Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-03-19
2002-10-29
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06472532
ABSTRACT:
FIELD OF INVENTION
This invention relates to the novel process for the manufacturing of 3-hydroxy-N,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 of the intermediates used.
wherein:
R
1
, R
2
, R
3
, R
6
are independently, hydrogen, lower alkyl,
R
4
is lower alkyl, hydrogen, lower alkoxy,
R
5
is hydrogen, an alcohol protective group, benzyl and a benzyl group optionally substituted with nitro, lower alkyl and lower alkoxy.
Lower alkyl groups include straight and branched chain hydrocarbon radicals from 1 to 6 carbon atoms.
Lower alkoxy groups include -O-[lower alkyl] wherein lower alkyl is defined above.
Alcohol protective group commonly used includes those which 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-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 the conversion compounds of formula II to 3-benzyloxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide, and 3-benzyloxy-N,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.
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.
A fourth aspect of this invention concerns the process of oxidizing a compound of formula III with TEMPO, sodium hypochlorite solution, sodium bicarbonate (baking soda) and potassium bromide to give a compound of formula II.
BACKGROUND OF INVENTION
This invention relates to certain 3-hydroxy-N,1,6-trialkyl-4-oxo-1,4-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 U.S. Pat. No. 4,840,958, U.S. Pat. No. 5,480,894, U.S. Pat. No. 5,688,815, J. Med. Chem. 1999, 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 published emphasizing the pharmacological properties of this class of compound, see WO98/54318. 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 WO98/54318. Compounds of formula I are chelators possessing high pFe
3+
values and show great promise in their ability to remove iron under in-vivo conditions.
3-Hydroxy-N,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 WO98/54318. Allomaltol (1) is converted to 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) 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 diemthyl sulfoxide and sulfur trioxide.pyridine complex to give 2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-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-pyran4(1H)-one (5). The 2-carboxyl derivative is reacted with dicyclohexyldiimide and 2-mercaptothiazoline and 4-dimethylaminopyridine to give the 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione (6) which is reacted with methylamine in tetrahydrofuran to give 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7). The 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7) is converted to 1,6-dimethyl-3-benzyloxy4(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-hydroxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (9):
Scheme 1: a. HCHO, NaOH; b. PhCH
2
Br, NaOH, MeOH, H
2
O; c. DMSO, SO
3
.pyridine, CHCl
3
, Et
3
N; d. sulfamic acid, NaClO
2
, acetone, water; e. DCC, CH
2
Cl
2
, 2-mercaptothiazoline; f. MeNH
2
, THF; g. MeNH
2
, MeOH; h. H
2
, Pd/C, EtOH.
The IUPAC name of the chemicals shown in Scheme 1 is further clarified below:
Compound (3): 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran4(1H)-one has an alternate IUPAC name 3-(benzyloxy)-2-(hydroxymethyl)-6-methyl-4H-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.
Compound (8): 1,6-dimethyl-3-benzyloxy4(1H)-pyridinone-2-carboxy-)N-methyl)-amide has an alternate IUPAC name: 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide.
Compound (9): 1,6-dimethyl-3-hydroxy4(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 number of advantages over the existing process:
1. It affords 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide in considerably higher yields than existing procedures.
2. It is amenable to industrial scale production since 3-hydroxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide can be made in less process steps from economically, commercially available reagents.
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-4(1H)-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(1H)-one to 3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-one. The conversion of 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one to 3-benzyloxy-2-carboxy-6-methyl-pyran-4(1H)-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.
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(1H)-one, 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide. The isolation of these intermediates involve extra process step, labour cost, and waste disposal, thereby rendering the process more expensive.
5. It eliminates the use of intermediate 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-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.
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-3-benzyloxy-6-methyl-pyran-4(1H)-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
Li Wanren
Tam Tim F.
Apotex Inc.
Morris Patricia L.
Nixon & Vanderhye P.C.
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