e.g. Filippa Pettersson or Cancer Res. 75(6) , 1102-12, (2015) or 10.1002/anie.201600521

Synthesis of five nevirapine metabolites

…, LJ Nummy, MD Ridges, A Salvagno

Index: Grozinger, Karl G.; Byrne, Denis P.; Nummy, Laurence J.; Ridges, Michael D.; Salvagno, Annette Journal of Heterocyclic Chemistry, 2000 , vol. 37, # 2 p. 229 - 239

Full Text: HTML

Citation Number: 27

Abstract

Abstract Nevirapine (1) is a non-nucleoside reverse transcriptase inhibitor marketed for HIV treatment by Boehringer Ingelheim as Viramune® since 1996. In vitro studies of nevirapine biotransformation using human liver microsomes demonstrated the formation of five major metabolites. This paper describes the syntheses of these metabolites.

2-Chlorpyridin-3-amin Structure

2-Chlorpyridin-...

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

2-Chloronicotinyl chloride Structure

2-Chloronicotin...

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

2-Chloronicotinic acid Structure

2-Chloronicotin...

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

S,S-dimethyl-N-(3-pyridyl)sulfinimine Structure

S,S-dimethyl-N-...

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

N/A Structure

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

N/A Structure

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

N/A Structure

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

N-(6-chloro-4-methylthiomethyl-3-pyridinyl)-2-cyclopropyl-3-pyridinecarboxamide Structure

N-(6-chloro-4-m...

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

N/A Structure

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

4-(1,2-epoxybutyl)-11-cyclopropyl-5,11-dihydro-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

4-(1,2-epoxybut...

~%

11-Cyclopropyl-5,11-dihydro-4-(hydroxyMethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

11-Cyclopropyl-...

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

~47%

3-Formyl Nevirapine Structure

3-Formyl Nevirapine

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

~95%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

2-Chloro-4-methyl-3-nitropyridine Structure

2-Chloro-4-meth...

~%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

N-cyclopropyl-4-methyl-3-nitropyridin-2-amine Structure

N-cyclopropyl-4...

~%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

2-Chloronicotinyl chloride Structure

2-Chloronicotin...

~%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

2-Chloronicotinic acid Structure

2-Chloronicotin...

~%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

N2-Cyclopropyl-4-Methyl-2,3-pyridinediamine Structure

N2-Cyclopropyl-...

~%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

~%

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

2-Chloro-4-methyl-3-nitropyridine Structure

2-Chloro-4-meth...

~%

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

N-cyclopropyl-4-methyl-3-nitropyridin-2-amine Structure

N-cyclopropyl-4...

~%

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

~30%

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

2-Chloronicotinyl chloride Structure

2-Chloronicotin...

~%

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

2-Chloronicotinic acid Structure

2-Chloronicotin...

~%

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

N2-Cyclopropyl-4-Methyl-2,3-pyridinediamine Structure

N2-Cyclopropyl-...

~%

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

2-Chloro-4-methyl-3-nitropyridine Structure

2-Chloro-4-meth...

~%

N2-Cyclopropyl-4-Methyl-2,3-pyridinediamine Structure

N2-Cyclopropyl-...

2-Chloronicotinyl chloride Structure

2-Chloronicotin...

N2-Cyclopropyl-4-Methyl-2,3-pyridinediamine Structure

N2-Cyclopropyl-...

~71%

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

2-Chloro-4-methyl-3-nitropyridine Structure

2-Chloro-4-meth...

~%

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

N-cyclopropyl-4-methyl-3-nitropyridin-2-amine Structure

N-cyclopropyl-4...

~%

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

2-Chloronicotinic acid Structure

2-Chloronicotin...

~%

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

(6-Butyl-5-decen-5-yl)-λ2-stannane Structure

(6-Butyl-5-dece...

3-Bromo Nevirapine Structure

3-Bromo Nevirapine

~66%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

2-Chloro-4-methyl-3-nitropyridine Structure

2-Chloro-4-meth...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

N-cyclopropyl-4-methyl-3-nitropyridin-2-amine Structure

N-cyclopropyl-4...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

2-Chloronicotinyl chloride Structure

2-Chloronicotin...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

2-Chloronicotinic acid Structure

2-Chloronicotin...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

N2-Cyclopropyl-4-Methyl-2,3-pyridinediamine Structure

N2-Cyclopropyl-...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

2-Chloro-N-[2-(cyclopropylamino)-4-methyl-3-pyridinyl]-3-pyridinecarboxamide Structure

2-Chloro-N-[2-(...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

N-[5-Bromo-2-(cyclopropylamino)-4-Methyl-3-pyridinyl]-2-chloro-3-pyridinecarboxamide Structure

N-[5-Bromo-2-(c...

~%

3-Ethenyl Nevirapine Structure

3-Ethenyl Nevirapine

nevirapine Structure

~20%

2-Nitro Nevirapine Structure

2-Nitro Nevirapine

2-Nitro Nevirapine Structure

2-Nitro Nevirapine

~85%

2-Amino Nevirapine Structure

2-Amino Nevirapine

7-chloro-5-cyclopropyl-9-methyl-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[a,d]cyclohepten-11-one Structure

7-chloro-5-cycl...

~%

2-Amino Nevirapine Structure

2-Amino Nevirapine

nevirapine Structure

~%

2-Amino Nevirapine Structure

2-Amino Nevirapine

5,11-dihydro-2-(4'-methoxybenzylamino)-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one Structure

5,11-dihydro-2-...

~%

2-Amino Nevirapine Structure

2-Amino Nevirapine

Synthesis of nevirapine and its major metabolite

[Grozinger; Fuchs; Hargrave; Mauldin; Vitous; Campbell; Adams Journal of Heterocyclic Chemistry, 1995 , vol. 32, # 1 p. 259 - 263]