- 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
-
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.
-
p. 2462 - 2477
(2020/11/18)
-
- Preparation method of amine compound
-
The invention relates to a preparation method of an amine compound, and belongs to the field of medicinal chemistry. According to the preparation method, 2-isopropyl-4-methoxyphenol is used as a starting material, and the amine compound can be obtained th
- -
-
Paragraph 0073-0086
(2020/09/16)
-
- NOVEL PROCESS FOR SYNTHESIS OF A PHENOXY DIAMINOPYRIMIDINE COMPOUND
-
Disclosed herein is a novel process for preparing Compound A free base, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide, and a citrate salt of Compound A with simplified chemistry and a high overall yield: Compound A. In one emb
- -
-
Page/Page column 16-17
(2019/11/12)
-
- Identification and SAR of novel diaminopyrimidines. Part 1: The discovery of RO-4, a dual P2X3/P2X2/3 antagonist for the treatment of pain
-
P2X purinoceptors are ligand-gated ion channels whose endogenous ligand is ATP. Both the P2X3 and P2X2/3 receptor subtypes have been shown to play an important role in the regulation of sensory function and dual P2X3/P2X2/3 antagonists offer significant potential for the treatment of pain. A high-throughput screen of the Roche compound collection resulted in the identification of a novel series of diaminopyrimidines; subsequent optimization resulted in the discovery of RO-4, a potent, selective and drug-like dual P2X3/P2X2/3 antagonist.
- Carter, David S.,Alam, Muzaffar,Cai, Haiying,Dillon, Michael P.,Ford, Anthony P.D.W.,Gever, Joel R.,Jahangir, Alam,Lin, Clara,Moore, Amy G.,Wagner, Paul J.,Zhai, Yansheng
-
scheme or table
p. 1628 - 1631
(2009/11/30)
-
- Diaminopyrimidines as P2X3 and P2X2/3 modulators
-
Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the compounds being of formula (I): wherein R1, R2, R3 and R4 are as defined herein.
- -
-
Page/Page column 17
(2008/12/08)
-
- Diaminopyrimidines as P2X3 and P2X2/3 modulators
-
Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): wherein D, X, Rs
- -
-
Page/Page column 31
(2008/06/13)
-
- Process for synthesis of phenoxy diaminopyrimidine derivatives
-
A method for preparing a compound of formula I the method comprising treating a compound of formula d with an iodination reagent, to form the compound of formula I, wherein R1, R2 and R3 are as defined herein.
- -
-
Page/Page column 19-20
(2010/11/26)
-
- Methods of using diaminopyrimidine P2X3 and P2X2/3 receptor modulators for treatment of respiratory and gastrointestinal diseases
-
Methods for treating respiratory and gastrointestinal diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.
- -
-
Page/Page column 108
(2010/11/26)
-
- Diaminopyrimidines as P2X3 and P2X2/3 antagonists
-
Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of formula (I): or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein D, X, Y, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined herein.
- -
-
Page/Page column 123
(2010/02/14)
-