grignard reaction, Remaining quantity of the benzene solution (600ml) and trimethyl orthoformate of the formula-XVII where R’ = R* = Me (119gr) were taken into two separate addition funnels and added to the reaction mass at reflux temperature over a period of 3-4 hrs. After the addition, the reaction mass was maintained at reflux for another 2hrs and cooled to 25°C. The reaction mass was filtered over a celite pad and washed the cake with 100ml of benzene. Benzene was removed from the reaction mass by ordinary distillation keeping a 20cm vigroux column, Excess trimethyl orthoformate was distilled under mild vaccum keeping the mass below 80°C. Finally, the residue was distilled under vaccum to afford 100gr (71%) of 4-(N, N-dimethylamino)butyraldehyde dimethyl acetal as a colorless liquid. B. p.: 80-85°C / 15-20mm). Example 2 Preparation of 4-(N, N-dimethylamino)butyraldehyde dimethyl acetal of the formula-I where R' = R? = R’ = Me using toluene as solvent: Preparation of 3-(N, N-dimethylamino)propyl chloride solution in toluene: Commercially available aqueous 3-(N, N-dimethylamino)propyl chloride hydrochloride n10 20 25 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 (230gr, 60% w/w) was taken into a IL three-necked round bottom flask and cooled to 15- 20°C. Aqueous sodium hydroxide (40gr in 60m! water) solution was slowly added to the above salt solution keeping the temperature below 20°C. After stirring for 30min, 300ml of toluene was added to the reaction mixture and stirred for 15min, The toluene layer was separated and the aqueous layer extracted with toluene (200ml). The combined toluene layer was taken into a clean and dry IL three-necked round bottom flask and heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the toluene solution was cooled to 25°C and decanted the colorless supernatant liquid into a 1L round bottom flask. Chemical assay of this toluene solution was 17% w/w. Preparation of the Grignard reagent and the compound of the formula-I wherein R’ =R’=R’=Me Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr), toluene (Omi), the above toluene solution (SOml), trimethyl orthoformate (20gr), and a small crystal of iodine under aitrogen atmosphere at 25°C. The contents were slowly heated to 75-80°C, After maintaining for about 20 min, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the toluene solution (600ml) and trimethyl orthoformate of the formula-XVII where R’ = R* = Me (119gr) were taken into two separate addition funnels and added to the reaction mass at 75-80°C over a period of 34 hrs, After the addition, the reaction mass was maintained at 75- 80°C for another 2hrs and cooled to 25°C. The reaction mass was filtered over a celite pad and washed the cake with 100ml of toluene. Toluene was removed from the reaction mass by ordinary distillation keeping a 20cm vigroux column, Excess trimethyl orthoformate was distilled under mild vaccum keeping the mass below 80°C. Finally, the residue was distilled under vaccum to afford 85gr (60%) of 4(N, N- dimethylamino)butyraldehyde dimethyl acetal as a colorless liquid. B. p.: 80-85°C / 15- 20mm), 1210 15 20 25 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Example 3 Preparation of 4-(N, N-dimethylamino)butyraldehyde dimethyl acetal of the formula-I where R' = R? = R® = Me using THF as solvent: Preparation of 3-(N, N-dimethylamino)propyl chloride solution in THF: Commercially available aqueous 3-(N, N-dimethylamino)propyl chloride hydrochloride (230gr, 60% wiw) was taken into a IL three-necked round bottom flask and cooled to 15- 20°C, Aqueous sodium hydroxide (40gr in 60ml water) solution was slowly added to the above salt solution keeping the temperature below 20°C. After stirring for 30min, 3-(N, N-dimethylamino)propyl chloride separated as an oil. The oil layer was separated and dried over 20gr of sodium hydroxide pellets. The compound layer was decanted and dissolved in 500 ml of THF. About 100ml of THF was distilled off from this layer and the residue to cooled to 25°C. Chemical assay of this THF solution (500gr) was 15% wiw. Preparation of the Grignard reagent and the compound of the formula-I wherein R* =R’=R°=Me Into a 2L four-necked round bottom flask were charged magnesium turnings (18gr), THE (50ml), the above THF solution (50gr), trimethyl orthoformate (10gr), and a small crystal of iodine under nitrogen atmosphere at 25°C. The contents were slowly heated to reflux temperature, After maintaining for about 20 min at reflux a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the THF solution (550gr) and trimethyl orthoformate of the formula-XVIJ where R’ = R* = Me (90gr) were taken into two separate addition funnels and added to the reaction mass at 75-80°C over a period of 3-4 hrs. After the addition, the reaction mass was maintained at reflux for another 2hrs and cooled to 25°C. The reaction mass was filtered over a celite pad and 1B10 Is 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 washed the cake with 100ml of THF, THF was removed from the reaction mass by ordinary distillation keeping a 20cm vigroux column. Excess trimethyl orthoformate was distilled under mild vaccum keeping the mass below 80°C. Finally, the residue was distilled under vaccum to afford 75gr (53%) of 4-(N, N-dimethylamino)butyraldehyde dimethyl acetal as a colorless liquid. B, p.: 80-85°C / 15-20mm) Example 4 Preparation of 4-(N, N-dimethylamino)butyraldehyde diethyl acetal of the formula-I where R! = R?= Me and R® = Et using benzene as solvent: Preparation of 3-(N, N-dimethylamino)propyl chloride solution in benzene A solution of 106gr of 3-(N, N-dimethylamino)propyl chloride in benzene (500ml) was prepared by following the procedure given in Example I (i) above. Preparation of the Grignard reagent and the compound of the formula-I where R'= R= Meand R°=Et Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr) under nitrogen atmosphere. Benzene (50ml), the above benzene solution (5Oml), triethy! orthoformate (20gr), and a small crystal of iodine were added to the reaction flask and slowly heated to reflux temperature. Within 15-20min of refluxing period, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of benzene solution and triethyl orthoformate of the formula-XVII where R® = R® = Et (174gr) were separately taken into two addition funnels and slowly added in 3-4hrs period to the reaction mixture under reflux temperature. The reaction mass was cooled to 25°C and filtered through celite pad. The cake was washed with benzene (100ml). Benzene was removed from the reaction mass using 20cm Vigroux column at atmospheric pressure. The residue was distilled under mild vaccum keeping mass 410 15 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 temperature below 100°C to get the excess triethyl orthoformate (60gr). Finally, 4-(N, N- dimethylamino)-butyraldehyde diethyl acetal was distilled under vaccum to get 125gr (75.8%) as colourless liquid. B p.: 140-150°C/15-20mm Example 5 Preparation of 4-(N, N-dimethylamino)butyraldehyde diethyl acetal of the formula-I where R' = R? = Me and R° = Et using cyclohexane as solvent: Preparation of 3-(N, N-dimethylamino)propyl chloride solution in cyclohexane: Commercially available aqueous 3-(N, N-dimethylamino)propyl chloride hydrochloride (230gr, 60% w/w) was taken into a IL three-necked round bottom flask and cooled to 15- 20°C. Aqueous sodium hydroxide (40gr in 60ml water) solution was slowly added to the above salt solution keeping the temperature below 20°C. After stirring for 30min, 300ml of cyclohexane was added to the reaction mixture and stirred for 1Smin, The cyclohexane layer was separated and the aqueous layer extracted with cyclohexane (200ml). The combined cyclohexane layer was taken into a clean and dry IL three-necked round bottom flask and heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the cyclohexane solution was cooled to 25°C and decanted the colorless supernatant liquid into a 1L round bottom flask. Chemical assay of this cyclohexane solution (650ml) was 16.5% wiw. Preparation of the Grignard reagent and the compound of the formula-I wherein R’ =R’=Me, R= Et Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr), cyclohexane (50m), the above cyclohexane solution (5Oml), triethyl orthoformate (20gr), and a small crystal of iodine were added into the flask and heated to reflux temperature. 1510 15 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Within 15-20min of reflux, vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the cyclohexane solution (600ml) and triethyl orthoformate of the formula-XVII where R? = R* = Et (175gr) were taken into two separate addition funnels and added to the reaction mass at reflux temperature over a period of 3-4 hrs, After the addition, the reaction mass was maintained at reflux for another 2hrs and cooled to 25°C. The reaction mass was filtered over a celite pad and washed the cake with 100ml of cyclohexane. Cyclohexane was removed from the reaction mass by ordinary distillation keeping a 20cm vigroux column. Excess triethyl orthoformate was distilled under mild vaccum keeping the mass below 80°C. Finally, the residue was distilled under vaccum to afford 120gr (72.8%) of 4-(N, N- dimethylamino)butyraldehyde diethyl acetal as a colorless liquid Example 6 Preparation of 4-(N-benzyl-N-methylamino)butyraldehyde diethylacetal of formula-I where R' = Me, R? = benzyl, R° = Et using benzene as solvent: Preparation of 3-(N-benzyl-N-methylamino)propanol: To a solution of 278gr of 3- bromopropanol in 400m! of methanol was added drop-wise a solution of 240gr of N- benzylmethylamine in 100ml of methanol. After 20min, the solution was heated under reflux and mainted for 16hr. The reaction mixture was cooled to room temperature and poured into water (1000ml) containing 100gr of NaOH. Product was extracted into benzene (2 x 500ml) and distilled off benzene to get 200gr of crude compound. This was distilled under high vaccum to get 150gr of distilled —3-(N-benzyl-N- methylamino)propanol 1610 15 20 28 ca 02487957 2004-11-30 Wo 03/101931 PCT/IN03/00016 Preparation of 3-(N-benzyl-N-methylamino)propyl chlori To a solution of 150gr of 3-(N-benzyl-N-methylamino)propanol in 200ml of benzene was added drop wise with g under nitrogen a solution of 200gr of thionyl chloride in 100ml of benzene. The mixture was refluxed for Shr and cooled to room temperature. The reaction mixture was neutralized by pouring into aqueous NaOH (50gr in 400ml water) and the product extracted into benzene (2 x 400ml). After distilling off benzene product was distilled under high vaccum to get 120gr of 3-(N-benzyl-N- methylamino)propyl chloride as colorless liquid Preparation of the Grignard reagent and 4-(N-benzyl-N-methylamino)- butyraldehyde diethyl acetal of formula-I where R'= Me, R?= benzyl, and R°=Et Into a IL four-necked round bottom flask were added magnesium turnings (7.0gr), benzene (25m), benzene solution (25ml) of N-(3-chloropropyl)-N-methylbenzylamine (prepared by dissolving S0gr of N-(3-chloropropyl)-N-methylbenzylamine in 250ml of benzene), triehtyl orthoformate (Sgr), and a small crystal of iodine under nitrogen atmosphere. After 15-20min of reflux, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the benzene solution and triethyl orthoformate of formula-XVII where R’ = R° = Et (SOgr) were separately taken into two pressure equalizing addition funnels and added slowly in 2-3hrs period at reflux temperature. After maintaining for another 2hrs at reflux temperature the reaction mass was cooled to 25°C and filtered off the solids. Benzene was removed by ordinary distillation from the filtrate. The residue was fractionally distilled to get 13gr of triethyl orthoformate of the formula-X VII where R’ = R* = Et and 46.7gr (70%) of 4-(N-benzyl- N-methylaminobutyraldehyde diethyl acetal, B. p.: 140-150°C/0.5mm. a10 20 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Example 7 Preparation of 4-(N-benzyl-N-methylamino)butyraldehyde diethylacetal of formula-I where R' = Me, R? = benzyl, R® = Et using cyclohexane as solvent: Preparation of the Grignard - reagent and 4(N-benzyl-N-methylamino)- butyraldehyde diethyl acetal of formula-I where R'= Me, R?= benzyl, and R°=Et Into a IL four-necked round bottom flask were added magnesium turnings (7.0gr), cyclohexan (25ml), cyclohexane solution (25ml) of —_N-(3-chloropropyl)-N- methylbenzylamine (prepared by dissolving S0gr of _N-(3-chloropropyl)-N- methylbenzylamine in 250ml of cyclohexane), triehtyl orthoformate (Sgr), and a small crystal of iodine under nitrogen atmosphere. After 15-20min of reflux, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the cyclohexane solution and triethyl orthoformate of formula-XVII where R® = R° = Et (S0gr) were separately taken into two pressure equalizing addition funnels and added slowly in 2-3hrs period at reflux temperature. After maintaining for another 2hrs at reflux temperature the reaction mass was cooled to 25°C and filtered off the solids. Cyclohexane was removed by ordinary distillation from the filtrate. The residue was fractionally distilled to get 1Sgr of triethyl orthoformate of the formula-XVII where R*= R° = Et and 45gr (67.5%) of 4-(N-benzyl-N-methylamino)butyraldehyde diethyl acetal.10 1s 20 28 ca 02487957 2004-11-30 Wo 03/101931 PCT/IN03/00016 Example 8 Preparation of 4-(N, N-dimethylamino)butyraldehyde diethyl acetal of formula-I where R! = R? = Me and R° = Et using benzene as solvent: Preparation of phenyl diethyl orthoformate of formula-III where R® = Et and RS = phenyl: Into a mixture of 44Sgr of triethyl orthoformate and 282gr of phenol was added 10 drops of ethanolic HCl. After stirring for 30min, ethanol formed in the reaction was distilled by connecting the system to a vigreux column (50cm) under vaccum (60-70 mm/Hg). Slowly the reaction mass was heated to 120-130°C and the product distilled. After washing the distillate with 10% NaOH and water dried over KxCOs and distilled under vaccum to get 370gr of phenyl diethyl orthoformate. Preparation of 3-(N, N-dimethylamino)propyl chloride solution in benzene: A solution of 3-(N, N-dimethylamino)propyl chloride (106gr) in benzene (500ml) was prepared as per the procedure given in Example 1 above, Preparation of the Grignard reagent and 4-(N, N-dimethylamino)butyraldehyde diethyl acetal of formula-I where R’ = R’ = Me and R® = Et Into a 2L three-necked round bottom flask was added magnesium turnings (25gr) under nitrogen atmosphere and SOm! of the above benzene solution added to the reaction flask. After adding a small crystal of iodine, reaction mass was heated to reflux temperature. After maintaining for 15 min, reaction got initiated and to the reaction mass remaining quantity of benzene solution was added slowly in 2-3hrs period. After the addition, reaction mass was maintained for Ihr and a solution of phenyl diethyl orthoformate (17 1gr) in benzene (200ml) was added slowly over a period of Ihr, After maintaining for 2hrs, reaction was cooled to 25°C and filtered on a celite pad. Solvent was removed from the reaction mass and the residue fractionally distilled to get 120gr (72.7%) of 4-(N, N- dimethylamino)butyraldehyde diethyl acetal. 1910 15 20 25 ca 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 Example 9 Preparation of 4-(N-piperidino)butyraldehyde diethyl acetal of formula- I where NR'R? = piperidino, R’ = Et using cyclohexane as solvent: Preparation of 1-(3-chloropropy!)piperidine: Into a IL three-necked RB flask were charged 100gr of piperidine, 120gr of triethyl amine, and 200ml of benzene and heated to 45°C. 1-Bromo-3-chloropropane (185gr) was slowly added to the reaction mixture between 45-50°C over a period of 2.Shrs, The reaction mixture was refluxed for 2hrs and cooled to 25°C. Solids formed in the reaction were filtered off and the filtrate distilled to give crude 1-(3-chloropropyl)piperidine. After high vaccum distillation 180gr of pure 1-(3-chloropropyl)piperidine, bp 120- 130°C/30mm Hg, Preparation of the Grignard reagent and 4-(N-piperidin)butyraldehyde diethyl acetal of formula-I where NR'R’ = piperidino and R° = Et Into a IL four-necked round bottom flask were added magnesium turnings (18gr), cyclohexane (5Oml), cyclohexane solution (SOml) of 1-(3-chloropropyl)piperidine (prepared by dissolving 100gr of 1-(3-chloropropyl)piperidine in 500ml of cyclohexane), triehtyl orthoformate (10gr), and a small crystal of iodine under nitrogen atmosphere. ‘After 15-20min of reflux, a vigorous reaction took place indicating the initiation of Grignard reaction. Remaining quantity of the cyclohexane solution and triethyl orthoformate of formula-XVII where R*= R° = Et (140gr) were separately taken into two pressure equalizing addition funnels and added slowly in 2-3hrs period at reflux temperature. After maintaining for another 2hrs at reflux temperature the reaction mass was cooled to 25°C and filtered off the solids. Cyclohexane was removed by ordinary distillation from the filtrate. The residue was fractionally distilled to get 35gr of triethyl 20cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 orthoformate of the formula-XVII where R? = R° = Et and 100gr (70%) of 4-(N- piperidino)butyraldehyde diethyl acetal, bp 120-130/I1mm Hg, The main advantages of the present invention are: i The process is very simple and economical. In general, all the required raw materials are commercially easily available. There is no step of high pressure hydrogenation due to which the process is safe. a10 20 28 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 We Claim: 1, An improved process for the preparation of compounds of formula-I R'R?NCH,CH2CH2CH(OR®)2 I Wherein, R! = R? = C)-Cie alkyl; C3-C7 cycloalkyl; R! = C1-Cie alkyl; R? = C3-Cy cycloalkyl; NR'R? = pyrrolidino, piperidino, morpholino, thiomorpholino, R' = Ci-Ce alkyl; R? = ArCHp; Ar = 4-R*-CeHs-, R* = MeO, EtO, Me, Et, NMez, NEtz, SMe, SEt, etc; R*= Cy-Ce alkyl; C3-C7 cycloalkyl which comprises: ) Gi) Reacting 3-(N, N-disubstitutedamino)propyl halide of formula-XXI, R'R?’NCH;CH2CH2X XXI wherein R', R? = as defined above, X = Cl or Br, with magnesium in the presence of a solvent to get the Gregnard reagent 3-(N, N-disubstitutedamino)- propylmagnesium halide Reacting the resulting 3-(N, N-disubstitutedamino)propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula-XVI, HC(OR*)(OR®), XVI wherein R° and R° is same or different and represent C; to Ce alkyl, C3 to C7 cycloalkyl, OR R? is as defined above and R* represents a phenyl radical using a Grignard reaction. Filtering off the resultant reaction mixture and distilling the filtrate to isolate the compound of the formula-I. 210 1s 20 25 cA 02487957 2004-11-30 wo 03/101931 PCT/IN03/00016 2. An improved process as claimed in claim 1 wherein the solvent used in step (i) is selected from non-polar hydrocarbon, aromatic solvent, ether solvent, etc. 3, An improved process as claimed in claims 1 & 2, wherein the non-polar hydrocarbon solvent used in step (i) is selected from hexane, cyclohexane, heptane, etc., preferably cyclohexane. 4, An improved process as claimed in claims 1 to 3 wherein the aromatic solvent used in step (i) may be benzene, toluene, xylene, etc., preferably benzene or toluene 5, An improved process as claimed in claims 1 to 4 wherein the ether solvent used in step (@ is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, preferably tetrahydrofuran or dioxane 6. An improved process as claimed in claims 1 to $ wherein the molar ratio between the Grignard reagent and the trisubstituted othoformate used is in the ratio of 1:1-3, preferably in the ratio of 1:1.2-1.5, 7. An improved process for the preparation of compounds of the formula-I as defined in claim 1 substantially as herein described with reference to the Examples. 2B