- 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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Read Online
- 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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- Method for preparing [...] lappin
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The invention discloses a preparation method for nevirapine. The method comprises the following steps: 1) reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide with cyclopropylamine in an organic solvent in the presence of alkylamine so as to obtain a reaction mixture containing 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide; and 2) mixing the reaction mixture obtained in the step (1) with an ether solvent or with a mixed solvent of the ether solvent and an aromatic hydrocarbon solvent in the presence of a base and allowing 2-cyclopropylamino-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridinecarboxamide to undergo a cyclization reaction so as to obtain a reaction mixture containing nevirapine. The method may further comprise a step of nevirapine purification. The method provided by the invention has mild reaction conditions and is easy to control; process operation of the method is simple and safe; and the product nevirapine has good yield and high purity.
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Paragraph 0089-0091
(2017/04/03)
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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 16; 17
(2016/12/22)
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- Process for preparing Nevirapine
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An improved process for preparing 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one of Formula (I).
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Page/Page column 3
(2010/06/13)
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- PREPARATION AND UTILITY OF NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Disclosed herein are non-nucleoside reverse transcriptase inhibitors having structural Formula ( I ), processes of preparation thereof, pharmaceutical compositions thereof, and the methods of their use thereof. Formula ( I )
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- AN IMPROVED PROCESS FOR PREPARING NEVIRAPINE
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An improved process for preparing 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one of Formula (I).
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Page/Page column 9-10
(2009/01/20)
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- AN IMPROVED PROCESS FOR INDUSTRIAL MANUFACTURE OF NEVIRAPINE
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An improved cost-effective, environmental friendly, industrial method for manufacture of Nevirapine.Formula (I):
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Page/Page column 23
(2008/06/13)
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- Novel crystalline forms of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido [3,2-b: 2',3'-e][1,4] diazepin-6-one (nevirapine)
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The present invention relates to novel crystalline forms of 11-cyclopropyl1-5, 11-dihydro-4-methyl-6H-dipyrido[3,2-b: 2′, 3′-e][1,4]diazepin-6-one, generically known as Nevirapine, and processes for making thereof. More specifically, the present invention provides novel crystalline Form-II and Form-III of Nevirapine.
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Page/Page column 3
(2008/06/13)
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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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- Process for preparing nevirapine
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A process for preparing nevirapine which comprises reacting 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide with cyclopropylamine followed by cyclisation of the product, wherein the reaction with cyclopropylamine is carried out in the presence of an oxide or hydroxide of an element of the second main or sub-group of the periodic table of elements.
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- Method for the preparation of 5,11-dihydro-6h-dipyrido [3,2-b:2',3'-e][1,4]diazepines
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This invention relates to a novel method for preparing certain dipyrido-diazepines.
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- Synthesis of nevirapine and its major metabolite
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Several synthetic methods were developed during the process optimization for the large scale synthesis of nevirapine (1), a non-nucleoside inhibitor of HIV-1 Reverse Transcriptase. The synthesis of its putative major metabolite 11-cyclopropyl-5,11-dihydro-4-hydroxymethyl-6H-[3,2-b:2',3'-e][1,4]dia zepin-6-one (2) and the oxidation of 2 to the corresponding aldehyde 3, are described.
- Grozinger,Fuchs,Hargrave,Mauldin,Vitous,Campbell,Adams
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p. 259 - 263
(2007/10/02)
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- 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection
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Disclosed are novel 5,11-dihydro-6H-dipyrido[3,2-b; 2',3'-e][1,4]diazepines. These are useful in the prevention or treatment of HIV infection.
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- Novel Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 1. Tricyclic Pyridobenzo- and Dipyridodiazepinones
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Novel pyridobenzodiazepinones (I), pyridobenzodiazepinones (II), and dipyridodiazepinones (III) were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in vitro at concentrations as low as 35 nM.In all three series, small substituents (e.g., methyl, ethyl, acetyl) are preferred at the lactam nitrogen, whereas slightly larger alkyl moieties (e.g., ethyl, cyclopropyl) are favored at the other (N-11) diazepinone nitrogen.In general, lipophilic substituents are preferred on the A ring, whereassubstitution on the C ring generally reduces potency relative to the corresponding compounds with no substituents on the aromatic rings.Maximum potency is achieved with methyl substitution at the position ortho to the lactam nitrogen atom; however, in this case an unsubstituted lactam nitrogen is preferred.Additional substituents on the A ring can be readily tolerated.The dipyridodiazepinone derivative 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyridodiazepin-6-one (96, nevirapine) is a potent (IC50 = 84 nM) and selective non-nucleoside inhibitor of HIV-1 reverse transcriptase, and has been chosen for clinical evaluation.
- Hargrave, Karl D.,Proudfoot, John R.,Grozinger, Karl G.,Cullen, Ernest,Kapadia, Suresh R.,et al.
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p. 2231 - 2241
(2007/10/02)
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