156928-10-8Relevant articles and documents
Preparation method of hexahydrofuranofuranol derivative, intermediate and preparation method thereof
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Paragraph 0082-0083; 0086; 0092-0093; 0096, (2021/02/05)
The invention relates to the field of medicine synthesis, in particular to a preparation method of a hexahydrofuranofuranol derivative, an intermediate and a preparation method thereof. The preparation method comprises a condensation reaction, a deprotection reaction and a cyclization reaction, wherein R1 and R2 are hydrogen or hydroxyl protecting groups, R3 is alkyl, acyl, ether, ester or aryl, and X is oxygen, sulfur or nitrogen. In the preparation process of the hexahydrofuranofuranol derivative, the compound shown in the formula I is subjected to a condensation reaction, so that the product with very high optical purity can be prepared by adopting the way. The preparation method can be used for commercially producing and preparing the darunavir key intermediate (3R, 3aS, 6aR)- hexahydrofuro-[2, 3-b]-3-ol, and is a very economical route suitable for industrial production.
Synthesis of hexahydro furo [2, 3 - b] furan - 3 - ol and its enantiomer
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, (2017/08/03)
The invention discloses synthetic methods of hexahydrofuro[2,3-b]furan-3-ol and an enantiomer thereof. The synthetic method of hexahydrofuro[2,3-b]furan-3-ol comprises the step c or the step b to the step c or the step a to the step c in the following synthetic route as shown in the description. The synthetic method of the enantiomer (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-ol comprises the step c to the step f or the step b to the step f or the step a to the step f in the following synthetic route as shown in the description, wherein R1 is selected from C1 to C4 alkyl or aralkyl, and R2 is selected from C1 to C4 alkyl. The synthetic methods provided by the invention have the advantages of cheap and easily available raw materials, simple operation, low cost and the like, are suitable for large-scale production, and have practical value for realization of industrialized production of darunavir.
Asymmetric One-Pot Synthesis of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A Key Component of Current HIV Protease Inhibitors
Sevenich, Adrian,Liu, Gong-Qing,Arduengo, Anthony J.,Gupton, B. Frank,Opatz, Till
, p. 1218 - 1223 (2018/06/18)
A concise and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, a key building block for several clinical and experimental HIV protease inhibitors including the highly important drug darunavir, was achieved via a one-pot procedure using furan and Cbz-protected glycol aldehyde as starting materials. A [2+2]-photocycloaddition between both reactants which can be prepared from wood-based starting materials according to the principles of xylochemistry, followed by hydrogenation and lipase-catalyzed kinetic resolution afforded the target compound in high yield and up to 99% ee.
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
supporting information, 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.
The efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its isomers
Kulkarni, Mukund G.,Shaikh, Yunnus B.,Borhade, Ajit S.,Dhondge, Attrimuni P.,Chavhan, Sanjay W.,Desai, Mayur P.,Birhade, Deekshaputra R.,Dhatrak, Nagorao R.,Gannimani, Ramesh
experimental part, p. 2394 - 2398 (2010/12/25)
The stereoselective synthesis of all the possible stereoisomers of bis-tetrahydrofyran alcohol, a ligand used for obtaining HIV protease inhibitors including Darunavir 1 and Brecanavir 2 has been achieved. A key intermediate 4-pentenal 5 was obtained by employing a Wittig olefination-Claisen rearrangement protocol from d-glyceraldehyde derivative 3 as a source of chirality. The 4-pentenal was readily converted in the bis-THF alcohol moiety in three steps.
Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors
Ghosh, Arun K.,Xu, Chun-Xiao,Rao, Kalapala Venkateswara,Baldridge, Abigail,Agniswamy, Johnson,Wang, Yuan-Fang,Weber, Irene T.,Aoki, Manabu,Miguel, Salcedo Gomez Pedro,Amano, Masayuki,Mitsuya, Hiroaki
scheme or table, p. 1850 - 1854 (2011/06/22)
A healthier HAART: We report the design, synthesis, biological evaluation, and X-ray crystallographic analysis of a new class of HIV-1 protease inhibitors. Compound 4 proved to be an extremely potent inhibitor toward various multidrug-resistant HIV-1 variants, representing a near 10-fold improvement over darunavir (DRV). Compound 4 also blocked protease dimerization with at least 10-fold greater potency than DRV.
Efficient synthesis of 3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol from glycolaldehyde
Canoy, Will L.,Cooley, Bob E.,Corona, John A.,Lovelace, Thomas C.,Millar, Alan,Weber, Aimee M.,Xie, Shiping,Zhang, Yong
scheme or table, p. 1103 - 1106 (2009/04/06)
A one-step diastereoselective (up to 98:2) synthesis of the bis-furan alcohol of Darunavir and other HIV drug candidates has been achieved utilizing the novel cyclizatlon of glycolaldehyde and 2,3-dihydrofuran. The cycloaddition was catalyzed by a variety of catalysts including those formed from tin(II) triflate and common chiral ligands such as BINAP and Evans's box ligands. An efficient and unique enzymatic process enhanced the enantiomeric purity to provide the target in optically pure form.
FITNESS ASSAY AND ASSOCIATED METHODS
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Page/Page column 18; Sheet 2, (2010/11/30)
The present invention provides an assay for determining the biochemical fitness of a biochemical species in a mutant replicating biological entity relative to its predecessor. The present invention further provides a continuous fluorogenic assay for measuring the anti-HIV protease activity of protease inhibitor. The present invention also provides a method of administering a therapeutic compound that reduces the chances of the emergence of drug resistance in therapy. The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, a prodrug, a composition, or an ester thereof, wherein A is a group of formulas (A), (B), (C) or (D); R1, R2, R3, R5 or R6 is H, or an optionally substituted and/or heteroatom-bearing alkyl, alkenyl, alkynyl, or cyclic group; Y and/or Z are CH2, O, S, SO, SO2, amino, amides, carbamates, ureas, or thiocarbonyl derivatives thereof, optionally substituted with an alkyl, alkenyl, or alkynyl group; n is from 1 to 5; X is a bond, an optionally substituted methylene or ethylene, an amino, O or S; Q is C(O), C(S), or SO2; m is from 0 to 6; R4 is OH, ═O (keto), NH2, or alkylamino, including esters, amides, and salts thereof; and W is C(O), C(S), S(O), or SO2. Optionally, R5 and R6, together with the N—W bond of formula (I), comprise a macrocyclic ring.
Research and development of an efficient synthesis of hexahydrofuro[2,3-b] furan-3-ol moiety - a key component of the HIV protease inhibitor candidates
Yu, Richard H.,Polniaszek, Richard P.,Becker, Mark W.,Cook, Charles M.,Yu, Lok Him L.
, p. 972 - 980 (2012/12/30)
A highly efficient method for synthesizing racemic hexahydrofuro[2,3-b] furan-3-ol has been developed utilizing a lanthanide catalyst, such as Yh(fod)3, to promote condensation of 23-dihydrofuran and glycolaldehyde dimer. Access to either optically enriched enantiomer of bisfuran alcohol can be obtained by using this method employing chiral ligands with the lanthanide catalyst In support of Gilead Sciences' protease inhibitor project, this method has been demonstrated to be a robust and scalable process with potential application for the construction of a variety of furo[2,3-b]furan derivatives.
PROCESS FOR PREPARATION OF HIV PROTEASE INHIBITORS
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Page/Page column 18-19, (2008/06/13)
A process for the synthesis of bisfuran intermediates useful for preparing antiviral HIV protease inhibitor compounds is hereby disclosed.
