Title of Invention

A NOVEL PROCESS FOR PREPARING PROTRIPTYLINE HYDROCHLORIDE

Abstract

ABSTRACT A process for preparing protriptyline hydrochloride comprising the steps of. subjecting N-Carbethoxy Amitriptyline to the step of hydrogenation in pressure of alcohol and palladium carbon; the solution is filtered and concentrated to obtain a derivative reacting the said derivative with dibutyl male ate in presence for palladium carbon under nitrogen atmosphere; subjecting the reaction mixture to the step of cooling and Alteration to recover palladium carbon and a crude mixture of dibutyl maleate, dibutyl succinate and protriptyline carbamate; subjecting the crude mixture to the step of Hydrolysis in potassium presence of hydroxide and N-nutyl alcohol; extracting the product with a the help of solvent in presence of water; washing the said product with water and distilled to obtain protriptyline base; subjecting the protriptyline base thus obtained to the step of dissolved in a solvent; treating the said solution with hydrochloric acid to obtain protriptyline hydrochloride.

Full Text

This Invention relates to a novel process for preparing protriptyline hydrochloride and cyclobenzaprine hydrochloride. BACKGROUND OF THE INVENTION. Protriptyline Hydrochloride and Cyclobenzaprine hydrochloride are well-known tricyclic amines having anti-depressant and Muscle relaxant pharmaceutical activity respectively. They have been synthesized from the conventional route. Protriptyline hydrochloride has been synthesized from Dibenzosuberone by three different procedures and all of them follow a similar reaction pattern. For Protriptyline: US Patent Nos: 3,309,404 (1967), 3,965,181 (1976), 3,271,451 (1966), 5,932,767 (1999), UK Patent GB 2,320926 (1998). The latest patent by Merck and Co uses dibenzosuberene as the starting material. Which is reacted with butyllithium to get the lithio salt and then treating this intermediate with bromo chloro propane to get 5-substituted dibenzocycloneptene. Which is reacted with manomethylamine under pressure to get Protriptyline base and which is finally converted to Protriptyline hydrochloride. The schematic representation is given below:- Still another object of this invention is to propose a commercially viable process for the manufacture of protriptyline hydrochloride and cyclobenzaprine hydrochloride. Further object of this invention is to propose a simple process for preparing protriptyline and cyclobenzaprine hydrochloride. Still further object of this invention is to propose a novel process for preparing protriptyline and cyclobenzaprine hydrochloride which give a better yield and quality. BRIEF DESCRIPTION OF THE INVENTION: According to this Invention there is provided a process for preparing protriptyline hydrochloride comprising the steps of: Subjecting N-Carbethoxy Amitriptyline to the step of hydrogenation in presence of alcohol and palladium carbon; The solution is filtered and concentrated to obtain a derivative reacting the said derivative with dibutyl maleate in process for palladium carbon under nitrogen atmosphere at 200-240°C; Subjecting the reaction mixture to the step of cooling and Alteration to recover palladium carbon and a crude mixture of dibutyl maleate, dibutyl succinate and protriptyline carbamate; Subjecting the crude mixture to the step of hydrolysis in presence of potassium hydroxide and N-nutyl alcohol; Extracting the product with the help of solvent in presence of water; Washing the said product with water and distilled to obtain protriptyline base; Subjecting the protriptyline base thus obtained to the step of dissolved in a solvent; Treating the said solution with hydrochloric acid to obtain protriptyline hydrochloride. In accordance to this invention there is also provided a process for preparing cyclobenzaprine hydrochloride comprising reacting Amltriptyline base with dibutyl maleate in presence of palladium carbon at 200-240°C; Subjecting the resultant reaction mixture to the step of cooling and filtering acidifying the reaction mixture with hydrochloric acid; subjecting the acidified mixture to the step of extraction using a solvent basclfying the water layer thus obtained using sodium hydroxide and extraction with a solvent; washing the solvent layer with water removing the solvent under pressure to obtain cyclobenzaprine base converting the said cyclobenzaprine base to cyclobenzaprine hydrochloride. DETAILED DESCRIPTION OF THE INVENTION: In this novel invention, both Protriptyline Hydrochloride and Cyclobenzaprine hydrochloride were synthesized from a novel new method by transfer hydrogenation method mediated by palladium carbon as the catalyst. We have used dialkyl Maleate as hydrogen acceptor. Procedure for the synthesis of Protriptyline Hydrochloride: N-Carbethoxy-Amitriptyline 1 (1 kg- prepared by refluxing amltriptyline with ethyl chioroformate as per the literature procedure) is hydrogenated in methanol (5 Lt) and 10% palladium carbon (30 g) at 5-6 kg of hydrogen pressure for 5-6 h. The methanol solution is filtered and concentrated to get saturated derivative 2 (1-1.05 kg). Which was then reacted with dibutylmaleate 3 (1.5-2 kg or dimethyl Maleate) with 4-7% of palladium (40-70 g, 10% Pd) carbon at 200-240°C for 3-8h under nitrogen atmosphere. The reaction mixture was cooled and filtered to recover Pd-C to get a mixture dibutyl Maleate 3 + dibutyl succinate 4 and Protriptyline carbamate 5 (2.5-3 kg). This crude mixture is hydroryzed with potassium hydroxide (2-6 kg) in N-nutyl alcohol (7.5 Lt) for 2-4 h at 100-130°C. EXAMPLE 1: Procedure for the synthesis of Protriptyline Hydrochloride: N-Carbethoxy-Amitriptyllne 1 (1 kg- prepared by refiuxlng amIIriptyline with ethyl chloroformate as per the literature procedure) is hydrogenated hi methanol (5 Lt) and 10% palladium carbon (30 g) at S kg of hydrogen pressure for S h. The methanol solution is filtered and concentrated to get saturated derivative 2 (1.05 kg). Which was then reacted with dibutylmaleate 3 (2 kg or aim ethyl Maleate) with 4-7% of palladium (40 g, 10% Pd) carbon at 200°C for 8h under nitrogen atmosphere. The reaction mixture was cooled and filtered to recover Pd-C to get a mixture dibutyl Maleate 3 + dibutyl succinate 4 and Protriptyline carbamate S (2.5 kg). This crude mixture is hydroryzed with potassium hydroxide (2 kg) in N-nutyl alcohol (7.5 Lt) for 2 h at 100°C. Cooled and added to water and extracted with toluene (2 Lt). Washed 3 times with water (3x2 Lt) and distilled to get Protriptyline base 6 (0.75 kg, 96%) as the only product. The Protriptyline base thus obtained is dissolved in toluene (3 Lt) and treated with hydrochloric acid to get Protriptyline hydrochloride 7 (650 g) as the only product having melting point 168-170°C with an assay of 99-100%. EXAMPLE 2: Procedure for the synthesis of Cyclobenzaprine Hydrochloride: Amitriptyline base 8 is reacted (1 kg, prepared by bascifylng amltrlptyllne hydrochloride) reacted with dibutyl Maleate 5 (1 kg, dialkyl Maleate) in the presence of 3-7% (30 g) of palladium carbon under nitrogen at 200°C for 3 h. The resultant reaction mixture is cooled and filtered (If required in the presence of some solvents like diehloromethane). The whole reaction mixture was acidified to pH-2 with dilute hydrochloric acid and extracted with toluene 3 times (3 Lt x 3). The water layer thus obtained was bascified to pH-10 with 20% sodium hydroxide solution and extracted with toluene (4 Lt). The toluene layer was washed with water and the toluene was removed under reduced pressure. The residue thus obtained contains and cyciobenzaprine base (950-970 g, 98%). Which is then converted to hydrochloride salt from the regular procedure to get 0.8-1 kg of Cyciobenzaprine hydrochloride 9 as white solid. Mp 217-220°C. Assay 99-101%. WE CLAIM 1. A process for preparing protriptyline hydrochloride comprising the steps of: subjecting N-Carbethoxy Amttriptyline to the step of hydrogenation in pressure of alcohol and palladium carbon; the solution is filtered and concentrated to obtain a derivative reacting the said derivative with dibutyl maleate in presence for palladium carbon under nitrogen atmosphere; subjecting the reaction mixture to the step of cooling and Alteration to recover palladium carbon and a crude mixture of dibutyl maleate, dibutyl succinate and protriptyline carbamate; subjecting the crude mixture to the step of Hydrolysis in presence of potassium hydroxide and N-nutyl alcohol; extracting the product with a the help of solvent in presence of water; washing the said product with water and distilled to obtain protriptyline base; subjecting the protriptyline base thus obtained to the step of dissolved in a solvent; treating the said solution with hydrochloric acid to obtain protriptyline hydrochloride. 2. The process as claimed in claim 1, wherein said alcohol is methanol. 3. The process as claimed in claim 1, wherein said solvent is toluene. 4. The process as claimed in claim 1, wherein the crude mixture is hydrogenated for 2 to 4 kg at 100-130°C. 5. The process as claimed in claim 1, wherein derivative is reacted with dibutylmaleate at 200 to 240°C for 3 to 8 h under nitrogen atmosphere. 6. The process as claimed in claim 1, wherein the said protriptyline hydrochloride has a melting point 168 to 170°C with an assay of 99-100%. 7. The process as claimed in claim 1, wherein said N-carbethoxy-Amitriptyline is prepared by refluxtng amttriptyline base with ethyl chloroform ate. 8. A process for preparing cyclobenzaprine hydrochloride comprising reacting Amitriptyline base with dibutyl maleate in pressure of palladium carbon; subjecting the resultant reaction mixture to the step of cooling and filtering acidifying the reaction mixture with hydrochloric acid; subjecting the acidified mixture to the step of extraction using a solvent bascifying the water layer thus obtained using sodium hydroxide and extraction with a solvent; washing the solvent layer with water removing the solvent under pressure to obtain cyclobenzaprine base converting the said cyclobenzaprine base to cyclobenzaprine hydrochloride. 9. The process as claimed in claim 8, wherein the solvent used in toluene. 10. The process as claimed in claim 8, wherein said Amitriptyline base is prepared by bascifying amitriptyline hydrochloride.

Documents:

387-CHE-2005 CORRESPONDENCE OTHERS 24-01-2012.pdf

387-CHE-2005 FORM-1 24-01-2012.pdf

387-CHE-2005 FORM-13 24-01-2012.pdf

387-CHE-2005 AMENDED CLAIMS 21-02-2014.pdf

387-CHE-2005 AMENDED CLAIMS 05-12-2014.pdf

387-CHE-2005 AMENDED PAGES OF SPECIFICATION 21-02-2014.pdf

387-CHE-2005 AMENDED PAGES OF SPECIFICATION 05-12-2014.pdf

387-CHE-2005 CORRESPONDENCE OTHERS 05-12-2014.pdf

387-CHE-2005 CORRESPONDENCE OTHERS 13-08-2014.pdf

387-CHE-2005 CORRESPONDENCE OTHERS. 27-11-2014.pdf

387-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 21-02-2014.pdf

387-CHE-2005 FORM-1 21-02-2014.pdf

387-CHE-2005 FORM-13 05-12-2014.pdf

387-CHE-2005 FORM-3 21-02-2014.pdf

387-CHE-2005 POWER OF ATTORNEY 21-02-2014.pdf

387-CHE-2005 POWER OF ATTORNEY 24-01-2012.pdf

387-CHE-2005 POWER OF ATTORNEY 12-10-2009.pdf

387-che-2005-abstract.pdf

387-che-2005-claims.pdf

387-che-2005-correspondnece-others.pdf

387-che-2005-description(complete).pdf

387-che-2005-form 1.pdf

387-che-2005-form 3.pdf

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