- Development of a green and sustainable manufacturing process for gefapixant citrate (MK-7264) Part 3: Development of a one-pot formylation-cyclization sequence to the diaminopyrimidine core
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The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic understanding of the cyclization step in the presence of guanidine was established by performing isotopic labeling experiments and identification of impurities. Guided by the mechanistic understanding, further attempts to modify the cyclization reaction by employing additives to reduce the triazine (9) formation and guanidine loading will also be presented. This newly developed method delivered compound 1 in 88-94% yield on a commercial scale and addressed the shortcomings of the early synthetic route including high PMI, low atom economy, long cycle-time, and multiple purifications to achieve the desired quality.
- Basu, Kallol,Lehnherr, Dan,Martin, Gary E.,Desmond, Richard A.,Lam, Yu-Hong,Peng, Feng,Chung, John Y.L.,Arvary, Rebecca A.,Zompa, Michael A.,Zhang, Si-Wei,Liu, Jinchu,Dance, Zachary E.X.,Larpent, Patrick,Cohen, Ryan D.,Guzman, Francisco J.,Rogus, Nicholas J.,Di Maso, Michael J.,Ren, Hong,Maloney, Kevin M.
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Method of making 1-(alkoxyphenyl)-5-(phenyl)biguanide compounds which are useful as agricultural fungicides
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The present invention provides an improved method of making 1-(alkoxyphenyl)-5-(phenyl)biguanide compounds which are useful as agricultural fungicides, having the formula: STR1 where R is alkyl, linear of branched, having from 1-14 carbon atoms; and acid addition salts thereof. The method comprises the steps of (a) alkylating a nitrophenol with a suitable alkyl halide in a reaction solvent to form an alkoxynitrobenzene intermediate, (b) reducing the nitro group of the itermediate in situ by catalytic hydrogenation to form an alkoxyaniline, and (c) condensing the alkoxyaniline with phenyldicyandiamide to form the desired biguanide as the acid addition salt. The invention also includes a novel isolation and purification procedure for obtaining purified biguanide acid addition salts and purified free biguanide base.
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