Process for large scale production of N-[4-(1-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride

A process for production of N-[4-(1-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (I), comprising:

• Step (i):
• reacting 4-hydroxy piperidine of formula (1) with cyclobutanone of formula (2)
• in presence of sodium triacetoxy borohydride in ethylene dichloride at a temperature in the range of 20° C. to 30° C. for a period of 12 hours to 14 hours to obtain 1-cyclobutylpiperidin-4-ol of formula (3);
• Step (ii):
• reacting 1-cyclobutylpiperidin-4-ol of formula (3) with 4-fluoro-1-nitrobenzene of formula (4)
• in tetrahydrofuran and sodium hydride at a temperature in the range of 30° C. to 45° C. for a period of 5 hours to 6 hours to obtain 4-(1-cyclobutylpiperidin-4-yloxy)-1-nitrobenzene of formula (5) and purifying the compound of formula (5) using 10% aqueous acetic acid solution at 25° C. to 30° C.;
• Step (iii):
• reducing 4-(1-cyclobutylpiperidin-4-yloxy)-1-nitrobenzene of formula (5) by using ammonium chloride and iron powder in water and ethyl alcohol at a temperature in the range of 70° C. to 85° C. for a period of 3 hours to 5 hours to obtain 4-(1-cyclobutylpiperidin-4-yloxy) aniline of formula (6);
• Step (iv):
• reacting 4-(1-cyclobutylpiperidin-4-yloxy) aniline of formula (6) with chloroacetylchloride of formula (7)
• in tetrahydrofuran and potassium carbonate at a temperature in the range of −10° C. to 0° C. for a period of 4.5 hours to 5.5 hours to obtain 2-chloro-N-[4-(1-cyclobutyl piperidin-4-yloxy) phenyl] acetamide of formula (8) and recrystallizing the compound of formula (8) using isopropanol and methanol under reflux for a period of 0.5 to 1 hour;
• Step (v):
• reacting 2-chloro-N-[4-(1-cyclobutyl piperidin-4-yloxy)phenyl]acetamide of formula (8) with morpholine of formula (9)
• in acetonitrile and potassium carbonate at a temperature in the range of 75° C. to 85° C. for a period of 20 hours to 30 hours to obtain N-[4-(1-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10);
• Step (vi):
• reacting N-[4-(1-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide of formula (10) in presence of isopropanolic hydrochloride and isopropanol
• at a temperature in the range of 20° C. to 30° C. for a period of 7 hours to 8.5 hours to obtain N-[4-(1-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11);
• Step (vii):
• recrystallization of N-[4-(1-Cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (11)
• in presence of isopropanol and methanol at a temperature in the range of 58° C. to 63° C. for a period of 4 hours to 5 hours to obtain N-[4-(1-cyclobutyl piperidin-4-yloxy) phenyl]-2-(morpholin-4-yl) acetamide dihydrochloride of formula (I).