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.
Synthetic method of saxagliptin intermediate
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, (2021/11/21)
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthetic method of a saxagliptin intermediate. The intermediate is compound I, compound A2 is taken as a raw material, and compound I is obtained through hydrolysis hydroxylation, hydrogenation and amino protecting reaction. The compound A2 is oxidized by taking 1 - adamantane methanol as a raw material. The resulting compound A2. Due to the fact that the synthetic route is shortened, the production cycle is shortened, and the production cost is greatly reduced. The compound A2 to the compound A3, the hydrolysis and the hydroxylation are synthesized in one step in one step, the amount of waste acid water is greatly reduced, and the optical chiral protecting group is kept off, and the chiral value of the final compound I is greatly improved. The whole reaction process is mild in condition, free of harsh anhydrous anaerobic reaction, greatly reduced in wastewater amount and extremely high in product optical activity.
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.
PROCESS FOR PREPARING DIPEPTIDYL PEPTIDASE IV INHIBITORS AND INTERMEDIATES THEREFOR
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, (2016/07/27)
A process for preparing an amine of the structure which comprises a. treating an aqueous solution of a keto acid of the structure with ammonium formate, nicotinamide adenine dinucleotide, dithiothreitol and partially purified phenylalanine dehydrogenase and/or formate dehydrogenase enzyme (PDH/FDH); and b. adjusting pH of the reaction mixture with sodium hydroxide to form the desired amine which is substantially free of undesirable excess ammonium ions.
Intermediate sand Geleg sandbank, its salt, its preparation process and its use (by machine translation)
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, (2016/10/08)
The invention discloses a saxagliptin intermediate, its salt, preparation method and application. The preparation method for the compound 1 or its salt comprises the step of: subjecting an intermediate compound 2 to reduction reaction at a reaction temperature ranging from -15DEG C to 45DEG C in a solvent under the effects of a reducing agent and an organic acid to obtain an intermediate compound 1 or its salt, with the reducing agent being a borohydride of an alkali metal. The preparation method for the compound 2 comprises the step of: under the protection of an inert gas and the action of the organic acid, reacting a compound B with a compound F in a solvent. The invention also discloses application of the intermediate compound or its salt in preparation of saxagliptin. The saxagliptin intermediate involved in the invention has the advantages of easy preparation, simple operation, mild condition, low cost and environmental friendliness, and can meet the requirements of industrial production. (formula 1 and formula 2).
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.
Intermediates for synthesizing sand Geleg sandbank N-tert-butoxycarbonyl-3-hydroxy-1-adamantyl-D-gly method
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Paragraph 0014; 0028; 0029, (2018/02/04)
The invention discloses a novel method of preparing an important saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine. The method comprises the following steps: S1, carrying out an asymmetric reduction amination reaction on 2-(3-hydroxyl-1-adamantyl)-2-oxo-tert-butyl acetate and benzylamine under the effect of a self-made chiral acylamino alcohol catalyst, and hydrolyzing ester to obtain 3-hydroxyl-1-adamantyl-D-glycine; and S2, carrying out a reaction on 3-hydroxyl-1-adamantyl-D-glycine and di-tert-butyl dicarbonate ester to obtain N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine. The synthetic method of the important saxagliptin intermediate N-t-butyloxycarboryl-3-hydroxyl-1-adamantyl-D-glycine provided by the invention is low in cost and available in raw materials, short in step, mild in reaction condition, simple and convenient to operate, high in synthetic efficiency, environment-friendly and suitable for industrialized production, and provides a novel path for preparing saxagliptin and intermediates thereof.
PROCESS FOR THE PREPARATION OF SAXAGLIPTIN AND ITS INTERMEDIATES
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, (2015/06/25)
The present invention provides intermediates of saxagliptin and processes for their preparation. The present invention also provides a process for the preparation of saxagliptin or salts or hydrates thereof by using the intermediates.
Protected amino hydroxy adamantane carboxylic acid and process for its preparation
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Paragraph 0296; 0297, (2015/11/24)
Dipeptidyl peptidase IV (DP 4) inhibiting compounds are provided. The provided compounds can be used for treating diabetes and related diseases, especially Type II diabetes, and other diseases as set out herein, employing such DP 4 inhibitor or a combination of such DP 4 inhibitor and one or more of another antidiabetic agent such as metformin, glyburide, troglitazone, pioglitazone, rosiglitazone and/or insulin and/or one or more of a hypolipidemic agent and/or anti-obesity agent and/or other therapeutic agent.
A convenient method for the synthesis of (S)-N-boc-3- hydroxyadamantylglycine: A key intermediate of saxagliptin
Wang, Anmin,Deng, Yu,Pan, Xinmei,Chen, Yingjie,Tao, Zhu,Liang, Dinghua,Hu, Xiangnan
, p. 627 - 631 (2014/07/21)
(S)-N-Boc-3-Hydroxyadamantylglycine is a key intermediate of saxagliptin. It was synthesized from 1- adamantanecarboxylic acid to afford 1-acetyladamantane (2), which was converted into 2-(1-adamantyl)-2-oxoacetic acid (3) through oxidation, and then into 1-adamantyl-2-hydroxyimino acetic acid (4) followed by treatment of hydroxylamine hydrochloride, then 4 was reducted and Boc-protected to give N-Boc-adamantylglycine (5), which was oxidized with KMnO4 and treated with a chiral base. Utilizing this route, (S)-N-Boc-3- Hydroxyadamantylglycine was prepared. This work is to elaborate a convenient route to synthesize (S)-N-Boc-3-Hydroxyadamantylglycine and provide a new idea for the synthesis of saxagliptin.
