- Taming Ambident Triazole Anions: Regioselective Ion Pairing Catalyzes Direct N-Alkylation with Atypical Regioselectivity
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Controlling the regioselectivity of ambident nucleophiles toward alkylating agents is a fundamental problem in heterocyclic chemistry. Unsubstituted triazoles are particularly challenging, often requiring inefficient stepwise protection-deprotection strategies and prefunctionalization protocols. Herein we report on the alkylation of archetypal ambident 1,2,4-triazole, 1,2,3-triazole, and their anions, analyzed by in situ 1H/19F NMR, kinetic modeling, diffusion-ordered NMR spectroscopy, X-ray crystallography, highly correlated coupled-cluster computations [CCSD(T)-F12, DF-LCCSD(T)-F12, DLPNO-CCSD(T)], and Marcus theory. The resulting mechanistic insights allow design of an organocatalytic methodology for ambident control in the direct N-alkylation of unsubstituted triazole anions. Amidinium and guanidinium receptors are shown to act as strongly coordinating phase-transfer organocatalysts, shuttling triazolate anions into solution. The intimate ion pairs formed in solution retain the reactivity of liberated triazole anions but, by virtue of highly regioselective ion pairing, exhibit alkylation selectivities that are completely inverted (1,2,4-triazole) or substantially enhanced (1,2,3-triazole) compared to the parent anions. The methodology allows direct access to 4-alkyl-1,2,4-triazoles (rr up to 94:6) and 1-alkyl-1,2,3-triazoles (rr up to 99:1) in one step. Regioselective ion pairing acts in effect as a noncovalent in situ protection mechanism, a concept that may have broader application in the control of ambident systems.
- Dale, Harvey J.A.,Hodges, George R.,Lloyd-Jones, Guy C.
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p. 7181 - 7193
(2019/05/10)
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- PURE INTERMEDIATE
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The present invention relates to an improved process for the preparation of Letrozole (I) and its synthetic intermediate 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III). In particular, it relates to a process to prepare Letrozole and its intermediate (III) substantially free from regioisomeric impurities. The present invention further relates to acid addition salts of 4-[(1-(1,2,4-triazolyl)methyl]benzonitrile (III) such as the oxalate salt, and also to Letrozole (I), the intermediate (III) and salts thereof preparable by the processes of the present invention.
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Page/Page column 40
(2012/03/26)
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- Process for the Preparation of Letrozole
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The present invention relates to the process for the preparation of Letrozole free from its regioisomer (7) and other impurities by selective extraction of desired intermediate (3) using suitable solvent and mixture of solvents.
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Page/Page column 6
(2010/08/07)
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- Process for the preparation of letrozole
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The invention provides a high-yield process for the preparation of letrozole having a high purity, without the need for removal of the 4-[1-(1,3,4-triazolyl)methyl]benzonitrile impurity at the intermediate stage. The invention also provides a process for the synthesis of letrozole in which formation of the impurity 4-[1-(1,3,4-triazolyl)methyl]benzonitrile during the first stage is minimized. In the process, a 4-(halomethyl)benzonitrile is reacted with a salt of 1H-1,2,4-triazole, reducing the formation of the impurity. Preferably, the preparation is conducted as a one-pot process.
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Page/Page column 6-7; 9
(2010/11/26)
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- PROCESS FOR THE PREPARATION OF LETROZOLE
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The present invention relates to the process for the preparation of Letrozole free from its regioisomer (7) and other impurities by selective extraction of desired intermediate (3) using suitable solvent and mixture of solvents.
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Page/Page column 2; 4; 5; 10-11
(2008/06/13)
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- A METHOD FOR THE SEPARATION OF THE LETROZOLE PRECURSOR 4-‘1-(1,2,4-TRIAZOLYL) METHYL!BENZONITRILE FROM ITS 1,3,4-TRIAZOLYL ISOMER
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A chemical method for the separation of letrozole precursor 4-[1-1,2,4-triazolyl)methyl]benzonitrile of formula (I) from the isomeric unwanted byproduct 4-[1-(1,3,4-triazolyl)methyl]benzonitrile of formula (II) of the reaction in which it is produced, which comprises (a) Preparing an isomeric mixtures of the compounds of formula (I) and (II) by conventional methods. (b) Dissolving the resultant crude isomeric mixture in dichloro methane (or) chloroform. (c) Adding 10-14% isopropylalcohol hydrochloride (IPACHI) to the resulting solution. (d) Adding isopropyl ether to precipitate undesired isomer is hydrochloride form. (e) Filtering off the undesired isomer hydrochloride. (f) Distilling off the filtrate completely. (g) Adding dilute sodium hydroxide solution and dichloromethane to the residue to liberate required isomer base of the formula (I). (h) Evaporating the separated dichloromethane layer and charging hexane or petroleum ether. (i) Centrifuging the resultant product of the formula (I) and washing with hexane or petroleum ether.
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Page/Page column 7-8
(2008/06/13)
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