- Development of a green and sustainable manufacturing process for gefapixant citrate (MK-7264) Part 2: Development of a robust process for phenol synthesis
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Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.
- Peng, Feng,Humphrey, Guy R.,Maloney, Kevin M.,Lehnherr, Dan,Weisel, Mark,Lévesque, Francois,Naber, John R.,Brunskill, Andrew P.J.,Larpent, Patrick,Zhang, Si-Wei,Lee, Alfred Y.,Arvary, Rebecca A.,Lee, Claire H.,Bishara, Daniel,Narsimhan, Karthik,Sirota, Eric,Whittington, Michael
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p. 2453 - 2461
(2020/11/18)
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- NOVEL PROCESS FOR SYNTHESIS OF A PHENOXY DIAMINOPYRIMIDINE COMPOUND
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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
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- Direct synthesis of anilines and nitrosobenzenes from phenols
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A one-pot synthesis of anilines and nitrosobenzenes from phenols has been developed using an ipso-oxidative aromatic substitution (iSOAr) process. The products are obtained in good yields under mild and metal-free conditions. The leaving group effect on reactions that proceed through mixed quionone monoketals has also been investigated and a predictive model has been established.
- St Amant,Frazier,Newmeyer,Fruehauf,Read De Alaniz
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supporting information
p. 5520 - 5524
(2016/07/06)
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- METHODS AND COMPOSITIONS FOR TREATING DISEASES AND CONDITIONS
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Provided herein include methods and compositions for treating diseases or conditions. In some embodiments provided are methods for treating one or more diseases or conditions selected from the group consisting of hypertension, heart failure, dyspnea, and
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- Methods of Using Diaminopyrimidine P2X3 and P2X 2/3 Receptor Modulators for Treatment of Acute and Sub-Acute Cough, Urge to Cough and Chronic Cough, in Respiratory Diseases
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Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with 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 Formu
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- Ethylene glycol as hydrogen donor for the syntheses of thymol analogues via hydrolysis of 4-methylcoumarins
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Treatment of 4-methylcoumarins with potassium hydroxide in ethylene glycol resulted in the formation of the 'normal' 2-isopropenylphenols and/or the 'abnormal' 2-isopropylphenols depending on the nature of the substrates. The solvent ethylene glycol was b
- Chang, Junbiao,Wang, Shuyang,Shen, Zhenhua,Huang, Gang,Zhang, Yueteng,Zhao, Jing,Li, Changwei,Fan, Fangfang,Song, Chuanjun
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supporting information
p. 6755 - 6757,3
(2012/12/12)
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- Identification and SAR of novel diaminopyrimidines. Part 2: The discovery of RO-51, a potent and selective, dual P2X3/P2X2/3 antagonist for the treatment of pain
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The purinoceptor subtypes P2X3 and P2X2/3 have been shown to play a pivotal role in models of various pain conditions. Identification of a potent and selective dual P2X3/P2X2/3 diaminopyrimidine antagonist RO-4
- Jahangir, Alam,Alam, Muzaffar,Carter, David S.,Dillon, Michael P.,Bois, Daisy Joe Du,Ford, Anthony P.D.W.,Gever, Joel R.,Lin, Clara,Wagner, Paul J.,Zhai, Yansheng,Zira, Jeff
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scheme or table
p. 1632 - 1635
(2009/10/15)
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- Diaminopyrimidines as P2X3 and P2X2/3 modulators
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Compounds of formula (I): wherein R1 and R2 are as defined herein. Also disclosed are methods of making and using the subject compounds.
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Page/Page column 19
(2008/12/08)
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- Diaminopyrimidines as P2X3 and P2X2/3 modulators
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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.
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Page/Page column 16-17
(2008/12/08)
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- Methods of using diaminopyrimidine P2X3 and P2X2/3 receptor modulators for treatment of respiratory and gastrointestinal diseases
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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.
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Page/Page column 92
(2010/11/26)
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- Process for synthesis of phenoxy diaminopyrimidine derivatives
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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.
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Page/Page column 19; 21-22
(2010/11/26)
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- Diaminopyrimidines as P2X3 and P2X2/3 modulators
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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
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Page/Page column 31
(2008/06/13)
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- Diaminopyrimidines as P2X3 and P2X2/3 modulators
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Compounds and methods for treating diseases mediated by a P2X3 and/or a P2X2/3 receptor antagonist, the compounds being of formula (I): wherein D, X, R1, R2, R3, R4, R5, R6
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Page/Page column 32-33
(2010/11/26)
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- Diaminopyrimidines as P2X3 and P2X2/3 antagonists
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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.
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Page/Page column 100
(2010/02/14)
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