Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF-4-(N,N-DISUBSTITUTEDAMINO)BUTYRLDEHYDE ACETALS

Abstract ABSTRACT The invention disclosed in this application relates to an improved process for the preparation of compounds of formula-I i Reacting 3-(N, N-disubstitutedamino)propyl halide of formula-XXI, Wherein, R<SUP>1</SUP> R<SUP>2</SUP> = as defined above, X = C1 or Br, with magnesium in the presence of a solvent to get the Grrgnard reagent 3-(N, N-disubstitutedamino)-propylmagnesium halide (ii) Reacting the resulting 3-(N, N-disubstitutedamino)propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula-XVII, Wherein, R<sup>3</sup> and R<SUP>5</SUP> is same or different and represent C<sub>1</sub> to C<sub>6</sub> alkyl, C<sub>3</sub> to C<sub>7</sub> cycloalkyl or R<sup>3</sup> is as defined above and R<SUP>5</SUP> represents phenyl radical (iii) Filtering off the resultant reaction mixture and distilling the filtrate to isolate the compound of the formula-I. These substituted butyraldehyde derivatives of the formula-I are very important building blocks for the synthesis of various tryptamine derivatives. In particular 4-(N, N-dimethylamino)butyraldehyde dimethyl or diethyl acetals are crucial intermediates for the synthesis of commercially available anti-migraine drugs, like sumatriptan, zolmitriptan, and rizatriptan.
Full Text

The present invention relates to an improved process for the preparation of 4-(N, N-disubstitutedamino)butyraldehyde acetals. The 4-(N, N-disubstitutedamino) butyraldehyde acetals of the present invention have the formula-I given below

The above mentioned substituted butyraldehyde derivatives of the formula-I are very important building blocks for the synthesis of various tryptamine derivatives. In particular, 4-(N, N-dimethylamino)butyraldehyde dimethyl or diethyl acetals are crucial intermediates for the synthesis of commercially available anti-migraine drugs, like sumatriptan (USP 4,816,470), zolmitriptan (WO 91 18897), and rizatriptan (EP 497512).
BACKGROUND OF THE INVENTION
In one general synthesis for compounds of formula-I wherein R1 = R2 = C2 and above and R3 = C2, Keglevic (Croat. Chem. Acta, 35, 175, 1963) reported the synthesis of these compounds in two steps starting from propynal diethyl acetal (Scheme-I). Propynal diethyl acetal was subjected to Mannich reaction with a disubstitutedamine and formaldehyde to give the intermediate of formula-Ill. The acetylenic intermediate of the formula-Ill was subjected to complete reduction with Pd/C to get the saturated derivatives of formula-IV (R1 = R2 = C2 and above).


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

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).

Starting material used in this process (compound of formula-VI) is not commercially available and is prepared in three steps starting from acrolein (see Scheme-Ill). 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 HCl 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.

Some of the main disadvantages in this route are:
i. Starting from commercially available acrolein the overall yield is onlyl 8.5%.
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-Ill), v. Requires high pressure hydrogenation used in the third step (Scheme-Ill).
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).


4-Aminobutyraldehyde dimethyl acetal of formula-XI was methylated using 37% formalin under hydrogen pressure (114kg^/cm^) with 10% Pd/C to get the compound of 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).

In the second route main disadvantages are:
i Requires very high pressure (114 kg ^/ cm^) hydrogenation. ii Basic raw material (compound of formula-XI) required in the process is not commercially available and is prepared in three steps (Scheme-V).

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-Chlorobutyryl chloride was reduced under 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) 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.

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).
ii. Rosenmund reduction is involved in the first step (scheme-VI). 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.

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-l 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%).

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

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-XVlII (Scheme-VII).

It is also known from the literature (Org. Synth. Coll. Vol. VI, p776, 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).

Based on the above mentioned information we directed our attention towards reacting orthoformates of the formula-XVII,


wherein R^ and R^ is same or different and represent Ci to Ce alkyl, C3 to C? 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,

cycloalkyl; NR^R^ = pyrrolidine, piperidino, morpholino, thiomorpholino, R^ =


iii Filtering the resulting reaction mixture and distilling the filtrate to isolate compound of the formula-I.
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.

In a 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 1:1.2-1.5
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-dimethyIamino)butyraldehyde dimethyl acetal of the formula-I where R^ = R^ = R^ = Me using Benzene as solvent:
Preparation of 3-(N, N-diiiiethylamino)propyl chloride solution in benzene:
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 benzene was added to the reaction mixture and stirred for 15min. 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 heated under reflux with a Dean-Stark apparatus. After removing moisture completely, the benzene solution was cooled to 25°C and decanted the colorless supernatant liquid into a IL 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^ = Me
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr) under Na atmosphere. Benzene (50ml), the above benzene solution (50ml), 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 lOOgr (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-dimethylainino)propyl chloride solution in toluene:
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 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 IL 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^ = R2 = R3 = Me
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr), toluene (50ml), the above toluene solution (50ml), trimethyl orthoformate (20gr), and a small crystal of iodine under nitrogen 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 flannels 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 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 vacciim 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 Uquid. B. p.: 80-85°C / 15-20mm).
Example 3
Preparation of 4-(N, N-dimethyIamino)butyraldehyde dimethyl acetal of the formula-I where R^ == R^ = R^ = Me using THF as solvent:
Preparation of 3-(N, N-dimethylaniino)propyl chloride solution in THF:
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 sah 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%
w/w.
Preparation of the Grignard reagent and the compound of the formula-l wherein R1
= R2 = R3 = Me
Into a 2L four-necked round bottom flask were charged magnesium turnings (18gr), THF (50ml), the above THF solution (50gr), trimethyl orthoformate (lOgr), 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-XVII 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 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 R1 = R2 = Me and R3 = 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 1 (!) above.

Preparation of the Grignard reagent and the compound of the formula-l where R1 = R2=Meand R3=Et
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr) under nitrogen atmosphere. Benzene (50ml), the above benzene solution (50ml), triethyl 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 R3 = R5 = 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 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 R1 = R2 = Me and R3 = Et using cyclohexane as solvent:
Preparation of 3-(N, N-dimethylamino)propyI 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 15min. 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 IL round bottom flask. Ghemical assay of this cyclohexane solution (650ml) was 16.5% w/w.
Preparation of the Grignard reagent and the compound of the formula-l wherein R1 = R2 = Me, R3 = Et
Into a 2L four-necked round bottom flask was charged magnesium turnings (25gr), cyclohexane (50ml), the above cyclohexane solution (50ml), triethyl 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 cyclohexane solution (600ml) and triethyl orthoformate of the formula-XVII where R^ = R^ = Et (175gr) were taken into two separate addition fiinnels 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)propanoI: To a solution of 278gr of 3-bromopropanol in 400ml 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 lOOgr 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.
Preparation of 3-(N-benzyI-N-methylamino)propyI chloride:
To a solution of 150gr of 3-(N-benzyl-N-methylamino)propanol in 200ml of benzene was added drop wise with stirring under nitrogen a solution of 200gr of thionyl chloride in 100ml of benzene. The mixture was refluxed for 8hr 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-niethyIamino)-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 (25ml), benzene solution (25ml) of N-(3-chloropropyl)-N-methylbenzylamine (prepared by dissolving 50gr of N-(3-chloropropyl)-N-methylbenzylamine in 250ml of benzene), triehtyl orthoformate (5gr), 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 R3 = R5 = Et (50gr) 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-XVIII where R3 = R5 = Et and 46.7gr (70%) of 4-(N-benzyl-N-methylamino)butyraldehyde diethyl acetal. B. p.: 140-150°C/0.5mm.
Example 7
Preparation of 4-(N-benzyl-N-methylamino)butyraldehyde diethylacetal of formula-I where R1 = Me, R2 = benzyl, R3 = Et using cyclohexane as solvent:
Preparation of the Grignard reagent and 4-(N-benzyl-N-niethylaniino)-butyraldehyde diethyl acetal of formula-I where R1 = Me, R2 = benzyl, and R3 =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 50gr of N-(3-chloropropyl)-N-methylbenzylamine in 250ml of cyclohexane), triehtyl orthoformate (5gr), 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 (50gr) were separately taken into two pressure equalizing addition fiinnels and added slowly in 2-3 hrs 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 15gr of triethyl orthoformate of the formuIa-XVII where R3 = R5 = Et and 45gr (67.5%) of 4-(N-benzyl-N-methylamino)butyraldehyde diethyl acetal.
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-in where R^ = Et and R* = phenyl:
Into a mixture of 445gr 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 K2CO3 and distilled under vaccum to get 370gr of phenyl diethyl orthoformate.
Preparation of 3-(N, N-diinethyIamino)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 50ml 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 (171gr) 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.
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 l-(3-chloropropyI)piperidine:
Into a IL three-necked RB flask were charged lOOgr of piperidine, 120gr of triethyl amine, and 200ml of benzene and heated to 45°C. l-Bromo-3-chloropropane (185gr) was slowly added to the reaction mixture between 45-50°C over a period of 2.5hrs. 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 l-(3-chloropropyl)piperidine. After high vaccum distillation 180gr of pure l-(3-chloropropyl)piperidine, bp 120-130°C/30mmHg.
Preparation of the Grignard reagent and 4-(N-piperidin)butyraIdehyde 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 (50ml), cyclohexane solution (50ml) of l-(3-chloropropyl)piperidine (prepared by dissolving lOOgr of l-(3-chloropropyl)piperidine in 500ml of cyclohexane), triehtyl orthoformate (lOgr), 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 fiinnels 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 orthoformate of the formula-XVII where R3 = R5 = Et and lOOgr (70%) of 4-(N-piperidino)butyraldehyde diethyl acetal, bp 120-130/1mm Hg.
The main advantages of the present invention are:
i. The process is very simple and economical.
ii. In general, all the required raw materials are commercially easily available.
iii There is no step of high pressure hydrogenation due to which the process is safe.


We Claim:
1. An improved process for the preparation of compounds of formula-I

i Reacting 3-(N,N-disubstitutedamino)propylhalide of formula-XXI,

presence of a solvent to get the Gregnard reagent 3-(N, N-disubstitutedamino)-propylmagnesium halide
(ii) Reacting the resulting 3-(N, N-disubstitutedamino)propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula-XVII,

cycloalkyl, OR R3 is as defined above and R5 represents a phenyl radical using a Grignard reaction.
(iii) Filtering off the resultant reaction mixture and distilling the filtrate to isolate the compound of the formula-I.

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 (i) is selected from diethyl ether, isopropyl ether, methyl tert-butyl ether, dioxane, tetrahydrofiiran, preferably tetrahydrofuran or dioxane.
6. An improved process as claimed in claims 1 to 5 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.


Documents:

411-mas-2002 abstract duplicate.pdf

411-mas-2002 abstract.pdf

411-mas-2002 claims duplicate.pdf

411-mas-2002 claims.pdf

411-mas-2002 correspondence others.pdf

411-mas-2002 correspondence po.pdf

411-mas-2002 description (complete) duplicate.pdf

411-mas-2002 description (complete).pdf

411-mas-2002 form-1.pdf

411-mas-2002 form-19.pdf

411-mas-2002 form-3.pdf

411-mas-2002 petition.pdf


Patent Number 198034
Indian Patent Application Number 411/MAS/2002
PG Journal Number 08/2007
Publication Date 23-Feb-2007
Grant Date 23-Jan-2006
Date of Filing 31-May-2002
Name of Patentee M/S. NATCO PHARMA LTD
Applicant Address NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033
Inventors:
# Inventor's Name Inventor's Address
1 PULLA REDDY MUDDASANI NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033
2 VENKAIAH CHOWDARY NANNAPANENI NATCO PHARMA LTD, NATCO HOUSE, ROAD NO.2, BANJARA HILLS, HYDERABAD 500 033
PCT International Classification Number A61K31/13
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA