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US 9,809,536 B2Granted
Process for making beta 3 agonists and intermediates
AssigneeMerck Sharp & Dohme Corp.
InventorsJohn Y. L. Chung, Kevin Campos, Edward Cleator, Robert F. Dunn, Andrew Gibson, R Scott Hoerrner, Stephen Keen, Dave Lieberman, Zhuqing Liu, Joseph Lynch, Kevin M. Maloney, Feng Xu, Nobuyoshi Yasuda, Naoki Yoshikawa, Yong-Li Zhong
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Abstract
The present invention is directed to a process for preparing a compound of formula I-11 through multiple-step reactions.
Claims19
A process for producing compound I-11:
- comprising:
- (a) reacting compound I-4:
- 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:
- (b) reducing said compound I-5 with a reducing agent at a temperature of 0° C. to 40° C. to produce compound I-6;
- (c) oxidizing said compound I-6 with an oxidizing agent in the presence of a solvent and a catalyst to produce compound I-7:
- (d) reacting said compound I-7 with phosphonate compound A-4:
- to produce compound I-8:
- (e) reducing said compound I-8 in the presence of a catalyst to produce compound I-9;
- (f) reacting said compound I-9 with an acid to produce compound I-10:
- 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.
11 more elements
A process for producing compound I-11:
- comprising:
- (a) reacting compound I-1:
- with benzoyl chloride and a protecting reagent to produce compound I-3:
- (b) reducing said compound I-3 in the presence of a ketoreductase (KRED) enzyme to produce compound I-4:
- (c) reacting said compound I-4 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:
- (d) reducing said compound I-5 with a reducing agent at a temperature of 0° C. to 40° C. to produce compound I-6;
- (e) oxidizing said compound I-6 with an oxidizing agent in the presence of a solvent and a catalyst to produce compound I-7:
- (f) reacting said compound I-7 with phosphonate compound A-4:
- to produce compound I-8:
- (g) reducing said compound I-8 in the presence of a catalyst to produce compound I-9;
- (h) reacting said compound I-9 with an acid to produce compound I-10:
- and
- (i) 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.
13 more elements
Dependencies are inferred from the claim text.