361442-00-4Relevant articles and documents
Preparation of an amino acid intermediate for the dipeptidyl Peptidase IV inhibitor, saxagliptin, using a modified phenylalanine dehydrogenase
Hanson, Ronald L.,Goldberg, Steven L.,Brzozowski, David B.,Tully, Thomas P.,Cazzulino, Dana,Parker, William L.,Lyngberg, Olav K.,Vu, True C.,Wong, Michael K.,Patel, Ramesh N.
, p. 1369 - 1378 (2007)
The non-proteinogenic amino acid 2-(3-hydroxy-1-adamantyl)-(2S)- aminoethanoic acid [2, (S)-3-hydroxyadamantylglycine], is a key intermediate required for the synthesis of Saxagliptin, a dipeptidyl peptidase IV inhibitor under development for treatment of type 2 diabetes mellitus. Keto acid 2-(3-hydroxy-1-adamantyl)-2-oxoethanoic acid (1) was converted to (S)-3-hydroxyadamantylglycine by reductive amination using a phenylalanine dehydrogenase from Thermoactinomyces intermedius expressed in a modified form in Pichia pastoris or Escherichia coli. NAD (nicotinamide adenine dinucleotide) produced during the reaction was recycled to NADH (reduced form of nicotinamide adenine dinucleotide) using formate dehydrogenase. Pichia pastoris produces an endogenous formate dehydrogenase when grown on methanol, and the corresponding gene was cloned and expressed in E. coli. The modified phenylalanine dehydrogenase contains two amino acid changes at the C-terminus and a 12-amino acid extension of the C-terminus. The modified enzyme is more effective with keto acid 1 than the wild-type enzyme, but less effective with the natural substrate, phenylpyruvate. Production of multi-kg batches was originally carried out with extracts of Pichia pastoris expressing the modified phenylalanine dehydrogenase from Thermoactinomyces intermedius and endogenous formate dehydrogenase, and further scaled up using a preparation of the two enzymes expressed in E. coli.
A process for preparing hydroxy adamantane glycine derivatives
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, (2017/07/14)
The invention aims to provide a novel and simple synthesis route of a hydroxyadamantylglycine derivative represented by the formula I, namely (aS)-a-[[(1,1-dimethylethoxy)carboxyl]-amino]-1-(3-hydroxyadamantyl)-acetic acid) or salts of the derivative through developing a novel compound. A novel compound namely 2(aS)-a-amino-1-adamantyl-acetamide represented by the formula III is taken as the primary raw material and then is subjected to hydrolysis reactions and hydroxy group introduction so as to obtain the (aS)-a-[[(1,1-dimethylethoxy)carboxyl]-amino]-1-(3-hydroxyadamantyl)-acetic acid) represented by the formula I or salts of the derivative. The invention further provides a synthesis method of the novel compound represented by the formula III. The synthesis method can solve the disadvantages that the cost of enzyme catalyzed reactions is high, the enzyme catalyzed reactions are unstable, the chemical catalysis method has a low ee value, and the reaction product is not easy to purify in the prior art, and thus is more suitable for industrial production.
A facile and economic method for the synthesis of (S)-N-Boc-3′-hydroxyadamantylglycine
Li, Jie,Jiang, Xue,Gan, Run,Zhang, Ming,Pan, Xinmei,Hu, Xiangnan
, p. 5709 - 5721 (2016/06/01)
(S)-N-Boc-3′-hydroxyadamantylglycine (I) is an important intermediate of saxagliptin for type 2 diabetes mellitus (T2DM). It was prepared from 1-adamantanecarboxylic acid(1) via mild reaction with sulfuric acid/nitric acid, VHA reagent (SOCl2/DMF) and sodium diethyl malonate, then was treated with hydrolysis, decarboxylation, alkalization and oxidation to give 2-(3-hydroxy-1-adamantyl)-2-oxoacetic acid (4), then through oximation, reduction and (Boc)2O protection to give the N-Boc-3′-hydroxyadamantylglycine(6), then was treated with quinidine to get (S)- N-Boc-3′-hydroxyadamantylglycine(I) and quinine to get (R)–N-Boc-3′-hydroxyadamantylglycine(II). Finally, Compound II was racemized by dicyclohexylcarbodiimide (DCC) and sodium?hydride (NaH) to afford compound 6. In this route, the overall yield of preparing compound I was about 35?% and the enantiomeric excess (ee) reach to 99?%. This route provided a novel idea for the preparation of (S)-N-Boc-3′-hydroxyadamantylglycine.