In this paper we report on several synthetic strategies to temozolomide which avoid the use of MI... more In this paper we report on several synthetic strategies to temozolomide which avoid the use of MIC. These are cyclization of 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) employing phosgene (or phosgene equivalents); nitrosative cyclization of the (N-methylcarbamoyl) ...
This report describes a novel regioselective contra-Michael addition to cinnamic esters that util... more This report describes a novel regioselective contra-Michael addition to cinnamic esters that utilizes NaNO2–ceric ammonium nitrate.
(24) Private communication from E. M. Arnett and J.-P. Cheng. ... Hydroxylated Metabolites of Lor... more (24) Private communication from E. M. Arnett and J.-P. Cheng. ... Hydroxylated Metabolites of Loratadine: An Example of Conformational Diastereomers Due to Atropisomerism ... John J. Piwinski,* Jesse K. Wong, Tze-Ming Chan, Michael J. Green, and Ashit K. Ganguly ...
Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3,... more Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3, 6, and 7. The key intermediate 5-amino-1-(N-methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully converted to 4 in 45% yield by employing sodium nitrite in aqueous tartaric acid at 0-5 degrees C. Compound 6 is prepared from nitrophenyl carbamate 14a and methylamine or directly from 5-aminoimidazole-4-carboxamide (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Temozolomide (4) is also prepared from 8-cyano-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7is prepared from either 5-diazoimidazole-4-carbonitrile (28) and methyl isocyanate or by diazotization of 5-amino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosgene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.
1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylat... more 1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylated the pyrrolidine enamines of cyclopentanone and cyclohexanone, and the resulting enaminones underwent transaminations with aryl amines under acidic conditions. The products then cyclized under basic conditions to linearly fused, tricyclic 3-phenylmethyl- and 3-(4-methoxyphenylmethyl)-4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[6]-1,2,3-triazolo[4,5-e]pyridines, and to 5,6,7,8-tetrahydro-4-aryl-3H-1,2,3-triazolo[4,5-b]quinolin-9(4H)-ones. Similar transaminations afforded the related 8-phenyl- and 8-(3-chlorophenyl)-1,5,7,8-tetrahydro-1-(phenylmethyl)-4H-thieno[3,4-e]-1,2,3-triazolo[4,5-b]pyridin-4-ones. Phase-transfer and catalytic hydrogenolyses of some of these intermediates furnished 4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[b]-1,2,3-triazolo[4,5-e]pyridines and 4-aryl-5,6,7,8-tetrahydro-3H,2,3-triazolo[4,5-b]quinoline-9-(4H)-ones.The 3-(4-methoxyphenylmethyl)-4-aryl intermediates were sterically crowded. Two protons from the methoxyphenylmethylphenylmethylgroups were dramatically shielded because of anisotropic effects exerted by the 4-aryl substituents.
A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high ... more A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.
32 Dixon et al. three-bond carbon-proton connectivity. A selective INEPT spectrum contains only t... more 32 Dixon et al. three-bond carbon-proton connectivity. A selective INEPT spectrum contains only the carbon resonances which are coupled to the pulsed proton with a coupling constant of about 4 Hz (13). Two selective INEPT spectra are shown in Fig. 4. When the НГ resonance at ...
Diketopiperazines, Sch 54794 and Sch 54796, have been isolated from a fungal fermentation. The st... more Diketopiperazines, Sch 54794 and Sch 54796, have been isolated from a fungal fermentation. The structures of these compounds have been established based on spectroscopic data analysis. Sch 54794 exhibited inhibitory activity in the platelet activating factor (PAF) ...
Two new C-nor/D-homo corticosteroids were isolated from the filtrate of the triene carbonate inte... more Two new C-nor/D-homo corticosteroids were isolated from the filtrate of the triene carbonate intermediate during the production of betamethasone. Their structures were elucidated based on NMR spectroscopic studies and mass spectral analyses. The mechanism of formation of each of these two steroids was postulated as a Wagner-Meerwein rearrangement of the corresponding 12beta-hydroxy steroid. The new 12beta-hydroxy corticosteroid was also isolated from the fermentation process of betamethasone synthesis. Its structure was identified via NMR and mass spectroscopic studies. Treatment of the new 12beta-hydroxy corticoid with PCl(5) at low temperature provided two C-nor/D-homo compounds in a ratio of 1:1. Conversion of 12beta-hydroxy corticoid into a corresponding 12beta-mesylate followed by heating in HOAc to 110 degrees C in the presence of NaOAc produced a mixture of the rearranged products in a 1:4 ratio.
In this paper we report on several synthetic strategies to temozolomide which avoid the use of MI... more In this paper we report on several synthetic strategies to temozolomide which avoid the use of MIC. These are cyclization of 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) employing phosgene (or phosgene equivalents); nitrosative cyclization of the (N-methylcarbamoyl) ...
This report describes a novel regioselective contra-Michael addition to cinnamic esters that util... more This report describes a novel regioselective contra-Michael addition to cinnamic esters that utilizes NaNO2–ceric ammonium nitrate.
(24) Private communication from E. M. Arnett and J.-P. Cheng. ... Hydroxylated Metabolites of Lor... more (24) Private communication from E. M. Arnett and J.-P. Cheng. ... Hydroxylated Metabolites of Loratadine: An Example of Conformational Diastereomers Due to Atropisomerism ... John J. Piwinski,* Jesse K. Wong, Tze-Ming Chan, Michael J. Green, and Ashit K. Ganguly ...
Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3,... more Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3, 6, and 7. The key intermediate 5-amino-1-(N-methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully converted to 4 in 45% yield by employing sodium nitrite in aqueous tartaric acid at 0-5 degrees C. Compound 6 is prepared from nitrophenyl carbamate 14a and methylamine or directly from 5-aminoimidazole-4-carboxamide (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Temozolomide (4) is also prepared from 8-cyano-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7is prepared from either 5-diazoimidazole-4-carbonitrile (28) and methyl isocyanate or by diazotization of 5-amino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosgene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.
1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylat... more 1-Phenylmethyl- and 1-(4-methoxyphenylmethyl)-5-chloro-1,2,3-triazole-4-carbonyl chlorides acylated the pyrrolidine enamines of cyclopentanone and cyclohexanone, and the resulting enaminones underwent transaminations with aryl amines under acidic conditions. The products then cyclized under basic conditions to linearly fused, tricyclic 3-phenylmethyl- and 3-(4-methoxyphenylmethyl)-4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[6]-1,2,3-triazolo[4,5-e]pyridines, and to 5,6,7,8-tetrahydro-4-aryl-3H-1,2,3-triazolo[4,5-b]quinolin-9(4H)-ones. Similar transaminations afforded the related 8-phenyl- and 8-(3-chlorophenyl)-1,5,7,8-tetrahydro-1-(phenylmethyl)-4H-thieno[3,4-e]-1,2,3-triazolo[4,5-b]pyridin-4-ones. Phase-transfer and catalytic hydrogenolyses of some of these intermediates furnished 4-aryl-8-oxo-4,5,6,7-tetrahydrocyclopenta[b]-1,2,3-triazolo[4,5-e]pyridines and 4-aryl-5,6,7,8-tetrahydro-3H,2,3-triazolo[4,5-b]quinoline-9-(4H)-ones.The 3-(4-methoxyphenylmethyl)-4-aryl intermediates were sterically crowded. Two protons from the methoxyphenylmethylphenylmethylgroups were dramatically shielded because of anisotropic effects exerted by the 4-aryl substituents.
A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high ... more A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.
32 Dixon et al. three-bond carbon-proton connectivity. A selective INEPT spectrum contains only t... more 32 Dixon et al. three-bond carbon-proton connectivity. A selective INEPT spectrum contains only the carbon resonances which are coupled to the pulsed proton with a coupling constant of about 4 Hz (13). Two selective INEPT spectra are shown in Fig. 4. When the НГ resonance at ...
Diketopiperazines, Sch 54794 and Sch 54796, have been isolated from a fungal fermentation. The st... more Diketopiperazines, Sch 54794 and Sch 54796, have been isolated from a fungal fermentation. The structures of these compounds have been established based on spectroscopic data analysis. Sch 54794 exhibited inhibitory activity in the platelet activating factor (PAF) ...
Two new C-nor/D-homo corticosteroids were isolated from the filtrate of the triene carbonate inte... more Two new C-nor/D-homo corticosteroids were isolated from the filtrate of the triene carbonate intermediate during the production of betamethasone. Their structures were elucidated based on NMR spectroscopic studies and mass spectral analyses. The mechanism of formation of each of these two steroids was postulated as a Wagner-Meerwein rearrangement of the corresponding 12beta-hydroxy steroid. The new 12beta-hydroxy corticosteroid was also isolated from the fermentation process of betamethasone synthesis. Its structure was identified via NMR and mass spectroscopic studies. Treatment of the new 12beta-hydroxy corticoid with PCl(5) at low temperature provided two C-nor/D-homo compounds in a ratio of 1:1. Conversion of 12beta-hydroxy corticoid into a corresponding 12beta-mesylate followed by heating in HOAc to 110 degrees C in the presence of NaOAc produced a mixture of the rearranged products in a 1:4 ratio.
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