US 9,809,536 B2
Process for making beta 3 agonists and intermediates
John Y. L. Chung, Edison, NJ (US); Kevin Campos, Berkeley Heights, NJ (US); Edward Cleator, Cambridge (GB); Robert F. Dunn, Towaco, NJ (US); Andrew Gibson, Hoddesdon (GB); R Scott Hoerrner, Westfield, NJ (US); Stephen Keen, Hoddesdon (GB); Dave Lieberman, Hoddesdon (GB); Zhuqing Liu, Edison, NJ (US); Joseph Lynch, Plainfield, NJ (US); Kevin M. Maloney, Piscataway, NJ (US); Feng Xu, Staten Island, NY (US); Nobuyoshi Yasuda, Mountainside, NJ (US); Naoki Yoshikawa, Hyogo (JP); and Yong-Li Zhong, Edison, NJ (US)
Assigned to MERCK SHARP & DOHME CORP., Rahway, NJ (US)
Appl. No. 14/354,161
Filed by Merck Sharp & Dohme Corp., Rahway, NJ (US)
PCT Filed Oct. 22, 2012, PCT No. PCT/US2012/061249
§ 371(c)(1), (2) Date Apr. 25, 2014,
PCT Pub. No. WO2013/062878, PCT Pub. Date May 2, 2013.
Claims priority of provisional application 61/552,200, filed on Oct. 27, 2011.
Prior Publication US 2014/0242645 A1, Aug. 28, 2014
Int. Cl. C07D 207/09 (2006.01); C07D 207/08 (2006.01); C12P 17/10 (2006.01)
CPC C07D 207/09 (2013.01) [C07D 207/08 (2013.01); C12P 17/10 (2013.01)] 19 Claims
 
1. A process for producing compound I-11:

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comprising:
(a) reacting compound I-4:

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with an acetonide protection reagent selected from the group consisting of 2,2-dimethoxy propane, 2,2-diethoxylpropane, 2-methoxypropene and acetone, to produce compound I-5:

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(b) reducing said compound I-5 with a reducing agent at a temperature of 0° C. to 40° C. to produce compound I-6;

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(c) oxidizing said compound I-6 with an oxidizing agent in the presence of a solvent and a catalyst to produce compound I-7:

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(d) reacting said compound I-7 with phosphonate compound A-4:

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to produce compound I-8:

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(e) reducing said compound I-8 in the presence of a catalyst to produce compound I-9;

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(f) reacting said compound I-9 with an acid to produce compound I-10:

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and
(g) reducing said compound I-10 in the presence of a catalyst to produce compound I-11;
wherein said P1 and said P2 are each independently selected from the group consisting of acyl (Ac), benzyl (Bn), t-butyloxycarbonyl (Boc), benzoyl (Bz), carbobenzyloxy (Cbz), 3,4-dimethoxybenzyl (DMPM), 9-fluorenylmethyloxycarbonyl (FMOC), 4-nitrobenzene sulfonyl (Ns), p-methoxybenzyl carbonyl (Moz), and p-toluene sulfonyl (Ts); and
said R1 is selected from the group consisting of C1-6alkyl, benzyl, and phenyl.