- Simple preparation method of nevirapine
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The invention relates to a simple preparation method of nevirapine. In the invention, 2-nitro-3-methyl-4-halo-5-oxo-n-valerate is obtained by 1,4-addition reaction of 2-nitroacetate and 2-halogenatedcrotonaldehyde, then 3-nitro-4-methylpyridine-2-one is obtained by cyclization with ammonia, and 2-chloro-3-nitro-4-methylpyridine is prepared by chlorination reagent. 2-cyclopropyl aminonicotinic acid is prepared from 2-chloronicotinic acid and cyclopropylamine through a first substitution reaction, 2-[N-cyclopropyl-N-(3-nitro-4-methylpyridine-2-yl)] aminonicotinic acid is prepared from 2-chloro-3-nitro-4-methylpyridine through a second substitution reaction, and nevirapine is prepared through catalytic hydrogenation and amidation reaction. The method has the advantages of cheap and easily available raw materials, mild process, simple and convenient operation, high reaction activity, high product yield and purity, and small amount of three wastes.
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Paragraph 0054; 0077-0080
(2019/10/01)
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- Increasing global access to the high-volume HIV drug nevirapine through process intensification
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Access to affordable medications continues to be one of the most pressing issues for the treatment of disease in developing countries. For many drugs, synthesis of the active pharmaceutical ingredient (API) represents the most financially important and technically demanding element of pharmaceutical operations. Furthermore, the environmental impact of API processing has been well documented and is an area of continuing interest in green chemical operations. To improve drug access and affordability, we have developed a series of core principles that can be applied to a specific API, yielding dramatic improvements in chemical efficiency. We applied these principles to nevirapine, the first non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV. The resulting ultra-efficient (91% isolated yield) and highly-consolidated (4 unit operations) route has been successfully developed and implemented through partnerships with philanthropic entities, increasing access to this essential medication. We anticipate an even broader global health impact when applying this model to other active ingredients.
- Verghese, Jenson,Kong, Caleb J.,Rivalti, Daniel,Yu, Eric C.,Krack, Rudy,Alcázar, Jesus,Manley, Julie B.,McQuade, D. Tyler,Ahmad, Saeed,Belecki, Katherine,Gupton, B. Frank
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p. 2986 - 2991
(2017/07/24)
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- LOWCOST, HIGH YIELD SYNTHESIS OF NEVIRAPINE
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Improved methods of producing the HIV drug substance, nevirapine are provided. The methods employ a cost effective and high yield synthetic methods for preparing the nevirapine building block 2-chloro-3-amino-4-picoline (CAPIC) and 2-cyclopropyl amino nicotinate (Me-CAN), and improvements in other steps of nevirapine synthesis.
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Page/Page column 30
(2016/12/22)
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- Synthesis and oxidation of 2-hydroxynevirapine, a metabolite of the HIV reverse transcriptase inhibitor nevirapine
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Nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′,3′-e][1,4]diazepin-6-one, NVP) is a non-nucleoside HIV-1 reverse transcriptase inhibitor used to prevent mother-to-child transmission of the virus. However, severe hepatotoxicity and serious adverse cutaneous effects have raised concerns about the safety of NVP administration. NVP metabolism yields several phenol-type derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid species that could react with bionucleophiles. The covalent adducts thus formed might be at the genesis of toxic responses. As an initial step to test this hypothesis, we synthesized the phenolic metabolite, 2-hydroxy-NVP, and investigated its oxidation in vitro. Using potassium nitrosodisulfonate and sodium periodate as model oxidants, we obtained evidence for fast generation of an electrophilic quinone-imine, which readily underwent hydrolytic conversion to fully characterized spiro derivatives, 1′-cyclopropyl-4-methyl-1H,1′H-spiro[pyridine-2, 2′-pyrido[2,3-d]pyrimidine]-3,4′,6(3′H)-trione in aqueous media and 1′-cyclopropyl-4-methyl-1′H,2H-spiro[pyridine-3,2′- pyrido[2,3-d]pyrimidine]-2,4′,6(1H,3′H)-trione in non-aqueous media. The spiro compound generated in aqueous solution underwent subsequent hydrolytic degradation of the NVP ring system, whereas the one formed in non-aqueous media was stable to hydrolysis. The product profile observed with the chemical oxidants in aqueous solution was replicated using lactoperoxidase-mediated oxidation of 2-hydroxy-NVP. These observations suggest that metabolic activation of NVP, via Phase I oxidation to 2-hydroxy-NVP and subsequent generation of a quinone-imine, could occur in vivo and play a role in NVP-induced toxicity.
- Antunes, Alexandra M. M.,Novais, David A.,Ferreira Da Silva,Santos, Pedro P.,Conceiao Oliveira,Beland, Frederick A.,Matilde Marques
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experimental part
p. 7822 - 7835
(2011/12/13)
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- Method for making nevirapine
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A process for making nevirapine, comprising the following steps: (a) reacting a 2-halo-3-pyridinecarbonitrile of the formula ?wherein X is a fluorine, chlorine, bromine or iodine atom, preferably chlorine or bromine, with cyclopropylamine, to yield 2-(cyclopropylamino)-3-pyridinecarbonitrile; (b) hydrolyzing the 2-(cyclopropylamino)-3-pyridinecarbonitrile to yield 2-(cyclopropylamino)-3-pyridine carboxylic acid; (c) isolating the 2-(cyclopropylamino)-3-pyridine carboxylic acid from the reaction medium; (e) treating the 2-(cyclopropylamino)-3-pyridine carboxylic acid with a chlorinating agent, to yield 2-(cyclopropylamino)-3-pyridinecarbonyl chloride; (f) reacting the 2-(cyclopropylamino)-3-pyridine carbonyl chloride with a 2-halo-4-methyl-3-pyridinamine of the formula ?wherein X is a fluorine, chlorine, bromine or iodine atom, preferably chlorine or bromine, to produce an N-(2-halo-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide; and (g) cyclizing the N-(2-halo-4-methyl-3-pyridinyl)-2-(cyclopropylamino)-3-pyridinecarboxamide by treatment with a strong base, to yield nevirapine.
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