Title of Invention

PROCESS FOR THE MANUFACTURING OF 3-HYDROXY-N,16-TRIALKYL-4-OXO-1,4-DIHYDROPYRIDINE-2-CARBOXAMIDE

Abstract

A process for the preparation of a compound formula II: wherein: R1 is hydrogen or a lower alkyl, R4 is a lower alkyl, hydrogen or a lower alkoxy, R5 is hydrogen or an alcohol protective group, comprising reacting a compound of formula III: where R1, R4 and R5 are as defined above, with a sodium hypochlorite solution, potassium bromide, TEMPO, and a phase transfer catalyst, so that said compound of formula II is produced.

Full Text

ORIGINAL 666/MUMNP/2004 9-1-2006 FORM 2 THE PATENT ACT, 1970 (39 OF 1970) COMPLETE SPECIFICTION (SEE SECTION 10, RULE 13) 1. "PROCESS FOR THE MANUFACTURING OF 3-HYDROXY-N, 16-TRIALKYL -4-0X0-1,4-DIHYDROPYRIDINE-2-CARBOXAMIDE" 2. APPLICANT NAME: 1) TAM,TIM FAT 155 Veneto Drive Woodbridge, Ontario Canada L4L8X6 2) LL,WANREN 2645 Kipling Avenue Apt. 1611 Etobicoke, Ontario Canada M9V3S6 3. Country: Both from Canada \\SERVER\d\bacloipo^e\Trademark\APOTEX\Patent\09 985 269\Forms\FORM 2.doc P1066-Div 2 TITLE OF INVENTION PROCESSES FOR THE MANUFACTURING OF 3-HYDROXY-/V,1,6-TRIALKYL-5 4-OXO-1.4-DIHYDROPYRIDINE-2-CARBOXAMIDE Field of Invention 10 This invention relates to the novel process for the manufacturing of 3-hydroxy-A/,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I, intermediates of formulae II and III useful in the manufacturing of such 4-oxo-1,4-dihydropyridine-2-carboxamide, and novel process for the manufacturing 15 of the intermediates used. P1066-Div 3 wherein: R1, R2, R3, R6 are independently, hydrogen, lower alkyl, R4 is lower alkyl, hydrogen, lower alkoxy, R5 is hydrogen, an alcohol protective group, benzyl and a benzyl group 5 optionally substituted with nitro, lower alkyl and lower alkoxy. The term "alkyl," as used herein, refers to saturated, straight or branched chain hydrocarbon radicals. Lower alkyl groups include straight and branched chain hydrocarbon radicals from 1 to 6 carbon atoms. Examples of alkyl radicals include 10 methyl, ethyl, propyl, iso-propyl, n-butyl, tert-butyl, neo-pentyl, and n-hexyl. The term "alkoxy," as used herein, refers to an alkyl group, as previously defined, attached to the parent molecular group through an oxygen atom. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neo-pentoxy and n-hexoxy. Lower alkoxy groups include -0-[lower alkyl] wherein lower alkyl is 15 defined above. Alcohol protective group commonly used includes those that are well known in the art, for example, benzyl, 2,6-dimethylbenzyl, 4-methoxybenzyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino) carbonylbenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, 4-picolyl, heptafluoro- 20 p-tolyl, tetrafluoro-4-pyridyl, formate, acetate, benzoate, benzyloxycarbonyl, methoxycarbonyl, t-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, methoxymethyl, benzyloxymethyl, methoxyethoxymethyl, t-butyl. According to further aspects of this invention, there are provided methods for 25 the conversion compounds of formula II to 3-benzyloxy-N1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide, and 3-benzyloxy-/V,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide, 3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide and 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide of formula I. 30 A third aspect of this invention relates to a process of reacting an acid of formula II with 1,1"-carbonyldiimidazole, alkylamine and an inert solvent to give a compound of formula I. 35 A fourth aspect of this invention concerns the process of oxidizing a P1066-Div 5 Background of Invention This invention relates to certain 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-5 dihydropyridine-2-carboxamide of formula I as orally active iron chelators. Members of the 3-hydroxy-4-oxo-1,4-dihydropyridine class are well known for their ability to chelate iron in physiological environment and these have been reported as useful in the treating iron related disorders such as thalassaemia and anemia, see US4840958, US5480894, US5688815, J. Med. Chem. 1999, 10 42(23), 4818-4823. 3-Hydroxy-N,1,6-trialkyl-4-oxo-1,4-dihydropyridine-2-carboxamide are bidentate iron I chelators with potential for oral administration, see Bioorganic & Medicinal Chemistry 9 (2001), 563-567. A patent application has been 15 published emphasizing the pharmacological properties of this class of compound, see W098/54318. Compounds of formula I have been tested in iron mobilization efficacy assay in rat via the mode of oral administration. The results are reported in Table 3 of W098/54318. Compounds of formula I are chelators possessing high pFe3+ values and show great promise in their ability 20 to remove iron under in-vivo conditions. 3-Hydroxy-A/,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide has been prepared by the method, described in examples 45 to 48, 53 and 58 of W098/54318. Allomaltol (1) is converted to 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) 25 according to the procedure described in FR1516463. The 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) is reacted with benzyl bromide in sodium hydroxide in a 10 : 1 mixture of methanol and water to give the 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3) which is then oxidized with dimethyl sulfoxide and sulfur 30 trioxide. pyridine complex to give 2-formyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one (4). Oxidation of the 2-formyl derivative with sulfamic acid and sodium hypochlorite in acetone and water affords 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one (5). The 2-carboxyl derivative is reacted with P1066-Div 6 dicyclohexyldiimide and 2-mercaptothiazoline and 4-dimethylaminopyridine to give the 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1 H)-pyran-2-yl)-1,3-thiazolidine-2-thione (6) which is reacted with methylamine in tetrahydrofuran 5 to give 3-benzyloxy-6-methyl-4(1 H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7). Compound (7) is converted to 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-methyl)-amide (8) with methylamine in alcohol. The 3-benzyloxy derivative was deprotected with hydrogenation using Pd/C in dimethylformamide as illustrated in Scheme 1 to give 1,6-dimethyl-3-hydroxy-4(1H)-pyridinone-2-10 carboxy-)N-methyl)-amide (9): P1066-Div 7 Scheme 1: a. HCHO, NaOH; b. PhCH2Br, NaOH, MeOH, H20; c. DMSO, S03.pyridine, CHCI3, Et3N; d. sulfamic acid, NaCI02, acetone, water; e. DCC, CH2CI2, 2-mercaptothiazoline; f. MeNH2, THF; g. MeNH2, MeOH; h. H2, Pd/C, EtOH. 5 The IUPAC name of the chemicals shown in Scheme 1 is further clarified below: Compound (3): 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one has an alternate IUPAC name 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-10 pyran-4-one. Compound (5): 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one has an alternate IUPAC name 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid. 15 Compound (8): 1,6-dimethyl-3-benzyloxy-4(1 H)-pyridinone-2-carboxy-(N-methyl)-amide has an alternate IUPAC name: 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide. 20 Compound (9): 1,6-dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N-methyl)-amide has an alternate IUPAC Name: 3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide. When compared to the above process, the applicant"s invention introduces a 25 number of advantages over the existing process: 1. It affords 1,6-dimethyl-3-benzyloxy-4(1 H)-pyridinone-2-carboxy-)N-methyl)-amide in considerably higher yields than existing procedures. 30 2. It is amenable to industrial scale production since 3-hydroxy-6-methyl- 4(1 H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide can be made in less process steps from economically, commercially available reagents. P1066-Div 8 3. It avoids the use of oxidizing agent such as DMSO, sulfur trioxide pyridine and the need for column chromatography using diethyl ether and the isolation of the intermediate 2-formyl-3-benzyloxy-6-methyl-pyran-5 4(1 H)-one. It avoids the generation of large amount of industrial waste and the execution of the synthesis in two distinct separate steps for the conversion of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one to 3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-one. The conversion of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1 H)-one to 3-benzyloxy-2-carboxy-6-methyl-10 pyran-4(1 H)-one is achieved in one single process step using baking soda (sodium bicarbonate), sodium hypochlorite solution, and TEMPO. The labour cost is significantly reduced because of the short reaction time and ease of work-up. 15 4. It avoids the isolation and purification of intermediates such as 3- hydroxy-2-hydroxymethyl-6-methyl-pyran-4(1H)-one, 3-benzyloxy-2-formyl-6-methyl-pyran-4(1 H)-one, (3-benzyloxy-6-methyl-4(1 H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide. The isolation of these intermediates involve extra process step, labor cost, and waste disposal, thereby rendering the process more expensive. 20 5. It eliminates the use of intermediate 3-(2-carbonyl-3-benzyloxy-6- methyl-4(1 H)-pyran-2-yl)-1,3-thiazolidine-2-thione. It does not use 2- mercaptothiazoline, which requires its removal as chemical waste in the later step. 25 6. It avoids the use of reagent dicyclohexyldiimide and the generation of dicyclohexylurea waste that are skin irritant. 7. It does not require three distinct steps for the conversion of 2-carboxyl- 30 3-benzyloxy-6-methyl-pyran-4(1 H)-one to 3-benzyloxy-N, 1,6-trialkyl-4-oxo- 1,4-dihydropyridine-2-carboxamide. The conversion is achieved in one single process step. The labour cost is significantly reduced because of the short reaction time and ease of work-up. 35 P1066-Div 9 8. An efficient process is described for the large scale manufacturing of 2-chlorokojic acid, a key intermediate for the synthesis of allomaltol. The 5 existing literature process is not amenable to large-scale synthesis. Therefore, one object of the invention is to provide novel process for the production of 1,6-dimethyl-3-benzyloky-4(1HVpyridinoae-2-carboxy-(N-methyl)-amide and 1,6-dimethyl-3-hydroxy-4(1 H)-pyridinone-2-carboxy-(N-10 methyl)-amide from readily available, inexpensive and relatively safe starting material. Other objects of this invention can be recognized by those skills in the art from the summary of invention and detailed description of embodiments thereof. 15 Summary of Invention According to one aspect of the invention, a process is provided to make the 20 compound of formula I which comprises of the step of oxidation of III to the acid of formula II in a single process step as shown in scheme 2. The oxidants are TEMPO, baking soda, sodium hypochlorite and potassium bromide. Compound II is then reacted with 1,1"-carbonyldiimidazole and ethylamine in an inert solvent to give a compound of formula I in a single 25 process step. The alcohol protective group R5 can be deprotected to give a P1066-Div 10 compound of formula I wherein R5 is hydrogen. The compound of formula III is in turn prepared from the compound of formula IV in a single process step. 5 Detailed Description of Invention Allomaltol (compound of formula IV wherein R1 = Me, R4 = H, R5 = H) is reacted with formaldehyde in a sodium hydroxide solution in methanol and water for a period of 6 to 16 hrs. Benzyl chloride was added and the reaction 10 was heated to reflux for 4 to 12 hours, preferably 6 hours. The benzylated alcohol (compound of formula III wherein R1 = Me, R4 = H, R5 = CH2Ph) is isolated by traditional means. This procedure eliminates the use of a more expensive reagent benzyl bromide and the need to isolate the diol intermediate 3-hydroxy-2-hydroxymethyl-6-methyl-pyran-4(1 H)-one. 15 The preparation is achieved in one manufacturing process step. The amount of methanol is critical for the success of the experiment, the preferred amount of solvent mixture is methanol and water in the ratio of 3 : 2. The alcohol III is then oxidized to the acid (compound of formula II wherein R1 20 = Me, R4 = H, R5 = CH2Ph) in a single process step. Jones reagent (chromium trioxide in sulfuric acid) converts the compound III to acid II in acetone, but the yield is extremely low and is less than 10%. A large amount of chromium waste is created. However, TEMPO, sodium hypochlorite, baking soda and potassium bromide affords the acid in very good yield, without 25 chromatography and further recrystallization. The reaction is carried out in an ice bath, with the internal reaction temperature of less than 10°C. The reagents are extremely cheap and the reaction time is less than 24 hours. TEMPO is used in catalytic amount. 30 The various procedures for the preparation of the acid of formula II can be found in Example 3 below. One preferred condition for the TEMPO oxidation of the compound of formula III at laboratory scale involves the use of dichloromethane as a solvent. 5 to 6 ml of dichlormethane is used per gm of a compound of formula II. A mixture of 10% sodium bicarbonate solution (0.8 to 0.9 mole of sodium bicarbonate per mole of 35 alcohol II) in water, sodium bicarbonate solid (2.5 mol per mole of alcohol of formula P1066-Div 11 II) and potassium bromide (rj.1 mole per mole of alcohol of formula II) is added to form a mixture. This mixture is vigorously stirred with a mechanical stirrer in a round bottom flask cooled in an ice bath. About 0.01 mole of TEMPO per mole of alcohol and a phase transfer catalyst such as 0.05 mole of tetra-n-butylammonium chloride 5 hydrate per mole of alcohol || are added. The oxidation is then initiated by the slow addition of two mole of Sodium hypochlorite in solution (strength 12 to 16% commercial grade) per mole of alcohol II used, with a temperature of the reaction maintained between 0 to 10°C. The preferred pH of the top aqueous layer is maintained between 7.5 to 8,5 during the reaction. To ensure the alcohol of formula 10 III is completely oxidized to the alcohol, additional sodium bicarbonate (0.7 to 0.9 mole per mole alcohol II) and potassium bromide (0.1 mole per mole of alcohol II) are added, followed again by the slow addition of sodium hypochlorite solution (0.6 to 0.8 mole per mole of alcohol II). A third cycle of addition of sodium bicarbonate and sodium hypochlorite solution is sometimes required to drive the reaction to 15 completion. The preferred m0de of work-up involves isolating the upper layer of the reaction, filtering off the insoluble salt and then using sodium thiosulfate to destroy any unreacted sodium hypochlorite. Upon acidification with hydrochloric acid to pH 1, the acid of formula II precipitated and can be isolated by suction filtration. 20 Another preferred procedure for the oxidation of alcohol II to acid of formula II in plant scale involves first suspending the alcohol II in a mixture of water and acetone. Sodium bicarbonate (one mo|e per mole of alcohol II) is then added with vigorous stirring in an ice bath. Potassjum bromide (0.3 mol per mole of alcohol II) and TEMPO (0.02 mole per mole of alcohol) are added when the internal temperature of 25 the reaction is at the range of 0 to 7°C, preferably at 5°C. Sodium hypochlorite solution ( 10% solution, 3 mole of sodium hypochlorite per mole of alcohol II) is added over a period of 2 to 4 hrs with the internal temperature maintained at below 10°C. The reaction mixture is maintained at a temperature below 10°C in an ice bath for an additional 3 hrs. Excess sodium hypochlorite is destroyed by the addition of solid 30 sodium bisulfite at temperature below 5°C. Hydrochloric acid is then added over a period of 0.5 to 1 hr to precipitate out the compound of formula II. After 2 to 4 hrs, the acid of formula III can be isolated by suction filtration. This procedure eliminates the use of halogenated solvent and the use of a phase transfer catalyst in manufacturing of the compound of formula l| when acetone and water are used as reaction solvents. P1066-Div 12 In compound of formula I wherein R6 is hydrogen and R3 = R2, the acid II is converted to the amide of formula I in one single process step. The acid is reacted with 1,1"-5 carbonyldiimidazole in an inert solvent over a period of several hours to give the intermediate A. Without isolation, a solution of methylamine (R3R6NH2 = CH3NH2) in alcohol is added to generate the amide intermediate B. Again without isolation, the reaction temperature is elevated to between 60 to 100°C, preferably 70 to 80°C for a few hours, to afford the amide of formula I wherein R6R3N = R2NH. A typical example 10 is the single process step manufacturing of a compound of formula I wherein R1 = Me, R2 = Me, R3 = Me, R6 = H, R4 = H, R5 = CH2Ph). The experimental procedure can be further found in example 4 below. The inert solvent used for the formation of intermediate A is preferably dimethylformamide or methyl isobutyl ketone. The alcohol used is methanol. For large- scale reaction, tetrahydrofuran is used to 15 replace the methanol. In a typical reaction, the acid of formula II is reacted with 1,1"-carbonyldiimidazole at temperature between 40 to 60°C, preferably 45 to 50°C for a period of 3 to 5 hrs, preferably 4 hrs. The solution is cooled to room temperature and then reacted with a solution of methylamine in tetrahydrofuran over a period of 1 to 4 hrs to give the key intermediate B. The excess inert solvent such as methyl isobutyl 20 ketone is removed by evaporation under vacuum. Without isolation, the intermediate B is mixed with a solution of methylamine (R2NH2 = CH3NH2) in methanol and heated at the reflux temperature of methanol for 1.5 to 2.5 hr. Additional methylamine in methanol is added from time to time, the reaction is further refluxed until all intermediate B is converted to the compound of formula I wherein R3R6N = R2NH. 25 One preferred method of isolation is to evaporate the solvent under vacuum and then prepare the hydrochloride salt of the compound of formula I by adding in hydrochloric acid in methanol. The hydrochloride salt can be easily isolated by filtration. In the preparation of a compound of formula I wherein the R2NH2 used is not the 30 same as R3R6NH, the acyl imidazole intermediate A is prepared in the same manner as above, and then reacted with a solution of R3R6NH2 to give the amide intermediate P1066-Div 13 C. A solution of RNH2 in alcohol is added and the mixture is refluxed in a similar manner above to give a compound of formula I. The product can be isolated by traditional means. Experimental procedure for this method can be found in example 5 below. 5 The 3-benzyl alcohol protective group (compound of formula I wherein R5 = CH2Ph) can be removed by hydrogenation reaction or by acid. Procedures for the removal of protective group can be found in Greene, T.W., in Protective Groups in Organic Synthesis, John Wiley & Sons, 198.1. 10 The starting materials required in this process are commercially available in kilogram to metric ton quantities. Allomaltol is prepared from the zinc reduction of 2-chlorokojic acid. The literature reported the use of excess thionyl chloride for the preparation of 2-chlorokojic acid. The reaction is 15 heterogeneous and the procedure is not amenable to large-scale synthesis and manufacture. However, 2-chlorokojic acid can be prepared from kojic acid using 1 to 1.2 equivalent thionyl chloride in an inert solvent. The preferred inert solvent is acetonitrile and the product is easily isolated by filtration. 20 The above description details a general method for the conversion of compound III to II then to compound I. The present invention will be more fully understood by the following examples 25 which illustrate the invention, but are not considered limiting to the scope of the invention. Example 1 Preparation of Chlorokojic acid 30 A 2-litre 3-neck round bottom flask was equipped with a mechanical stirrer. The flask was charged with kojic acid (0.25 kg, 1.759 mol) and 750 ml acetonitrile at 0°C. The kojic acid was insoluble in acetonitrile and stayed as a suspension. Thionyl chloride (140 ml, 1.919 mol) was added dropwise via a dropping funnel at ice bath P1066-Div 14 temperature. The solid slowly dissolved to give a red clear solution. After 15 minutes, a white solid appeared. After 3 hrs at 0°C, the insoluble solid was filtered. The solid was filtered by suction filtration. The solid was mixed with water (0.5L) and 5 then filtered. The acetonitrile mother liquor was reduced to 15% of the original volume and filtered. The solid was washed with water (200 ml) and then acetonitrile (50 ml). The combined solid was dried to constant weight (269 g, 95.2% yield). M.p. 166 -168°C [lit value 166 - 167°C]. 1H-NMR (DMSO-d6) δ: 4.66 (s, 2H, CH2CI), 6.57 (s, 1H, CH), 8.12 (s, 1H, CH), 9.3 (br. s, 1H, OH). 10 Example 2 Preparation of 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one Procedure I: 15 Allomaltol (Chem Abstract 1968-51 -OP) was prepared from chlorokojic acid according to literature procedure published in J. Med. Chem., 1996, 39, 3659-3670. Allomaltol (12.6g, 0.1 mol) was added to a solution of sodium hydroxide (4.4g, 0.11 mol) in water (60 ml). Formaldehyde (9 ml, 37% solution, 0.111 mol) was added dropwise at 0°C. The mixture was stirred at room temperature. A solid started to appear after 20 1.5 hr. Methanol (50 ml) was added and the mixture was left stirring for 16 hrs. The mixture was heated to 40°C to effect dissolution of all insoluble solids. Benzyl chloride (12.65 ml, 0.109 mol), tetra-N-butylammonium chloride (71 mg, 0.25 mmol) was added. The mixture was heated to reflux for 3.5 hr. The solution was cooled and the pH of the solution dropped to pH = 1. A solution of sodium hydroxide (2.5 g, 25 0.0625 mol) in water (10 ml) was added. PhCH2CI (2 ml, 0.0173 mol) was added. The mixture was heated to reflux for 1.5 hr. The pH of the solution was at pH 12.5. The solution was cooled to room temperature. Methanol was removed by evaporation under reduced pressure. The mixture was cooled to 0°C and extracted with dichloromethane (3 x 100 ml). The dichloromethane layer was washed with 30 brine, dried over sodium sulfate and evaporated to give red oil. The oil was mixed with ethyl acetate (250 ml) and heated to effect dissolution. The solution was cooled slowly with stirring to room temperature. A solid appeared. The mixture was cooled in an ice bath for one hr. The solid was isolated by filtration and dried to constant weight (14.5 gm). The mother liquor was evaporated to 15% of the original volume. 35 A solid was formed upon cooling to room temperature and then 0°C. Suction filtration P1066-Div 15 gave an additional 1.7 gm of the titled compound. The total amount of solid isolated was 15.86 g (64.45% yield). H-NMR (CDCI3) 5: 4.31 (s, 2H, CH2OH), 5.21 (s, 2H, CH2Ph), 6.21 (s, 1H, CH), 7.38 (br. s, 5H, Ph). M.p. 115-116°C (lit. 114- 116°C). 5 Example 3: Preparation of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid 10 Procedure I: A 1-litre 3-neck round bottom flask was equipped with a mechanical stirrer and a dropping funnel. Dichloromethane (100 ml) was added to the flask followed by 3- (benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (15.87 g, 0.064 mol). 15 Sodium bicarbonate solution (10%, 100 ml, 0.12 mol) was added, followed by solid sodium bicarbonate (13.5 g, 0.161 mol) and potassium bromide (764 mg, 6.42 mmol). The mixture was cooled in an ice bath. The internal temperature of the reaction mixture was 3°C. 20 TEMPO (100 mg, 0.64 mmol) and tetra-n-butylammonium chloride hydrate (750 mg, 2.7 mmol) were added. Sodium hypochlorite solution (14.6%, 23 ml, 0.045 mol, see note 3) was added dropwise, maintaining the reaction temperature below 7°C. The addition of sodium hypochlorite solution (14.6%, 23 ml, 0.045 mol) took 25 minutes.1 The pH of the top layer was checked and measured a value of 9.0. 25 Sodium hypochlorite solution (14.6%, 25 ml, 0.049 mol) was added dropwise1 over a period of 60 minutes, maintaining the reaction temperature below 7°C. Sodium bicarbonate solution (10%, 50 ml, 0.06 mol) was then added and the pH of the solution was measured after 15 minutes. At this time, the reaction mixture was white 30 in color. The pH of the top layer was checked and had a value of pH 6.4. Sodium hypochlorite solution (14.6%, 19 ml, 0.037 mol) was added dropwise over 20 minutes, the pH of the upper layer was now at pH 7.4.2 Sodium bicarbonate (13.5 g, 0.161 mol), TEMPO (60 mg, 0.384 mmol), KBr (700 mg, 5.88 mmol) was added, 35 followed by dichloromethane (20 ml). Sodium hypochlorite (14.6%, 11.5 ml, 0.022 mol) was added dropwise over one hr, maintaining the reaction temperature below 7°C. TLC (EtOAc: hexane) showed that only a small amount of 3-(benzyloxy)-6- P1066-Div 16 methyl-4-oxo-4H-pyran-2-carbaldehyde was present. The reaction mixture was filtered under suction. The filtrate was transferred to a separatory funnel and the lower layer was returned to the reaction vessel. 5 The upper layer was transferred to a round bottom flask and mixed with 1 gm of sodium thiosulfate to destroy residual sodium hypochlorite. The solution was evaporated under reduced pressure for 5 minutes to remove residual solvent. The solution was cooled in an ice bath and stirred. Concentrated hydrochloric acid was added dropwise until the solution reached pH 1. A white precipitate appeared and 10 was filtered after 1 hr at 0°C. The wet mass weighed 24 g. The reaction vessel with the dichloromethane layer was mixed with sodium bicarbonate solution (10%, 50 ml, 0.059 mol), sodium bicarbonate (13.5 g, 0.161 mol), potassium bromide (700 mg, 5.88 mmol), tert-n-butylammonium chloride 15 hydrate (500 mg, 1.8 mmol) and mechanically stirred. Sodium hypochlorite solution (14.6%, 14 ml, 0.0274 mol) was added dropwise over a period of 1 hr. The mixture was stirred for an additional 10 minutes and then the two layers were separated. The upper layer was treated with sodium thiosulfate (1 gm) and then stirred. Concentrated hydrochloric acid was added dropwise until the solution reached pH 1. 20 A white precipitate appeared and was filtered after 1 hr at 0°C. The wet mass weighed 2 g. The combined solid was washed with water and dried to constant weight (15.223 g, 91.1% yield). H-NMR (DMSO-d6) 5: 2.30 (s, 3H, Me), 5.10 (s, 2H, PhCH2), 7.35 (m, 25 2H, Ph), 7.43 (m, 2H, Ph). Mass spec: 261 (M + 1). M.p. 173-174°C [decomposition] (lit 173-175°C). Note 1: The solution turned yellow upon addition of the sodium hypochlorite. Addition was stopped until the mixture turned white in color. The addition of sodium 30 hypochlorite was resumed and to maintain the yellow color. Note2: The pH of the reaction was measured with a pH meter. Note3: Sodium hypochlorite solution was titrated before use. The following procedure is representative: Sodium thiosulfate pentahydrate (12.405 g) was dissolved in water in a 250 ml 35 volumetric flask. The solution was diluted to 250 ml. Potassium iodide (3 g) was P1066-Div 17 suspended in 100 ml acetic acid in a 250 ml flask and stirred for 30 minutes at room temperature. The test sodium hypochlorite solution (2 ml) was pipetted into this mixture. A brown color was formed immediately and the mixture was titrated against 0.2M sodium thiosulfate solution from a buret until the solution turned colorless. The 5 amount of solution required to the end point is Vs. Therefore 0.5 * 0.2M * Vs = MNacci * 2 ml. The molarity of the sodium hypochlorite solution MNa0ci was calculated. 10 Procedure II A 500 ml round bottom flask was equipped with a stirrer and a dropping funnel. Dichloromethane (15 ml) was added to the flask followed by 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (3 g, 0.01233 mol). Sodium bicarbonate (2.6 g, 0.031 mol) and potassium bromide (146 mg, 0.001233 mol) and water (5 ml) 15 was added. The mixture was cooled in an ice bath. The internal temperature of the reaction mixture was 3°C. TEMPO (19.26 mg, 0.123 mmol) and tetra-n-butylammonium chloride hydrate (140.5 mg, 0.615 mmol) were added. Sodium hypochlorite solution (4.7%, 25 ml, 0.0158 20 mol) was added dropwise, maintaining the reaction temperature below 7°C. The addition took 30 minutes. The pH of the solution dropped to 6.4. Sodium bicarbonate (4.3 g, 0.0512 mol) was added. The pH rose to 7.5. Sodium hypochlorite solution (4.7%, 23 ml, 0.0145 mol) was added dropwise over a 25 period of 20 minutes, maintaining the reaction temperature below 7°C. One drop of the solution was removed and tested with a test tube containing potassium iodide (20 mg) in acetic acid (2 ml). The solution turned yellow. This showed that very little excess of sodium hypochlorite was present. 30 At 2.5 hr since the start of the experiment, the two phases were separated. The aqueous phase mixed with sodium thiosulfate (1 g) in water (2 ml). The solution was evaporated for 5 minutes to remove residual organic solvent and then acidified to pH 1 with stirring at 0°C with dropwise addition of concentrated HCI. A white precipitate appeared and was filtered after cooling at 0°C for 1 hr. The white solid was washed 35 with water and then dried to constant weight (2.76 g, 87% yield). P1066-Div 18 Procedure III: A 1-litre 3-neck round bottom flask was equipped with a mechanical stirrer and a dropping funnel. Dichloromethane (300 ml) was added to the flask followed by 3-5 (benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (63.48 g, 0.2574 mol). Sodium bicarbonate solution (10%, 200 ml, 0.24 mol) was added, followed by solid sodium bicarbonate (54 g, 0.6428 mol) and potassium bromide (3.06 g, 0.02574 mol). The mixture was cooled in an ice bath. The internal temperature of the reaction mixture was 3°C. TEMPO (400 mg, 0.00256 mol) and tetra-n- 10 butylammonium chloride hydrate (2.98 g, 0.01287 mol) were added. Sodium hypochlorite solution (14.6%, 250 ml, 0.49 mol) was added dropwise, maintaining the reaction temperature below 7°C. The addition of sodium hypochlorite solution took 35 minutes. The pH of the top layer was checked and measured a value of 8.0. Solid sodium bicarbonate (27 g, 0.321 mol) was added, followed by the dropwise 15 addition of sodium hypochlorite solution (14.6%, 100 ml, 0.195 mol) over a period of 50 minutes at ice bath temperature. Solid sodium bicarbonate (20 g, 0.238 mol), 10% sodium bicarbonate solution (100 ml, 0.119 mol), potassium bromide (3 g, 0.0252 mol), and tetra-n-butylammonium chloride hydrate (2 g, 0.0087 mol) was added. Sodium hypochlorite solution (14.6%, 85 ml, 0.167 mol) was added dropwise over a 20 period of two hrs. The pH of the solution dropped to 6.0. Solid sodium bicarbonate (16 g, 0.190 mol) and potassium bromide (3 g, 0.025 mol) were added, followed by the dropwise addition of sodium hypochlorite solution (14.6%, 50 ml, 0.098 mol) over 10 minutes. After 30 minutes of stirring at ice bath temperature, the reaction mixture was filtered under suction. The filtrate was transferred to a separatory funnel. The 25 upper layer was transferred to a round bottom flask and mixed with 1 gm of sodium thiosulfate to destroy residual sodium hypochlorite. The solution was evaporated under reduced pressure for 5 minute to remove residual solvent The solution was cooled in an ice bath and stirred. Concentrated hydrochloric acid was added dropwise until the solution reached pH 1. A white precipitate appeared and was 30 filtered after 1 hr at 0°C. The solid was washed with water and dried to constant weight (49.04 g, 73% yield). P1066-Div 19 Procedure IV: A 250 ml round bottom flask was equipped with a stirrer and a dropping funnel. Dichloromethane (5 ml) was added to the flask followed by 3-(benzyloxy)-2-5 (hydroxymethyl)-6-methyl-4H-pyran-4-one (1 g, 4.06 mmol). Sodium bicarbonate (314 mg, 3.74 mol) and potassium bromide (96.5 mg, 0.81 mmol) in water (2.5 ml) were added. The mixture was cooled in an ice bath. The internal temperature of the reaction mixture was 3°C. 10 TEMPO (6.4 mg, 0.041 mmol) was added. Sodium hypochlorite solution (4.7%, 7.5 ml, 4.73 mmol) was added dropwise, maintaining the reaction temperature below 7°C. After 1.5 hr, TLC (EtOAc/hexane) showed all the starting material has been converted to the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carbaldehyde. At this time, the mixture was red in color. An additional amount of sodium hypochlorite 15 solution (4.7%, 6.5 ml, 4.1 mmol) was added dropwise at ice bath temperature. The mixture was stirred at ice bath temperature for 1 hr. The two layers were separated. The aqueous layer was tested for excess hypochlorite. One drop of the solution was mixed with Kl (20 mg) in acetic acid (2 ml). The solution turned yellow indicating that there was very little sodium hypochlorite left. The aqueous layer was evaporated 20 under reduced pressure for 3 minutes to remove organic solvent. It was cooled in an ice bath and rapidly stirred. Cone. HCI was added until the pH reached 1. An insoluble white solid appeared and was isolated by suction filtration. The material was washed with water and dried to constant weight (800 mg). The dichloromethane layer from the extraction was mixed a suspension of potassium bromide (84 mg, 0.71 25 mmol) and sodium bicarbonate (180 mg, 2.14 mmol) in water (3 ml) at ice bath temperature. Sodium hypochlorite (4.7%, 3 ml, 1.89 mmol) was added dropwise. After 1 hr, the two layers were separated; the aqueous phase was extracted with dichloromethane (5 ml), and then evaporated to remove residual organic solvent. The aqueous phase was acidified to pH 1 by the dropwise addition of cone. HCI at 30 ice bath temperature. The insoluble white solid was filtered and dried to constant weight (203 mg). The combined product (1.003 g) was isolated in 98.9% yield. Procedure V A 5-litre 3-necked round bottom flask was equipped with a mechanical stirrer, a 35 thermometer, a dropping funnel and a nitrogen inlet/outlet line. The flask was P1066-Div 20 charged with 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (370.0g, 1.5025 mol) and water (740mL, 2 volumes). The orange slurry was stirred vigorously for 5 min. The flask was then charged with acetone (740ml_, 2 volumes). After 20 min, sodium bicarbonate (126.2g, 1.5023 mol) was added, and the flask was placed 5 in an ice-bath. When the internal temperature of the flask reached 5°C (ca. in 90 min), the flask was charged with potassium bromide (53.7g, 0.4513 mol), followed with TEMPO (4.80g, 0.0301 mol). A 10% sodium hypochlorite (bleach) solution (336.0g, 4.5137 mol) was added over a period of 135 min. The pH of the resulting solution was 7.5 and the internal temperature was 10°C. At the beginning of bleach 10 addition, the mixture had a deep yellow color. The mixture was stirred at ice-bath temperature for another 3h. The progress of the reaction was monitored by TLC (100% EtOAc as eluent). The flask was charged with a 10% weight of sodium bisulfite (37g) to destroy any residual bleach. A Kl starch test was shown to be negative. The contents of the flask were cooled in ice (internal temperature ca. 5°C). 15 Cone. HCI (360mL, 3.7558 mol) was added over 35 min and the pH of the resulting solution was 0.35. After stirring for 2 h, the solid was filtered and washed with a water/acetone mixture (2x400 mL, 5/1 ratio, v/v). The damp solid was a lacrimator and was set aside to air-dry overnight. A 5 L 3-necked RBF was charged with the damp solids from 2 other similar experiments (same reaction scales) and from the 20 experiment described above followed by EtOAc (3.3 L, 3 volumes). The mixture was stirred at RT for 3 h. The solid was filtered and washed with EtOAc (2x1 L). The damp solid was dried in an oven under vacuum at 50°C for 16 h. The white solid weighed 889.0g. Karl Fisher test = 0.12% water; corrected weight = 887.9g (76%). 25 Example 4 Preparation of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide Procedure I 30 1,1"-carbonyldiimidazole (3.2 g, 19.7 mmol) was added to a solution of the 3- (benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (3.2 g, 12.3 mmol) in DMF (25 ml) at room temperature. The resulting solution was heated at 45 to 50°C for 3 hrs. A clear yellow solution was observed. A solution of methylamine in methanol (25 ml of 1M solution, 27.33 mmol) was added. The reaction mixture was stirred at 35 65 to 70°C for 3 hr under pressure in a sealed system. The reaction was cooled P1066-Div 21 between 40 to 50°C at which time a solution of methylamine in methanol (20 ml of 1M solution, 21.87 mmol) was added. The solution was stirred at 65 to 70°C for 15 hrs under pressure. The solvent was removed under reduced pressure and dichloromethane was added (150 ml). The solution was washed with water and dried 5 over magnesium sulfate (2 g). Solvent evaporation gave a yellow oil that was passed through a short silica gel column (3" height by 1" diameter). The column was eluted with 10% methanol in ethyl acetate to give the titled compound (2.3 g, yield 66%). H-NMR (CDCI3) 8: 2.20 (s, 3H, Me), 2.68 (d, 3H, NHMe), 3.49 (s, 3H, NMe), 5.03 (s, 2H, PhCH2), 6.14 (s, 1H, CH), 7.32 (m, 5H, Ph), .788 (br. s, 1H, NH). H-NMR 10 (DMSO-d6): 2.28 (s, 3H, Me), 2.74 (d, 3H, NHMe), 3.42 (s, 3H, NMe), 5.05 (s, 2H, PhCH2), 6.20 (s, 1H, CH), 7.33 (m, 5H, Ph), 8.77 (br. s, 1H, NH). Mass spect. 287 (M + 1). M.p. 187.5 - 188.5°C (lit m.p. 164-165.5°C: source p. 35, W098/54138). 15 Procedure II 1,1"-carbonyldiimidazole (0.5 g, 3.07 mmol) was added to a solution of the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylicacid (0.5 g, 1.92 mmol) in DMF (25 ml) at room temperature. The resulting solution was heated at 45 to 50°C for 2.5 hrs. A clear yellow solution was observed. A solution of methylamine in methanol (5 20 ml of 2M solution, 0.01 mol) was added. The reaction mixture was stirred at 45 to 50°C for 2.5 hrs, and then stirred at room temperature for 15 hrs. A solution of methylamine in methanol (5 ml of 2M solution, 0.01 mol). The solution was stirred at 65 to 70°C for 2 hrs in a sealed tube. The solvent was removed under reduced pressure and dichloromethane was added (50 ml). The solution was washed with 25 water and dried over magnesium sulfate. Solvent evaporation gave a yellow oil, which was passed through a short silica gel column (3" height by 1" diameter). The column was eluted with 10% methanol in ethyl acetate to give the titled compound (0.27 g, yield 72%). 30 Procedure III: Preparation of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide hydrochloride A solution of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (600 g, 2.306 mol) was added to a 5 litre 3-neck round bottom flask equipped with a mechanical 35 stirring, thermometer and 18 litre of MIBK (methyl isobutyl ketone). The mixture was P1066-DJV 22 stirred vigorously for 20 minutes. 1,1"-carbonyldiimidazole (472.2 g, 2.767 mol) was added portion wise over 30 minutes. The mixture was heated until the internal temperature of the flask is at 50°C, and the reaction was maintained at this temperature for 4 hrs. The internal temperature of the reaction was cooled to 20°C. 5 600 g of 14% methylamine solution (88.8 g methylamine, 2.86 mol) in tetrahydrofuran was added while maintaining the internal temperature of the reaction to below 30°C (a solution of 14.8% methylamine in tetrahydrofuran was prepared by condensing methylamine (155 g) into 1 litre of tetrahydrofuran at 0 to 5°C). The mixture was stirred for 1 hr at room temperature, and then concentrated under reduced pressure 10 to give about 3 to 3.5 L total volume. Methanol (1.8 L) was added and the mixture was stirred for 25 minutes. The mixture was heated to 30°C, and a solution of 26% methylamine in methanol (100 g solution, equivalent to 26 g methylamine, 0.8 mol) was added. The mixture was heated to reflux for 1.5 hr and cooled to 45°C. The addition of 26% methylamine in methanol (100 g solution, equivalent to 26 g 15 methylamine, 0.8 mol) was repeated five times in exactly the same manner as above, with the material heated to reflux for 1.5 hr after each addition. The solution was evaporated under reduced pressure, and then the residual oil co-evaporated with methanol (2 x 600 ml) to remove the excess methylamine. Methanol (600 ml) was added, followed by the addition concentrated hydrochloric acid (32%, 1 kg) over 1.5 20 hr at ice bath temperature. The mixture was evaporated under vacuum to give a thick solid. The solid was mixed with MBIK (600 ml) and methanol (150 ml) and then evaporated. The co-evaporation was repeated with MIBK (600 ml) and methanol (150 ml). The residue was mixed with methanol (600 ml) and MIBK (1500 ml), and cooled to 5°C. The insoluble solid was filtered and then washed 2 x 600 ml of a 3 :1 25 mixture of MJBK and methanol. The damp solid was mixed with 1.2 L of isopropanol and stirred for 2 hr. The mixture was cooled to 1°C and then filtered. The filter cake was washed with 2 x 400 ml of ice-cold isopropanol and then dried in a vacuum oven overnight. This gives 372.2 g of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide hydrochloride. H-NMR (DMSO-d6): 2.61 (s, 3H, Me), 30 2.80 (d, 3H, NHMe), 3.80 (s, 3H, NMe), 5.18 (s, 2H, PhCH2), 7.35 (m, 5H, Ph), 7.48 (s, 1H, CH), 9.15 (m, 1H, NH). Example 5 Preparation of 3-(benzyloxy)-N, N-diethyl-1, 6-dimethyl-4-oxo-1, 4-35 dihydropyridine-2-carboxamide P1066-Div 23 1,1"-carbonyldiimidazole (1.87g, 111.53 mmol)was added to a solution of the 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.0 g, 7.69 mmol) in DMF (15 ml) at room temperature. The resulting solution was heated at 40 °C for 3 hrs. A clear yellow solution was observed. Diethylamine (1.08 ml, 9.2 mmol) was added. 5 The reaction mixture was stirred at 40 to 45°C for 2 hrs. The reaction was cooled to room temperature at which time a solution of methylamine in methanol (11 ml of 2M solution in methanol, 15.4 mmol) was added. The solution was stirred at 65 to 70°C for 15 hrs under pressure. The solvent was removed under reduced pressure and dichloromethane was added (70 ml). The solution was washed with water and dried 10 over magnesium sulfate (1 g). Solvent evaporation gave light yellow oil as a crude product. The column was eluted with 10% to 25 % methanol in ethyl acetate to give the titled compound (1.74 g, yield 67%). H-NMR (CDCI3) a: 1.09 (t, J=7.11 Hz, 3H, Me), 1.16 (t, J=7.04 Hz 3H, Me), 2.34 (s, 3H, Me), 3.13-3.30 (m, 2H, CH2), 3.47 (s, 3H, NMe), 3.50-3.60 (m, 2H, CH2), 4.91 (d, J=10.76 Hz, 1H, CH2), 5.52(d, J=10.74 15 Hz, 1H, CH2), 6.41 (s, 1H, CH), 7.10-7.33 (m, 5H, Ph), Mass spect. 329 (M + 1). Example 6 Preparation of JV,N-diethyl-3-hydroxy-1,6-dimethyl-4-oxo-1,4-dihydropyridine-2-20 carboxamide Pd(OH)2 on charcoal (0.1 g) was added to a solution of 3-(benzyloxy)-N, N-diethyl-1, 6-dimethyl-4-oxo-1, 4-dihydrQpyridine-2-carboxamide (1.0 g, 3.05 mmol) in ethanol (100 ml) under nitrogen. The mixture was hydrogenated at 50-psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was 25 washed with ethanol (3x10 ml). The ethanol filtrate was evaporated to give a slightly red solid (0.66 g, 94%). Melting point: 128 to 130°C. H-NMR (CDCI3) a: 1.19 (t, J=7.11 Hz, 3H, Me), 1.30 (t, J=7.00 Hz, 3H, Me), 2.36 (s, 3H, Me), 3.36 (m, 2H, CH2), 3.38 (s, 3H, NMe), 3.64 (q, J=6.90 Hz, 2H, CH2), 6.35 (s, 1H, CH), Mass spect. 239 (M +1). 30 Example 7 Preparation of 3-hydroxy-A/,l ,6-trimethyl-4-oxo-1,4-dihydropyridine-2- carboxamfde P1066-Div 24 Pd(OH)2 on charcoal (0.2 g) was added to a solution of 3-(benzyloxy)-N,1,6-trimethyl-4-0X0-1,4-dihydropyridine-2-carboxamide (1.25 g, 4.366 mmol) in ethanol (120 ml) under nitrogen. The mixture was hydrogenated at 50-psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was washed 5 with ethanol (3 x 25 ml). The Celite cake was further stirred with ethanol (100 ml) and then filtered through Celite. The combined ethanol filtrate was evaporated to give a solid (0.86 g, quantitative yield). Melting point: >250°C. H-NMR (CDCI3: DMSO-d6 [2:1]) 8: 1.81 (s, 3H, Me), 2.34 (d, 3H, NHMe), 3.01 (s, 3H, NMe), 5.67 (s, 1H, CH), 7.88 (s, 1H, NH). Elemental Analysis: Calc. C 55.09; H 6.6; N 14.28. 10 Found. C 54.67; H 6.31; N 14.12. P1066-Parent 25 WE CLAIM 1. A process for the preparation of a compound formula II: 5 wherein: R1 is hydrogen or a lower alkyl, R4 is a lower alkyl, hydrogen or a lower alkoxy, R5 is hydrogen or an alcohol protective group, comprising reacting a compound of formula III: 10 where R1, R4 and R5 are as defined above, with a sodium hypochlorite solution, potassium bromide, TEMPO, and a phase transfer catalyst, so that said compound of formula II is produced. 15 2. The process of claim 1 wherein: R1is methyl, R4is hydrogen, Rsis benzyl. 20 3. The process of claim 1 wherein the phase transfer catalyst is tetra-n- butylammonium chloride. 4. The process of claim 1 wherein said reaction is affected at a 25 temperature between 0°C and 10°C. P1066-Parent 26 5. The process of claim 1 wherein said alcohol protective group is benzyl or a benzyl group substituted with nitro, a lower alkyl or a lower alkoxy. 5 Signature 10 Date 13-12-2005 \\Servertd\backupofpe\Trademar«APOTEX\Patent\D9 985 269\Formaamendeded parent claim.doc

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