Title of Invention

AN IMPROVED MANUFACTURING PROCESS FOR METHYL PHENIDATE AND INTERMEDIATES THEREOF

Abstract

An improved manufacturing process for preparation of a compound corresponding to the general Formula II, n n Formula II Formula I where R denotes CONR1R2, COOCH3, COOH; X denotes hydrogen, CI, Br, OMe, NH2; R1R2 are independently Hydrogen or C1-C3 alkyl groups, characterized by selective reduction of a compound of Formula I, where R, R1 R2, and X have the same meanings as defined above, using a palladium catalyst in presence of molar equivalent amount of organic acid or/and inorganic acid in suitable alcoholic solvent.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION [See section 10; Rule 13] "An improved manufacturing process for Methylphenidate and intermediates thereof (a) IPCA LABORATORIES LIMITED (b) 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India (c) Indian Company incorporated under the Companies Act 1956 The following specification particularly describes the nature of this invention and the manner in which it is to be performed: FIELD OF INVENTION The present invention relates to selective reduction of pyridine ring in a biaryl system comprising a- substituted or non-substituted benzene ring. This invention further relates more specifically, not exclusively, to the manufacture of methylphenidate. BACKGROUND OF THE INVENTION Formula I Formula II Biaryl compound of Formula I (wherein R=CONR1R2, COOCH3, COOH; X=H, CI, Br, OMe, NH2; R1R2- H or C1-C3 alkyl groups), specifically substituted oc-phenyl- α -pyridyl-2-acetic acid and its derivatives such as amide, ester are the key intermediates, in the preparation of pharmaceutical drug methylphenidate (Formula II, wherein R= COOCH3; X = H) and its acid addition salts. Methylphenidate is used for the treatment of Attention Deficit Hyperactive Disorder (ADHD). Methylphenidate is also used as central nervous system stimulant. 2) Another objective of the present invention is to provide a process wherein problems associated with the impurity generation and isolation of the compound of formula II are reduced or completely minimized. 3) Yet another objective of the present invention is to provide a simple, economical and plant friendly process for the manufacture of α-phenyl - α-pipyridyl -2-acetic acid and their derivatives thereof. 4) Further object of the present invention is to provide a process specifically for the manufacture of the pharmaceutical compound, methylphenidate, in high yield and purity on an industrial scale. SUMMARY OF THE PRESENT INVENTION The present invention discloses the selective and complete reduction of pyridine ring in a compound of formula I with the use of a moderately active catalyst viz. Palladium on carbon in a solvent such a C1-C4 alcohols in the presence of molar quantities of organic and/or inorganic acid. In another aspect, the invention provides a specific process for preparation of methylphenidate by the selective reduction of pyridine ring of compound of Formula I wherein R= COOCH3, COOH, CONR1R2; X= H; R1R2= H or C1-C3 alkyl groups and the conversion into methyl ester by methods known in the art. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to substituted α-phenyl-α-pyridyl derivatives of Formula II wherein R and X has the following meanings. R denotes CONR1R2, COOCH3, COOH; and X= H, CI, Br, OMe, NH2 wherein, R1R2 are independently hydrogen, C1-C3 alkyl groups include all isomeric forms. The invention further involves the manufacture of methylphenidate of the Formula II wherein R= COOCH3; X= H by the reduction of a compound of Formula I wherein R=CONR1R2, COOCH3, COOH; X= H where R1R2 are as defined above, which are important intermediates for the production of methylphenidate. In accordance with the above basic objective of the present invention, suitable procedure is that oc-phenyl-oc-pyridyl derivative of Formula 1 which is suspended in C1 -C4 straight or branched chain alcoholic solvents in the presence of equimolar amounts of organic and/or inorganic acids. Representative example of solvents used are methanol, ethanol, isopropanol etc. and the molar quantities of acids used to protonate the pyridine ring are sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, phosphoric acid or in combination thereof. Although the selection of a particular acid is not critical to the success of the invention, acetic acid and perchloric acid are preferred. In a typical procedure, Palladium on carbon is added to the suspended reaction mass and the reaction proceeds at a temperature from room temperature to 70 °C under hydrogen pressure of 5 kg/cm to 15 kg/cm and completes in 15 to 30 hrs. The palladium on carbon of various capacity used in the present invention are 5% to 10%, although not critical but for economic reasons 5% palladium is preferred. The duration of completion of reaction depends on the parameters such as temperature, hydrogenation pressure etc. known to those skilled in the art. The reaction is advantageously carried out in methanol. After completion of the reaction the catalyst was removed by filtration and the filtrate was advantageously concentrated for recovery of solvent and the obtained residue, contains catalytic amount of acid used in the reaction, was diluted with water, basified with alkali solution to isolate the product of Formula II (wherein R=CONR1R2, COOCH3, COOH; X=H, CI, Br, OMe, NH2; R1R2= H or C1-C3 alkyl groups). The catalyst used in the hydrogenation reaction of oc-phenyl - α - pyridyl - 2 - acetic acid and their derivatives of Formula I are, more specifically, 5 % Palladium on carbon (50% wet). Catalyst quantity varies from 10 to 15 gm per 100 gm of the starting oc-phenyl-oc-pyridyl -2- acetic acid derivative. The suitable volume of solvent for carrying out the We claim 1. An improved manufacturing process for preparation of a compound corresponding to the general Formula II, n n Formula II Formula I where R denotes CONR1R2, COOCH3, COOH; X denotes hydrogen, CI, Br, OMe, NH2; R1R2 are independently Hydrogen or C1-C3 alkyl groups, characterized by selective reduction of a compound of Formula I, where R, R1 R2, and X have the same meanings as defined above, using a palladium catalyst in presence of molar equivalent amount of organic acid or/and inorganic acid in suitable alcoholic solvent. 2. The process as claimed in claim 1 wherein, the said reaction is carried out in C1-C4 alcoholic solvents in all isomeric forms. 3. The process as claimed in claims 1 and 2 wherein, the said alcohols used are methanol, ethanol, propanol and isopropanol. 4. The process as claimed in claim 1 wherein, the said organic and/or inorganic acids includes sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, phosphoric acid or in combination thereof. 5. The process as claimed in claim 1 wherein, the said palladium catalyst used is 5% to 10% palladium adsorbed on carbon. 6. The process as claimed in claim 1 or 5 wherein, the said palladium catalyst is more preferably 5% palladium adsorbed on carbon. 7. The process as claimed in claim 1 wherein, the reaction is carried out at a temperature of 35°C to 70 °C and a hydrogenation pressure of 5 kg/cm2 to 15 kg/cm2. 8. An improved manufacturing process specifically for methylphenidate comprising selective reduction of a compound of Formula I wherein R = CONR1R2, COOCH3, COOH; X= H, and R1R2 are independently Hydrogen or C1-C3 alkyl groups using palladium catalyst in presence of molar equivalent amount of organic and/or inorganic acid in a suitable solvent resulting into a compound of Formula II, wherein R, R1, R2, X and converting the same to methylphenidate. 9. The process as claimed in claim 8 wherein, the said reaction is carried out in C1-C4 alcoholic solvents in all isomeric forms. 10. The process as claimed in claim 8 wherein, the said alcohols are selected from methanol, ethanol, propanol and isopropanol. 11. The process as claimed in claim 8 wherein, the said organic or inorganic acids include sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, and phosphoric acid or in combination thereof. 12. The process as claimed in claim 8 wherein, the said palladium catalyst used is 5% to 10% palladium adsorbed on carbon. 13. The process as claimed in claims 8 or 12 wherein, the said palladium catalyst is more preferably 5% palladium adsorbed on carbon. 14. The process as claimed in claim 8 wherein the reaction is carried out at a temperature of 35°C to 70 °C and a hydrogenation pressure of 5 kg/cm2 to 15 kg/cm2. 15. An improved manufacturing process for preparation of methylphenidate and its intermediates as substantially described herein with reference to the foregoing examples 1 to 2. Dated this the 11th day of June 2004 v - - Dr. Gopakumar G. Nair Agent for the Applicant FIELD OF INVENTION The present invention relates to selective reduction of pyridine ring in a biaryl system comprising a- substituted or non-substituted benzene ring. This invention further relates more specifically, not exclusively, to the manufacture of methylphenidate. BACKGROUND OF THE INVENTION Biaryl compound of Formula I (wherein R=CONR1R2, COOCH3, COOH; X=H, CI, Br, OMe, NH2; R1R2= H or C1-C3 alkyl groups), specifically substituted α-phenyl-cc-pyridyl-2-acetic acid and its derivatives such as amide, ester are the key intermediates, in the preparation of pharmaceutical drug methylphenidate (Formula II, wherein R= COOCH3; X = H) and its acid addition salts. Methylphenidate is used for the treatment of Attention Deficit Hyperactive Disorder (ADHD). Methylphenidate is also used as central nervous system stimulant. H I I I Formula I Formula II Another objective of the present invention is to provide a process wherein problems associated with the impurity generation and isolation of the compound of formula II are reduced or completely minimized. 3) Yet another objective of the present invention is to provide a simple, economical and plant friendly process for the manufacture of α-phenyl - α-pipyridyl -2-acetic acid and their derivatives thereof. 4) Further object of the present invention is to provide a process specifically for the manufacture of the pharmaceutical compound, methylphenidate, in high yield and purity on an industrial scale. SUMMARY OF THE PRESENT INVENTION The present invention discloses the selective and complete reduction of pyridine ring in a compound of formula I with the use of a moderately active catalyst viz. Palladium on carbon in a solvent such a C1-C4 alcohols in the presence of molar quantities of organic and/or inorganic acid. In another aspect, the invention provides a specific process for preparation of methylphenidate by the selective reduction of pyridine ring of compound of Formula I, wherein R= COOCH3, COOH, CONR1R2; X= H; R1R2= H or C1-C3 alkyl groups, to form a compound of Formula l\, wherein R, X, R1R2 have the same meaning as defined above. The resulting Compound of Formula II (where R = COOH or CON R1R2) is then converted into methyl ester of Formula II by methods known in the art. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to process for selective reduction of pyridine ring in substituted oc-phenyl-oc-pyridyl derivatives of Formula I wherein R and X has the following meanings. R denotes CONR1R2, COOCH3, COOH; and X= H, CI, Br, OMe, NH2 wherein, R1R2are independently hydrogen, C1-C3 alkyl groups include all isomeric forms (i. e straight chain or branched chain e.g., isopropyl). The invention further involves the manufacture of methylphenidate of the Formula II wherein R= COOCH3; X= H by the reduction of a compound of Formula I wherein R=CONR1R2, COOCH3, COOH; X= H where R1R2 are as defined above, which are important intermediates for the production of methylphenidate. In accordance with the above basic objective of the present invention, suitable procedure is that oc-phenyl-oc-pyridyl derivative of Formula 1 which is suspended in C1 -C4 straight or branched chain alcoholic solvents in the presence of equimolar amounts of organic and/or inorganic acids. Equi-molar quantity of acid is used only to protonate the Nitrogen atom on pyridine ring. Representative example of solvents used are methanol, ethanol, isopropanol etc. and the molar quantities of acids used to protonate the pyridine ring are sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, phosphoric acid or in combination thereof. Although the selection of a particular acid is not critical to the success of the invention, acetic acid and perchloric acid are preferred. In a typical procedure, Palladium on carbon is added to the suspended reaction mass and the reaction proceeds at a temperature from room temperature to 70 °C under hydrogen pressure of 5 kg/cm to 15 kg/cm and completes in 15 to 30 hrs. The palladium on carbon of various capacity used in the present invention are 5% to 10%, although not critical but for economic reasons 5% palladium is preferred. The duration of completion of reaction depends on the parameters such as temperature, hydrogenation pressure etc. known to those skilled in the art. The reaction is advantageously carried out in methanol. After completion of the reaction the catalyst was removed by filtration and the filtrate was advantageously concentrated for recovery of solvent and the obtained residue, contains catalytic amount of acid used in the reaction, was diluted with water, basified with alkali solution to isolate the product of Formula II (wherein R=CONR1R2, COOCH3, COOH; X=H, CI, Br, OMe, NH2; R1R2= H or C,-C3 alkyl groups). The catalyst used in the hydrogenation reaction of oc-phenyl - oc - pyridyl -2 - acetic acid and their derivatives of Formula I are, more specifically, 5 % Palladium on carbon (50% wet). Catalyst quantity varies from 10 to 15 gm per 100 gm of the starting oc-phenyl-oc-pyridyl -2- acetic acid derivative. The suitable volume of solvent for carrying out the We claim A process for manufacturing a piperidine compound corresponding to the general Formula II, wherein R denotes CONR1R2, COOCH3, COOH; X denotes hydrogen, CI, Br, OMe, NH2; R1R2 are independently Hydrogen or C1-C3 alkyl groups, comprising: Formula I Formula II a) selective reduction of a pyridine ring in a compound of Formula I, wherein R, R1 R2, and X have the same meanings as defined above, using a palladium catalyst under hydrogen atmosphere in presence of molar equivalent amount of an organic acid or/and inorganic acid in a suitable alcoholic solvent medium; and b) isolating the compound of Formula II from said reaction medium. 2. The process as claimed in claim 1 wherein, the said reaction is carried out in C1-C4 straight or branched chain alcoholic solvents. 3. The process as claimed in claims 1 and 2 wherein, the said alcohols used are methanol, ethanol, propanol and isopropanol, preferably in methanol. 4. The process as claimed in claim 1 wherein, the said organic and/or inorganic acids includes sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, phosphoric acid or in combination thereof. 5. The process as claimed in claim 1 wherein, the said palladium catalyst used is preferably in the range of 5% to 10% palladium adsorbed on carbon. 6. The process as claimed in claim 1 and 5 wherein, the said palladium catalyst is more preferably 5% palladium adsorbed on carbon. 7. The process as claimed in claim 1 wherein the reaction is carried out at a temperature of 35°C to 70 °C and a hydrogenation pressure of 5 kg/cm2 to 15 kg/cm2. 8. A process for manufacturing methylphenidate comprising complete reduction of pyridine ring in a compound of Formula I, wherein R = CONR1R2, COOCH3, COOH; X=~- II, and R1R2 are independently Hydrogen or C1-C3 alkyl groups, using palladium catalyst under hydrogen atmosphere in presence of molar equivalent amount of organic and/or inorganic acid in a suitable solvent to a piperidine compound of Formula II, wherein R, R1 R2, X have the same meaning as above; and converting said compound of formula II to methylphenidate. Formula I Formula II 9. The process as claimed in claim 8 wherein the said reaction is carried out in C1-C4 alcoholic solvents in all isomeric forms in presence of catalytic amounts of organic and/or inorganic acids includes sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, phosphoric acid or in combination thereof. 10. The process as claimed in claim 9 wherein the said alcohols are selected from methanol, ethanol, propanol and isopropanol but, more preferably in methanol. 11. The process as claimed in claim 8 wherein the said organic or inorganic acids include sulfuric acid, hydrochloric acid, acetic acid, perchloric acid, and phosphoric acid or in combination thereof. 12. The process as claimed in claim 8 wherein, the said palladium catalyst used is preferably 5% to 10% palladium adsorbed on carbon. 13. The process as claimed in claims 8 and 12 wherein the said palladium catalyst is more preferably 5% palladium adsorbed on carbon. 14. The process as claimed in claim 8 wherein the reaction is carried out at a temperature of 35°C to 70 °C and a hydrogenation pressure of 5 kg/cm2 to 15 kg/cm2. 15. An improved manufacturing process for preparation of methylphenidate and its intermediates as substantially described herein with reference to the foregoing examples 1 to 2. Dated this the 11th day of June 2004 Dr. Gopakumar G. Nair Agent for the Applicant

Documents:

651-mum-2004-abstract(15-6-2004).pdf

651-mum-2004-abstract(granted)-(7-5-2009).pdf

651-mum-2004-cancelled pages(18-1-2005).pdf

651-mum-2004-claims(18-01-2005).doc

651-mum-2004-claims(18-01-2005).pdf

651-mum-2004-claims(complete)-(15-6-2004).pdf

651-mum-2004-claims(granted)-(7-5-2009).pdf

651-mum-2004-correspondence(05-08-2005).pdf

651-mum-2004-correspondence(29-2-2008).pdf

651-mum-2004-correspondence(ipo)-(09-11-2004).pdf

651-mum-2004-correspondence(ipo)-(5-6-2009).pdf

651-mum-2004-description(complete)-(15-6-2004).pdf

651-mum-2004-description(granted)-(7-5-2009).pdf

651-mum-2004-form 1(15-06-2004).pdf

651-mum-2004-form 1(15-6-2004).pdf

651-mum-2004-form 1(25-6-2004).pdf

651-mum-2004-form 19(10-09-2004).pdf

651-mum-2004-form 2(complete)-(15-6-2004).pdf

651-mum-2004-form 2(complete)-(18-01-2005).doc

651-mum-2004-form 2(complete)-(18-01-2005).pdf

651-mum-2004-form 2(granted)-(7-5-2009).pdf

651-mum-2004-form 2(title page)-(complete)-(15-6-2004).pdf

651-mum-2004-form 2(title page)-(granted)-(7-5-2009).pdf

651-mum-2004-form 26(15-6-2004).pdf

651-mum-2004-form 3(11-07-2005).pdf

651-mum-2004-form 3(15-06-2004).pdf

651-mum-2004-form 3(29-2-2008).pdf

651-mum-2004-power of attorney(15-06-2004).pdf

651-mum-2004-specification(amended)-(18-1-2005).pdf