- Development of a new variant of the migita reaction for carbon#sulfur bond formation used in the manufacture of tetrahydro-4-[3-[4-(2-methyl-1H-imidazol-1- yl)phenyl]thio]phenyl-2H-pyran-4-carboxamide
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Palladium-catalyzed carbon-sulfur bond formation using modified Migita reaction conditions was explored and applied to the synthesis of a former antiasthma drug candidate, tetrahydro-4-[3-[4-(2-methyl-1H-imidazol-1-yl)phenyl] thio]phenyl-2H-pyran-4-carboxamide (5). The reaction was developed into a general method for thioaryl halide cross-coupling, and a specific example of its use to synthesize a key intermediate, tetrahydro-4-[3-(4-fluorophenyl)thio] phenyl-2H-pyran-4-carboxamide (6) was demonstrated at large scale to provide phase II clinical supplies of 5. Comparison of the multistep phase I process and the two-step phase II process showed an overall yield advantage over the bond-forming steps from common starting material (1) to API 5 of 40%. The ligand effect in the modified Migita reaction is described in detail. The second step of the scale-up process illustrated formation of carbon-nitrogen bonds without use of palladium catalysis, providing a contrast to the first reaction; both reactions were developed into efficient single-vessel direct isolation processes.
- Norris, Timothy,Leeman, Kyle
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p. 869 - 876
(2013/01/03)
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- Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate
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Structural modification of imidazole 5-lipoxygenase (5-LO) inhibitors for optimizing inhibitory potency, pharmacokinetic behavior and toxicity (ocular) profile led to 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6- tetrahydro-2H-pyran-4-car
- Mano, Takashi,Stevens, Rodney W.,Ando, Kazuo,Kawai, Makoto,Kawamura, Kiyoshi,Nakao, Kazunari,Okumura, Yoshiyuki,Okumura, Takako,Sakakibara, Minoru,Miyamoto, Kimitaka,Tamura, Tetsuya
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p. 965 - 973
(2007/10/03)
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- 5-Lipoxygenase inhibitors: Convenient synthesis of 4-[3-(4- heterocyclylphenylthio)phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide analogues
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A convenient synthetic route to 4-[3-(4-heterocyclylphenylthio)phenyl]-3,4, 5,6-tetrahydro-2H-pyran-4-carboxamide analogues as 5-LO inhibitors is described. This methodology enabled rapid development of structure-activity relationships (SARs) leading to i
- Mano, Takashi,Stevens, Rodney W.,Okumura, Yoshiyuki,Kawai, Makoto,Okumura, Takako,Sakakibara, Minoru
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p. 2611 - 2615
(2007/10/03)
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- Process for making 5-lipoxygenase inhibitors having varied heterocyclic ring systems
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process is described for preparing a compound of Formula (1.3.0): comprising: establishing a reaction mixture consisting of in an aprotic solvent; in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH;
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- Process for making 5-lipoxygenase inhibitors having varied heterocyclic ring systems
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A novel process intermediate, tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-2H-pyran-4-carboxamide, of the formula: is described, as well as its use in a process of preparing 5-lipoxygenase inhibitors of the formula: which comprises establishing a reaction mixture consisting of: and an electron deficient monocyclic or benzo-fused bicyclic N-heterocycle containing two nitrogen atoms of the formula: ?in an aprotic solvent; in the presence of a carbonate of the formula: (M)2-CO3, where M is an alkali metal, Group 1/Ia element, selected from the group consisting of lithium, Li; sodium,Na; potassium, K; rubidium, Rb; and cesium, Cs; followed by heating of said reaction mixture under a nitrogen atmosphere; whereby there is produced the desired compound of the above-recited formula.
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Page column 37
(2008/06/13)
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- Process for preparing 5-lipoxygenase inhibitors
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The present invention relates to the process for preparing a compound of the formula wherein A is C1-C6alkyl, an aryl which is mono or disubstituted with F, Cl, Br, OCH3, C1-C3alkyl or benzy. In the p
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- 5-lipoxygenase inhibitors
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Novel compounds having the ability to inhibit 5-lipoxygenase enzyme and having the following formula I: STR1 and the pharmaceutically acceptable salts thereof, wherein Ar1 is a heterocyclic moiety which is selected from imidazolyl, pyrrolyl, py
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