253265-97-3Relevant articles and documents
The Chiron Approach to (3 R,3 aS,6 aR)-Hexahydrofuro[2,3- b]furan-3-ol, a Key Subunit of HIV-1 Protease Inhibitor Drug, Darunavir
Ghosh, Arun K.,Markad, Shivaji B.,Robinson, William L.
, p. 1216 - 1222 (2020/12/22)
We describe an enantioselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol which is a key subunit of darunavir, a widely used HIV-1 protease inhibitor drug for the treatment of HIV/AIDS patients. The synthesis was achieved in optically pure form utilizing commercially available sugar derivatives as the starting material. The key steps involve a highly stereoselective substrate-controlled hydrogenation, a Lewis acid catalyzed anomeric reduction of a 1,2-O-isopropylidene-protected glycofuranoside, and a Baeyer-Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand alcohol was converted to darunavir efficiently.
Industrial production method of high-purity Derenavir intermediate
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Page/Page column 4-6, (2019/05/04)
The invention relates to the technical field of biochemical engineering, in particular to an industrial production method of a Derenavir intermediate (3R,3aS,6aR)-hydroxyhexahydrofuro[2,3-beta]-furylsuccinimidyl carbonate. Compared with the prior art, the provided industrial production method of (3R,3AS,6AR)-hydroxyhexahydrofuro[2,3-beta]-furyl succinimidyl carbonate can achieve efficient and stable production of high-quality (3R,3AS,6AR)-hydroxyhexahydrofuro[2,3-beta]-furyl succinimidyl carbonate with the purity higher than 99%, and the content of unknown single impurities is lower than 0.1%.
Practical synthesis of the bicyclic darunavir side chain: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol from monopotassium isocitrate
Moore, Gary L.,Stringham, Rodger W.,Teager, David S.,Yue, Tai-Yuen
, p. 98 - 106 (2017/11/30)
A practical synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol?a key intermediate in the synthesis of darunavir?from monopotassium isocitrate is described. The isocitric acid salt, obtained from a high-yielding fermentation fed by sunflower oil, was converted in several steps to a tertiary amide. This amide, along with the compound's ester functionalities, was reduced with lithium aluminum hydride to give, on acidic workup, a transient aminal-triol. This was converted in situ to the title compound, the bicyclic acetal furofuranol side chain of darunavir, a protease inhibitor used in treatment of HIV/AIDS. Key to the success of this process was identifying an optimal amide that allowed for complete reaction and successful product isolation. N-Methyl aniline amide was identified as the most suitable substrate for the reduction and the subsequent cyclization to the desired product. Thus, the side chain is produced in 55% overall yield from monopotassium isocitrate.
METHOD FOR PRODUCING HEXAHYDROFUROFURANOL DERIVATIVE
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Paragraph 0016; 0017; 0023; 0024, (2018/09/11)
PROBLEM TO BE SOLVED: To provide a method for producing a hexahydrofurofuranol derivative represented by the formula (I-1). SOLUTION: There is provided a method for producing a hexahydrofurofuranol derivative which comprises: a step A of mixing a compound represented by the formula (II-1), di(N-succinimidyl) carbonate and a base in the presence of one or more solvents selected from ethers and acetic esters to obtain an objective compound; a step B of mixing the solution in the step A with 2-propanol to precipitate the objective compound; and a step B of filtering the objective compound precipitated in the step B to separate the objective compound. SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
A Concise One-Pot Organo- and Biocatalyzed Preparation of Enantiopure Hexahydrofuro[2,3-b]furan-3-ol: An Approach to the Synthesis of HIV Protease Inhibitors
Kanemitsu, Takuya,Inoue, Mizuho,Yoshimura, Nono,Yoneyama, Kazutoshi,Watarai, Rie,Miyazaki, Michiko,Odanaka, Yuki,Nagata, Kazuhiro,Itoh, Takashi
, p. 1874 - 1880 (2016/05/09)
A simple and efficient one-pot synthesis of enantiopure hexahydrofuro[2,3-b]furan-3-ol, a crucial component of HIV-1 protease inhibitors, was developed. The one-pot process involves an organocatalytic condensation followed by an enzymatic optical resolution. The condensation of 1,2-dihydrofuran and glycolaldehyde was achieved using Schreiner's thiourea catalyst (1 mol-%). A subsequent lipase-catalyzed kinetic resolution gave the target alcohol with >99 % ee. To demonstrate the practicality of this method, Darunavir, an HIV-1 protease inhibitor used to treat multi-drug-resistant HIV, was synthesized.
PROCESS FOR THE PREPARATION OF [(1 S,2R)-3-[[(4-AMINOPHENYL)SULFONYL] (2-METHYLPROPYL)AMINO]-2-HYDROXY-1 -(PHENYLMETHYL)PROPYL]-CARBAMIC ACID (3R,3AS,6AR)HEXAHYDRO FURO[2,3-B]FURAN-3-YL ESTER AND ITS AMORPHOUS FORM
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Page/Page column 23, (2017/04/21)
The present invention relates to an improved process for the preparation of [(1 S,2R)-3-[ [(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy- 1 -(phenylmethyl)propyl] - carbamic acid (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl ester compound of formula- 1 represented by the following structural formula:
Research and Development of an Efficient Synthesis of a Key Building Block for Anti-AIDS Drugs by Diphenylprolinol-Catalyzed Enantio- and Diastereoselective Direct Cross Aldol Reaction
Hayashi, Yumi,Aikawa, Toshiaki,Shimasaki, Yasuharu,Okamoto, Hiroaki,Tomioka, Yosuke,Miki, Takashi,Takeda, Masahiro,Ikemoto, Tetsuya
, p. 1615 - 1620 (2016/09/23)
An efficient method for synthesizing 1-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}oxy)pyrrolidine-2,5-dione (1), a key building block for HIV protease inhibitors, has been developed. A diphenylprolinol-catalyzed highly enantio- and diastereoselective cross aldol reaction of polymeric ethyl glyoxylate with an aldehyde was used as the key step. Acetalized aldol adduct was reduced with NaBH4 to give the diol intermediate in quantitative yield. The acetal exchange reaction followed by hydrogenation with Pd/C catalyst afforded 1′ in 95% yield over 2 steps. The condensation of 1′ with a carbonate gave crystalline 1 (>99/1 dr, > 99% ee) after single crystallization. This is a highly practical synthetic method since environmentally benign organocatalysis is utilized, the amount of catalyst is reduced to 3 mol %, and all of the intermediates before 1′ can be used without any purification.
swiss that Wei method for the preparation of intermediates (by machine translation)
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Paragraph 0066 - 0669, (2016/10/10)
The invention relates to the technical field of heterocyclic chemistry, especially relates to a condensed ring system containing oxygen atoms as the only heterocycle atoms, concretely discloses a preparation method of a Darunavir intermediate. The method comprises the following steps: obtaining a compound of formula (3) by using (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol as a raw material to react with triphosgene under alkaline conditions, then directly reacting with a compound of formula (7) to obtain a compound of formula (8); or obtaining a compound of formula (3) to react with an N-hydroxyl compound to prepare active ester, and then reacting with the compound of formula (7) to obtain the compound of formula (8).
METHOD FOR PRODUCING HEXAHYDROFUROFURANOL DERIVATIVE
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Paragraph 0171-0173, (2015/07/02)
The invention provides a method for producing efficiently and inexpensively on an industrial scale compound (VII) having a desired diastereomer ratio and enantiomer excess, intermediates useful in this method, and methods for producing the intermediates; and a method for producing compound (VIII), which is obtained from compound (I) and compound (II) by the route showing below.
PROCESS FOR THE PREPARATION OF DARUNAVIR AND DARUNAVIR INTERMEDIATES
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Page/Page column 31, (2011/08/21)
The present invention relates to a process for the preparation of darunavir, a nonpeptide protease inhibitor (PI), useful for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens. The present invention further relates to processes for the stereo-directed preparation of darunavir intermediates, in particular (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol and to certain novel intermediates obtained by such processes.
