Title of Invention | NOVEL PROCESS FOR PREPARING OPIPRAMOL DIHYDROCHLORIDE |
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Abstract | ABSTRACT A novel process for preparing opipramol dihydrochloride comprising dissolving potassium salt in water adding iminostilbine to the salt solution in a ratio of 1:5 w/w with respect to water followed by bromo chtoro prepare in a ratio of 1:2 w/w with respect \o iminostilbine followed by 2 to 15% PTC to form a reaction mixture; refluxing the said reaction mixture for 24 to 30 hrs. cooling the reaction mixture to separate the heavy organic layer removing the excess water by decantation and excess CBP under pressure to obtain the residue subjecting the residue to the step of heating with piperazino ethanol at 100 to 120°C for to obtain Opipramol base; purifying the opipramol base; subjecting the purified opipramol base to the step of crystallization; treating the crystals with acetone IPA HCI medium to obtaining opipramol dihydrochloride. |
Full Text | This invention relates to a novel process for preparing oplpramol ^hydrochloride. BACKGROUND OF THE INVENTION. Oplpramol dihydrochloride Is known to have interesting anti-depressant pharmacological activity. It has been synthesized from the conventional procedures. For Opipramol di-hydro chloride: US Patent nos: 5,599,929 (Toro Pharmaceuticals), European Patent: 1,468,992 A1 (2004) Both the patents use Iminostilbine as starting material. In the US Patent, weak bases like ammonium phosphate is used as bases in the presence of large amount of bromo-chloro propane in refluxing toluene as medium. The reaction scheme is given below- The latest patent by Farchemla, describes N-alkylatlon mediated by potassium carbonate in the presence of phase transfer catalyst like PEG in the presence of smalt amount of water. Which also requires large amount of bromochloro propane as one of the react ant. OBJECTS OF THE INVENTION. An object of this invention is to propose a novel process for preparing opipramol ^hydrochloride. Another object of this invention is to propose a process for preparing opipramol dihydrochlorlde which is environmentally friendly. Further object of this invention is to propose a process for preparing opipramol dihydrocrtloride which is commercially viable. Still further object of this invention is to propose a process which gives a better yield of opipramol hydrochloride. BRIEF DESCRIPTION OF THE INVENTION: According to this invention there is provided a process for preparing oplpramol dinydrochloride comprising dissolving potassium salt in water; adding iminostilbine to the salt solution in a ratio of 1:5 w/w with respect to water followed by bromo chloro prepare in a ratio of 1:2 w/w with respect to iminostilbine followed by trfphenyl methl phosphonium bromide to form a reaction mixture; 2 to 15% PTC refluxing the said reaction mixture for 24 to 30 hrs. cooling the reaction mixture to separate the heavy organic layer removing the excess water by decantafion and excess CBP under pressure to obtain the residue subjecting the residue to the step of heating with piperazino ethanol at 100 to 120°C for to obtain Opipramol base; purifying the opipramol base; subjecting the purified opipramol base to the step of crystallization; treating the crystals with acetone IPA HCI medium to obtaining opipramol dinydrochloride. DETAILED DESCRIPTION OF THE INVENTION: The main highlight of this invention is the use of water as solvent which in turn reduces the amount of solvent used In the reaction. Potassium carbonate (1.2 eq, or KOH-1 eq) dissolved in water. Charge Iminostilbine (193 g) followed by bromo chloro propane (230 g) followed by triphenyl methyl phosphonium bromide 1*2% (any other PTC 1-10%) and reflux for 24-30 h. Cool the reaction mixture and separate the heavy organic layer. Remove any excess water by separation/decantation. Excess CBP was removed under reduced pressure and the residue was heated with piperazino ethanoi at 100-120°C for 8-16 h in the absence of solvent to get Opipramol base. Which was purified by acidification and removing any non-polar Impurity by extraction with toluene. The water layer was bascified with sodium carbonate and cooled to 10 degree to get crystals of Opipramol base (310 g, 84.9 %) which was converted to hydrochloride in acetone-lPA HCI medium to get Opipramol dihydrochlorlde as the only product. EXAMPLE: Synthesis of N-3-chloro propyl Iminostilbine: Potassium carbonate (1.2 eq, or KOH-1eq) dissolved in water. Charge Iminostilbine (193 g) followed by bromo chloro propane (230 g) followed by triphenyl methyl phosphonium bromide 1-2% (any other PTC 1-10%) and reflux for 26 h. Cool the reaction mixture and separate the heavy organic layer. Remove any excess water by separation/decantation. Excess CBP was removed under reduced pressure and the residue was heated with piperazino ethanol at 120°C for 10 h in the absence of solvent to get Opipramol base. Which was purified by acidification and removing any non-polar impurity by extraction with toluene. The water layer was bascifled with sodium carbonate and cooled to 10 degree to get crystals of Opipramol base (310 g, 84.9 %) which was converted to hydrochloride in acetone-lPA HCI medium to get Opipramol dihydrochioride as the only product. WE CLAIM 1. A novel process for preparing opipramol dihydrochloride comprising dissolving potassium salt in water adding Imlnostllblne to the salt solution in a ratio of 1:5 w/w with respect to water followed by bromo chloro prepare in a ratio of 1:2 w/w with respect to iminostilbine followed by 2 to 15% PTC to form a reaction mixture; refiuxing the said reaction mixture for 24 to 30 hrs. cooling the reaction mixture to separate the heavy organic layer removing the excess water by decantation and excess CBP under pressure to obtain the residue subjecting the residue to the step of heating with piperazlno ethanol at 100 to 120°C for to obtain Opipramol base; purifying the opipramol base; subjecting the purified opipramol base to the step of crystallization; treating the crystals with acetone IPA HCI medium to obtaining opipramol dihydrochloride. 2. The process as claimed in claim 1, wherein said potassium salt is selected from potassium carbonate and Potassium hydroxide. 3. The process as claimed in claim 1, wherein said PTC is tetrabutyl phosphonium salt, aliquot 336 preferably, triphenyl methyl phosphonium bromide. 4. The process as claimed in claim 1, wherein the residue is heated at 100- 120°C for 8 to 16 hours in the absence of solvent. 5. The process as claimed in claim 1, wherein the crystals of opipramol base is obtained by bascifying the water layer with said carbonate and then cooling the water layer to 10°C. |
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388-CHE-2005 AMENDED CLAIMS 14-02-2014.pdf
388-CHE-2005 AMENDED PAGES OF SPECIFICATION 14-02-2014.pdf
388-CHE-2005 CORRESPONDENCE OTHERS 15-09-2014.pdf
388-CHE-2005 CORRESPONDENCE OTHERS 24-01-2012.pdf
388-CHE-2005 FORM-1 24-01-2012.pdf
388-CHE-2005 FORM-13 24-01-2012.pdf
388-CHE-2005 FORM-3 14-02-2014.pdf
388-CHE-2005 POWER OF ATTORNEY 14-02-2014.pdf
388-CHE-2005 POWER OF ATTORNEY 24-01-2012.pdf
388-CHE-2005 AMENDED CLAIMS 05-12-2014.pdf
388-CHE-2005 AMENDED PAGES OF SPECIFICATION 05-12-2014.pdf
388-CHE-2005 CORRESPONDENCE OTHERS 05-12-2014.pdf
388-CHE-2005 CORRESPONDENCE OTHERS. 27-11-2014.pdf
388-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 14-02-2014.pdf
388-CHE-2005 FORM-1 14-02-2014.pdf
388-CHE-2005 FORM-13 11-09-2014.pdf
388-CHE-2005 POWER OF ATTORNEY 12-10-2009.pdf
388-che-2005-correspondnece-others.pdf
388-che-2005-description(complete).pdf
Complete document with amendments.pdf
Complete document with marked amendments.pdf
Covering Letter to examination report.pdf
Patent Number | 264235 | |||||||||
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Indian Patent Application Number | 388/CHE/2005 | |||||||||
PG Journal Number | 51/2014 | |||||||||
Publication Date | 19-Dec-2014 | |||||||||
Grant Date | 16-Dec-2014 | |||||||||
Date of Filing | 07-Apr-2005 | |||||||||
Name of Patentee | R.L. FINE CHEM | |||||||||
Applicant Address | NO.15 KHB INDUSTRIAL AREA, YELAHANKA NEW TOWN, BANGALORE - 560 064, INDIA | |||||||||
Inventors:
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PCT International Classification Number | C07D223/00 | |||||||||
PCT International Application Number | N/A | |||||||||
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PCT Conventions:
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