2-Chloro-5-(4-(methylsulfonyl)phenyl)pyrazine

2-Chloro-5-(4-(methylsulfonyl)phenyl)pyrazine

1H NMR (DMSO-d6, 400 MHz) δ 9.24 (d, J = 1.5 Hz, 1H), 8.93 (d, J = 1.2 Hz, 1H), 8.38 (d, J = 8.5 Hz, 2H), 8.09 (d, J = 8.5 Hz, 2H), 3.29 (s, 3H). 
13C NMR (100.6 MHz, DMSO-d6) 149.0, 148.5, 144.6, 142.7, 142.4, 139.8, 128.2, 128.1, 43.9. 
HRMS calcd for C11H10ClN2O2S (M + H)+ 269.0146, found, 269.0143.

Paper

Development of Large-Scale Routes to Potent GPR119 Receptor Agonists

Richard T. Matsuoka*†, Eric E. Boros#, Andrew D. Brown†, Kae M. Bullock†, Will L. Canoy‡, Andrew J. Carpenter#, Jeremy D. Cobb†,Shannon E. Condon†, Nicole M. Deschamps†, Vassil I. Elitzin†, Greg Erickson†,Jing M. Fang#, David H. Igo§, Biren K. Joshi‡, Istvan W. Kaldor#, Mark B. Mitchell†, Gregory E. Peckham#, Daniel W. Reynolds‡, Matthew C. Salmon†, Matthew J. Sharp†, Elie A. Tabet#, Jennifer F. Toczko†, Lianming Michael Wu‡, and Xiao-ming M. Zhou†

†API Chemistry Department, ‡Analytical Science & Development Department, #Medicinal Chemistry Department, and§Particle Sciences and Engineering Department, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00157, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00157

Publication Date (Web): July 13, 2016

Copyright © 2016 American Chemical Society

*E-mail: richard.t.matsuoka@gsk.com.

Abstract

Practical and scalable syntheses were developed that were used to prepare multikilogram batches of GSK1292263A (1) and GSK2041706A (15), two potent G protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an SNAr synthetic strategy.

• Supporting Info

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KHAJURAHO, MADHYA PRADESH, INDIA

Khajuraho Group of Monuments

The Khajuraho Group of Monuments is a group of Hindu and Jain temples in Madhya Pradesh, India, about 175 kilometres southeast of Jhansi. They are one of the UNESCO World Heritage Sites in India.Wikipedia

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(E)-3-(3-((phenylamino)sulfonyl)phenyl)acrylic acid

Preparation of (E)-3-(3-((phenylamino)sulfonyl)phenyl)acrylic acid (6)

Malonic acid (145 g, 1.4 mol) was added in batches to a solution of 3-formyl-N-phenylbenzenesulfonamide 5 (240 g, 0.9 mol) and piperidine (18 mL, 0.2 mol) in pyridine (700 mL), then the mixture was stirred at 105–110 °C for 8.5 h. When TLC analysis indicated the disappearance of 5, the reaction mixture was cooled to ambient temperature and slowly poured into chilled 5% aqueous solution of sodium hydroxide (2.4 L) below 20 °C (pH: 9–10). The reaction mixture was washed with EA (1.2 L), and the separated organic layer was extracted with 5% aqueous solution of sodium hydroxide (600 mL). The aqueous layers were combined and cooled to 10–20 °C, then it was acidified slowly with 50% sulfuric acid (600 mL) below 20 °C (pH: 1–2). After the solution stirred for an additional 30 min at 15–20 °C, the solid obtained was collected by filtration and then washed with water (2.4 L) followed by n-hexane (1 L). The filter cake was dried in a vacuum oven at 50 °C to afforded colorless solid (E)-3-(3-((phenylamino)sulfonyl)phenyl)acrylic acid (244 g, 83%). mp 154–156 °C. 1H NMR (400 MHz, DMSO-d6) δ = 12.62 (bs, 1H), 10.32 (s, 1H), 8.01 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.63–7.56 (m, 2H), 7.24 (m, 2H), 7.11–7.01 (m, 3H), 6.55 (d, J = 16.0 Hz, 1H). MS (ESI):m/z = 326.0 [M+Na] +.

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KHAJURAHO, MADHYA PRADESH, INDIA

Khajuraho Group of Monuments

The Khajuraho Group of Monuments is a group of Hindu and Jain temples in Madhya Pradesh, India, about 175 kilometres southeast of Jhansi. They are one of the UNESCO World Heritage Sites in India.Wikipedia

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3-Formyl-N-phenylbenzenesulfonamide

Preparation of 3-Formyl-N-phenylbenzenesulfonamide (5)

Pyridine (96 mL, 1.5 mol) was added to a solution of aniline (118 mL, 1.3 mol) in EA (600 mL), and the mixture was stirred at 0–5 °C. Then the solution of 3-formylbenzenesulfonyl chloride 4 (200 g, 1.0 mol) in EA (400 mL) was added slowly to the reaction mixture over 1.5 h while maintaining the reaction temperature below 5 °C. The solution was stirred at 0–5 °C for 1 h and then at ambient temperature for 19 h. When the reaction was deemed to be complete with no 4 detected by TLC, the reaction mixture was washed with a 10% aqueous solution of hydrochloric acid (two portions of 500 mL) followed by washing with water (500 L), 5% aqueous solution of sodium bicarbonate (500 mL), and then brine (500 mL); dried with sodium sulfate anhydrous; filtered; and concentrated to afford yellow solid 3-formyl-N-phenylbenzenesulfonamide (242 g, 93%). Crude 5was used directly into next step. A sample of purified 5 as a white solid was analyzed as follows.

1H NMR (CDCl3, 400 MHz) δ = 10.38 (s, 1H), 10.00 (s, 1H), 8.29 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 7.27–7.23 (m, 2H), 7.16–7.01 (m, 3H).

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KHAJURAHO, MADYA PRADESH, INDIA

Khajuraho Group of Monuments

The Khajuraho Group of Monuments is a group of Hindu and Jain temples in Madhya Pradesh, India, about 175 kilometres southeast of Jhansi. They are one of the UNESCO World Heritage Sites in India.Wikipedia

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