- A stereoselective anti-aldol route to (3R,3aS,6aR)-hexahydrofuro[2,3-b] furan-3-ol: A key ligand for a new generation of HIV protease inhibitors
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A stereoselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol, an important high affinity P2-ligand, in high enantiomeric excess (>99%) is reported. The synthesis features an ester-derived titanium enolate based highly stereoselective anti-aldol reaction as the key step. Georg Thieme Verlag Stuttgart.
- Ghosh, Arun K.,Li, Jianfeng,Perali, Ramu Sridhar
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- 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
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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.
- Hayashi, Yumi,Aikawa, Toshiaki,Shimasaki, Yasuharu,Okamoto, Hiroaki,Tomioka, Yosuke,Miki, Takashi,Takeda, Masahiro,Ikemoto, Tetsuya
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- Comparing the greenness and sustainability of three routes to an HIV protease inhibitor intermediate
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The greenness and sustainability of three different routes for the synthesis of (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol (bis-furan alcohol), an advanced intermediate for a group of HIV protease inhibitors, including the FDA approved darunavir, used in antiretroviral (ARV) therapy, were compared. The method involved a comparison of (i) waste generated using theE-factor and relative to industrial benchmarks using the innovative Green Aspiration Level (iGAL) method, (ii) solvent usage on the basis of solvent intensity (SI) and properties according to the GSK solvent guide, and (iii) Green Motion scores according to the MANE methodology.
- Akakios, Stephanie Gina,Bode, Moira Leanne,Sheldon, Roger Arthur
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- The efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol and its isomers
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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.
- 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
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- Efficient synthesis of 3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol from glycolaldehyde
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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.
- Canoy, Will L.,Cooley, Bob E.,Corona, John A.,Lovelace, Thomas C.,Millar, Alan,Weber, Aimee M.,Xie, Shiping,Zhang, Yong
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- Practical synthesis of the bicyclic darunavir side chain: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol from monopotassium isocitrate
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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.
- Moore, Gary L.,Stringham, Rodger W.,Teager, David S.,Yue, Tai-Yuen
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- 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
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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.
- Kanemitsu, Takuya,Inoue, Mizuho,Yoshimura, Nono,Yoneyama, Kazutoshi,Watarai, Rie,Miyazaki, Michiko,Odanaka, Yuki,Nagata, Kazuhiro,Itoh, Takashi
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- Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir
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An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol.
- Black, David M.,Davis, Roman,Doan, Brian D.,Lovelace, Tom C.,Millar, Alan,Toczko, Jennifer F.,Xie, Shiping
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- An Efficient Synthesis of the Bicyclic Darunavir Side Chain Using Chemoenzymatic Catalysis
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Herein, we describe a chemoenzymatic synthesis of the bicyclic fragment of Darunavir. A ketoreductase was identified using metagenomic mining to catalyze a highly enantio- and diastereoselective dynamic kinetic resolution of a β-ketolactone. Subsequent lactone reduction with diisobutylaluminum hydride and phase transfer cyclization affords the bicyclic acetal fragment in 39% yield over four steps.
- Charnock, Simon J.,Finnigan, James D.,Hyster, Todd K.,Lim, Jesmine,Riehl, Paul S.
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- METHODS FOR MAKING DARUNAVIR P2-LIGAND PRECURSORS
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A method for making an optically active P2-ligand precursor comprising converting D-xylose or a derivative thereof or D-glucose or a derivative thereof to the optically active P2-ligand precursor.
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- Ru-catalyzed asymmetric transfer hydrogenation of α-acyl butyrolactone via dynamic kinetic resolution: Asymmetric synthesis of bis-THF alcohol intermediate of darunavir
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The Ru-catalyzed enantio- and diastereoselective dynamic kinetic resolution of α-(benzyloxy/benzoyloxy)acyl-γ-butyrolactones has been examined via transfer hydrogenation. Employing the in situ prepared (R,R)-Ru-FsDPEN catalyst, the transfer hydrogenation of using formic acid/triethylamine at rt gave the corresponding (S)-3-((S)-2-(benzyloxy/benzoyloxy)-1-hydroxyethyl)dihydrofuran-2(3H)-one with good to excellent diastereo- and enantioselectivity. One of the resulting hydrogenation product prepared on gram scales was utilized for the synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3–b]furan-3-ol (1), a key synthetic intermediate of various HIV protease inhibitors such as darunavir with excellent enantio- (95% ee) and diastereoselectivities (dr 95:5).
- More, Ganesh V.,Malekar, Pushpa V.,Kalshetti, Rupali G.,Shinde, Mahesh H.,Ramana, Chepuri V.
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supporting information
(2021/02/16)
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- Catalytic asymmetric synthesis of hexahydro-furofuran-3-ol and its pyran derivatives
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The catalytic asymmetric synthesis of hexahydro-furofuran-3-ol, a key fragment of HIV protease inhibitors, is reported. A signature event is represented by the sequential metal catalysis that combines the Pd-catalyzed asymmetric hydroalkoxylation of ene-alkoxyallene and ring-closing metathesis (RCM). Notably, this unprecedented and highly chemoselective approach allows for a unified access to pyranofuranol and furopyranol derivatives.
- Kim, Mijin,Rhee, Young Ho
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supporting information
p. 3584 - 3587
(2021/05/10)
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- Method For Preparing Hexahydrofuro-Furanol Derivative, Intermediate Thereof And Preparation Method Thereof
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The invention relates to the field of pharmaceutical synthesis, in particular to the preparation method of hexahydrofuro-furanol derivative, intermediates thereof and preparation methods thereof. The preparation methods comprises the steps of halogenation reaction, acylation reaction, enzymatic reduction reaction, reaction with amine compounds, reduction ring closure reaction (A1, A2, B, Cp1, CL, Cf) wherein, R1, R2, R3 are hydrogen or hydroxy protecting groups; R4 and R5 are the same or different and are phenyl, alkyl or substituted phenyl. In the preparation process of hexahydrofuro-furanol derivatives, the chirality is constructed by enzymatic method, and the product can be prepared with very high optical purity by adopting such technical means. The preparation method can be used to prepare the key intermediate, (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, of Darunavir, in commercial production, which is a very economical route suitable for industrial production.
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Paragraph 0061-0062
(2021/06/11)
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- Preparation method of hexahydrofuranofuranol derivative, intermediate and preparation method thereof
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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.
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Paragraph 0077-0078; 0081; 0087-0088; 0091
(2021/02/05)
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- 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
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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.
- Ghosh, Arun K.,Markad, Shivaji B.,Robinson, William L.
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p. 1216 - 1222
(2020/12/22)
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- Method For Preparing Hexahydrofuro-Furanol Derivative, Intermediate Thereof And Preparation Method Thereof
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The invention relates to the field of pharmaceutical synthesis, in particular to a preparation method of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivatives and their intermediates. The preparation method is carried out starting from compound Formula A1. In the preparation of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol derivatives, the chirality was constructed by enzymatic method, and the products were prepared with high optical purity. The preparation method can be used to produce the key intermediates of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol of darunavir commercially, which is a very economical route suitable for industrial production.
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- Method for preparing dianavir intermediate
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The invention discloses a method for preparing a Darunavir intermediate and particularly relates to a preparation method of a compound of formula I shown in the description.
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Paragraph 0064-0069
(2021/03/06)
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- Industrial production method of high-purity Derenavir intermediate
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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%.
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Paragraph 0014; 0026-0030; 0035-0039; 0044-0048; 0053-0057
(2019/05/04)
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- Asymmetric One-Pot Synthesis of (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-ol: A Key Component of Current HIV Protease Inhibitors
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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.
- Sevenich, Adrian,Liu, Gong-Qing,Arduengo, Anthony J.,Gupton, B. Frank,Opatz, Till
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p. 1218 - 1223
(2018/06/18)
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- A process for preparing swiss that Wei intermediates (by machine translation)
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The invention discloses a method for preparing swiss that Wei intermediates of the method, the method condensable acetyl acetic acid ethyl ester as the raw material, after 4 step reaction to obtain the key swiss that Wei middle style I compound. The method has reasonable process, the operation is simple, low cost, high yield, through this method can better realize the industrialization, the production efficiency is improved. (by machine translation)
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Paragraph 0026; 0027; 0028
(2017/09/01)
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- Method for preparing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol
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The invention belongs to the field of chemical synthesis, and discloses a method for preparing a darunavir intermediate namely (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol. According to the method, (R)-3-hydroxyl-4-acetaldol derivatives (I) are used as raw materials, and under the action of a catalyst, the (R)-3-hydroxyl-4-acetaldol derivatives (I) stereoselectively react with an ethanediol derivative so as to obtain an intermediate (II); and the obtained intermediate (II) is subjected to protecting group removal, and under the acid condition, cyclization is performed, so that the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is obtained. According to the preparation method, the raw materials are low in cost and easy to obtain, the reaction stereoselectivity is high, the operation is simple, the route is short, the cost is low, and the method is suitable for industrialized production of darunavir.(As shown in the description).
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Paragraph 0031; 0033; 0036; 0042; 0045; 0051; 0060
(2017/08/30)
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- Synthesis of hexahydro furo [2, 3 - b] furan - 3 - ol and its enantiomer
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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.
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- 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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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:
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- METHOD FOR PRODUCING HEXAHYDROFUROFURANOL DERIVATIVE
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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
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Paragraph 0015
(2018/09/11)
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- METHOD FOR PRODUCING HEXAHYDROFUROFURANOL DERIVATIVE
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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.
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Paragraph 0164-0167
(2015/07/02)
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- Crystalline Darunavir
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The present invention relates to a non-solvated crystalline Darunavir, process for its preparation and pharmaceutical composition comprising it. The present invention also relates to a process for the preparation of amorphous Darunavir from a non-solvated crystalline Darunavir.
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- PROCESS FOR THE PREPARATION OF (3R, 3AS, 6AR)-HEXAHYDROFURO [2, 3- B] FURAN-3-OL
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The present invention relates to a novel process for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2, 3-b]furan-3-ol of formula I by reacting a compound of formula VII with the compound of formula R2-OH in the presence of haloginating agent to obtain a compound of formula VI and treating a compound of formula VI with dehaloginating agent to obtain a compound of formula V by reducing a compound of formula V, followed by cylization to obtain compound of formula IV and separating the enantiomer and diastereomers from compound of formula IV to yield a compound of formula I. Compound of formula I is useful as an intermediate in the preparation of protease inhibitors, in particular broad spectrum HIV protease inhibitors, the present invention also relates to process for the preparation of Darunavir from (3R, 3aS, 6aR)-hexahydrofuro[2, 3-b]furan-3-ol.
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- Enzymatic process for the preparation of butyrolactones
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The invention relates to a process for the preparation of a compound of formula wherein R1 is selected from the group consisting of hydrogen, C2-11-acyl, C4-9-cycloalkanoyl, aryl, aralkyl, aroyl, hetaryl, hetaralkyl and hetaroyl, comprising a biotransformation of a compound of formula wherein R1 is as defined above, wherein said biotransformation is carried out using a polypeptide having aldo-keto reductase activity or a microorganism containing same.
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Paragraph 0104
(2013/09/12)
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- PROCESS FOR THE PREPARATION OF (3R, 3AS, 6AR)-HEXAHYDROFURO [2, 3- B] FURAN-3-OL
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The present invention relates to a novel process for the preparation of (3R, 3aS, 6aR)- hexahydrofuro [2, 3-b] furan-3-ol of formula I by reacting a compound of formula VII with the compound of formula R2-OH in the presence of haloginating agent to obtain a compound of formula VI and treating a compound of formula VI with dehaloginating agent to obtain a compound of formula V by reducing a compound of formula V, followed by cylization to obtain compound of formula IV and separating the enantiomer and diastereomers from compound of formula IV to yield a compound of formula I. Compound of formula I is useful as an intermediate in the preparation of protease inhibitors, in particular broad spectrum HIV protease inhibitors, the present invention also relates to process for the preparation of Darunavir from (3R, 3aS, 6aR)-hexahydrofuro [2, 3-b] furan-3-ol.
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- PROCESSES AND INTERMEDIATES FOR PREPARING SUBSTITUTED HEXAHYDROFURO [2,3-B] FURANS
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The invention described herein pertains to processes and compounds useful in the preparation of bis-tetrahydrofurans. The invention described herein also pertains to compounds useful for treating HIV infections.
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Page/Page column 12; 24; 25
(2012/06/16)
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- Stereoselective synthesis of cis-fused perhydrofuro[2,3-b]furan derivatives from sugar-derived allyl vinyl ethers
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A stereoselective methodology has been developed for the construction of cis-fused perhydrofuro[2,3-b]furans, via 3-C-branched glycal derivatives, involving Claisen rearrangement of sugar-derived allyl vinyl ethers, followed by a one-pot ozonolysis and acid-mediated acetalization. The methodology was used for the stereoselective synthesis of the P2 ligand in the recently FDA approved HIV protease inhibitor darunavir (Prezista). The methodology was also successfully used for the synthesis of cis-fused perhydro-5-oxofuro[2,3-b] furan derivatives.
- Sridhar, Perali Ramu,Reddy, Gadi Madhusudhan,Seshadri, Kalapati
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p. 6228 - 6235
(2013/01/15)
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- PROCESS FOR THE PREPARATION OF DARUNAVIR AND DARUNAVIR INTERMEDIATES
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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.
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Page/Page column 34
(2011/08/21)
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- Biocatalytic resolution of bis-tetrahydrofuran alcohol
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A simple and efficient process has been developed to effect the kinetic resolution of the racemic alcohol 2 using immobilized lipase to afford the desired optically pure (R)-bis-tetrahydrofuran (bis-THF) alcohol 3, to facilitate the rapid progression of a clinical candidate. Rapid optimization and development of reproducible and scalable processes are essential to meet aggressive timeframes for preclinical, safety, and early clinical drug development. Process parameters were initially scoped and optimized using a combination of a rational bioprocess screening design and parallel microscale empirical studies, specifically accounting for scale-up and downstream processing considerations. The choices of reaction solvent, acyl donor, and immobilized biocatalyst proved to be critical factors in the design of a conveniently scalable and enantioselective enzymatic resolution process. The improved process was initially validated on 3-g and then 90-g scale in simple impeller-stirred reactors, exhibiting excellent reproducibility. This methodology was successfully implemented on a multikilogram scale to give the target alcohol 3 with >99% ee.
- Khmelnitsky, Yuri L.,Michels, Peter C.,Cotterill, Ian C.,Eissenstat, Michael,Sunku, Venkataiah,Veeramaneni, Venugopal R.,Cittineni, Hariprasad,Kotha, Gopal R.,Talasani, Shyamsunder R.,Ramanathan, Krishna K.,Chitineni, Vakula K.,Venepalli, Bhaskar R.
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experimental part
p. 279 - 283
(2011/10/01)
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- Design, synthesis, and X-ray structure of substituted bis-tetrahydrofuran (bis-THF)-derived potent HIV-1 protease inhibitors
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We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (Ki = 2.9 pM; IC50 = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.
- Ghosh, Arun K.,Martyr, Cuthbert D.,Steffey, Melinda,Wang, Yuan-Fang,Agniswamy, Johnson,Amano, Masayuki,Weber, Irene T.,Mitsuya, Hiroaki
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scheme or table
p. 298 - 302
(2011/06/21)
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- Synthesis of bioactive natural products by asymmetric syn-and anti-aldol reactions
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The use of several variants of the asymmetric aldol reaction as key steps in the syntheses of bioactive target molecules is described. Georg Thieme Verlag Stuttgart.
- Ghosh, Arun K.,Dawson, Zachary L.
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scheme or table
p. 2992 - 3002
(2010/04/02)
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- METHOD FOR THE SYNTHESIS OF HEXAHYDROFURO (2, 3-B) FURAN-3-OL COMPOUNDS
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The present invention relates to a method for the synthesis of enantiomerically and diastereomerically enriched hexahydro-furo[2,3-b]furan-3-ol compounds by aldol coupling of two suitable O-protected hydroxyaldehydes and subsequent removal of the protecting groups and (optionally simultaneous) cyclization of the resulting aldol compound and subsequent isolation of the desired compounds. The resulting composition can be further diastereomerically enriched through the intermittent acylation or aroylation of the compound and further optionally using a stereoselective hydrolyzing enzyme.
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Page/Page column 24-25
(2008/06/13)
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- FITNESS ASSAY AND ASSOCIATED METHODS
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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.
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Page/Page column 18; Sheet 2
(2010/11/30)
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- 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
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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.
- Yu, Richard H.,Polniaszek, Richard P.,Becker, Mark W.,Cook, Charles M.,Yu, Lok Him L.
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p. 972 - 980
(2012/12/30)
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- PROCESS FOR PREPARATION OF HIV PROTEASE INHIBITORS
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A process for the synthesis of bisfuran intermediates useful for preparing antiviral HIV protease inhibitor compounds is hereby disclosed.
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Page/Page column 18-19
(2008/06/13)
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- METHOD FOR PRODUCING HEXAHYDROFUROFURANOL DERIVATIVE
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Disclosed is a method for producing a compound (IV) which comprises a step for obtaining a compound (III) by reacting a compound (I) with a compound (II) in the presence of an optionally substituted cyclic secondary amine, and a step for obtaining the compound (IV) by removing R1 and R2 from the compound (III) sequentially or at a time and then cyclizing the compound from which the R1 and R2 are removed. Also disclosed is a method for producing a high-purity compound (IV), an intermediate thereof, and a method for producing the intermediate.
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Page/Page column 30-31
(2008/06/13)
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- METHODS FOR THE PREPARATION OF (3R,3aS,6aR) HEXAHYDRO-FURO[2,3-b]FURAN-3-OL
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The present invention relates to methods for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol (6) as well as a novel intermediate, (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one (4) for use in said methods. More in particular the invention relates to a stereoselective method for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol, as well as methods for the crystallization of (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan- 2-one and for the epimerization of (3aR,4R,6aS) 4-methoxy-tetrahydro-furo[3,4-b]-furan-2-one to (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one.
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Page/Page column 47
(2008/06/13)
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- Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
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The present invention provides a method for producing compound (XIV) useful as an intermediate for pharmaceutical agents efficiently and economically on an industrial scale without using ozone oxidation and highly toxic reagent, and an intermediate used for this method. Particularly, the present invention provides a method for producing a compound having an absolute configuration represented by the formula (XV) and an enantiomer thereof without using a technique such as optical resolution and the like, and an intermediate used for this method. (1) Compound (XIII) as a starting material is led to compound (I), and after introducing a protecting group, subjected to reduction and cyclization to give compound (XIV). Particularly, compound (XIII) as a material is led to compound (I) via compound (XX) to produce compound (XIV). Using an optically active compound (XIII) as a starting material, a compound having an absolute configuration represented by the formula (XV) and the like are produced highly stereoselectively. (2) Compound (XXI) as a starting material is stereoselectively reduced to give compound (XXII), and by introduction of a protecting group, reduction and cyclization, compound (XXVI) is obtained, and by inverting hydroxyl group, compound (XV) is produced. wherein each symbol is as defined in the specification.
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- Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3- b]furan-3-ol
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(Chemical Equation Presented) Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O- isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.
- Quaedflieg, Peter J. L. M.,Kesteleyn, Bart R. R.,Wigerinck, Piet B. T. P.,Goyvaerts, Nicolaas M. F.,Vijn, Robert Jan,Liebregts, Constantinus S. M.,Kooistra, Jaap H. M. H.,Cusan, Claudia
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p. 5917 - 5920
(2007/10/03)
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- Production method of hexahydrofurofuranol derivative, intermediate therefor and production method thereof
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The present invention provides a method for producing compound (XIV) useful as an intermediate for pharmaceutical agents efficiently and economically on an industrial scale without using ozone oxidation and highly toxic reagent, and an intermediate used for this method. Particularly, the present invention provides a method for producing a compound having an absolute configuration represented by the formula (XV) and an enantiomer thereof without using a technique such as optical resolution and the like, and an intermediate used for this method. (1) Compound (XIII) as a starting material is led to compound (I), and after introducing a protecting group, subjected to reduction and cyclization to give compound (XIV). Particularly, compound (XIII) as a material is led to compound (I) via compound (XX) to produce compound (XIV). Using an optically active compound (XIII) as a starting material, a compound having an absolute configuration represented by the formula (XV) and the like are produced highly stereoselectively. (2) Compound (XXI) as a starting material is stereoselectively reduced to give compound (XXII), and by introduction of a protecting group, reduction and cyclization, compound (XXVI) is obtained, and by inverting hydroxyl group, compound (XV) is produced. wherein each symbol is as defined in the specification.
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Page/Page column 27
(2008/06/13)
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- PREPARATION OF STEREOISOMERS OF (3ALPHA, 3ALPHA/BETA, 6ALPHA/BETA) HEXAHYDROFURO[2,3-b]FURAN-3-OL
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The present invention provides processes and compounds that are useful in the preparation of (3α, 3aβ, 6aβ)-hexahydrofuro[2,3-b]furan-3-ol and diastereoisomers thereof, which are useful in the preparation of compounds that may be inhibitors of HIV aspartyl protease.
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- Stereoselective photochemical 1,3-dioxolane addition to 5-alkoxymethyl-2(5H)-furanone: Synthesis of bis-tetrahydrofuranyl ligand for HIV protease inhibitor UIC-94017 (TMC-114)
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A convenient synthesis of (3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan, a high-affinity non-peptidal ligand for HIV protease inhibitor UIC-94017, is described. This inhibitor is undergoing advanced clinical trials. The synthesis utilizes a novel stereoselective photochemical 1,3-dioxolane addition to 5(S)-benzyloxymethyl-2(5H)-furanone as the key step. The requisite furanone derivative was prepared in high enantiomeric excess by an immobilized lipase-catalyzed selective acylation of (±)-1-(benzyloxy)-3-buten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst. Optically active bis-THF was converted to protease inhibitor 2 (UIC-94017).
- Ghosh, Arun K.,Leshchenko, Sofiya,Noetzel, Marcus
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p. 7822 - 7829
(2007/10/03)
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- METHOD OF PREPARING (3R, 3aS, 6aR) -3- HYDROXYHEXAHYDROFURO [2, 3-b] FURAN AND RELATED COMPOUNDS
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A method of synthesizing (3R, 3aS, 6aR) -3- hydroxyhexahydrofuro [2, 3-b] furan (I), and related compounds, in high yield and high enantiomeric selectivity is disclosed. Also disclosed is a method of manufacturing (5S) -5-(benzyloxymethyl) -5H-furan-2-one.
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- Stereoselective synthesis of optically active perhydrofuro[2,3-b]furan derivatives
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(1R,5S)-2,8-Dioxabicyclo[3.3.0]octan-3-one and its derivatives, important subunits in various biologically active natural products, have been synthesized based on a new approach using the asymmetric oxyselenenylation of 2,3-dihydrofuran as the key step.
- Uchiyama, Masahiko,Hirai, Manabu,Nagata, Momoko,Katoh, Rui,Ogawa, Risa,Ohta, Akihiro
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p. 4653 - 4656
(2007/10/03)
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- Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
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Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
- Ghosh,Kincaid,Walters,Chen,Chaudhuri,Thompson,Culberson,Fitzgerald,Lee,McKee,Munson,Duong,Darke,Zugay,Schleif,Axel,Lin,Huff
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p. 3278 - 3290
(2007/10/03)
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- Evaluation of furofuran as a P2 ligand for symmetry-based HIV protease inhibitors
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The hexahydrofurofuranyloxy group was evaluated as a conformationally constrained P2 ligand for symmetry-based HIV protease inhibitors. A number of compounds showed nM level activity against HIV in MT4 cells and lower protein binding than the licensed protease inhibitor ritonavir. However, replacement of 5-thiazole of ritonavir with a furofuran caused a reduction of the bioavailability in vivo.
- Chen, Xiaoqi,Li, Lin,Kempf, Dale J.,Sham, Hing,Wideburg, Norman E.,Saldivar, Ayda,Vasavanonda, Sudthida,Marsh, Kennan C.,McDonald, Edith,Norbeck, Daniel W.
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p. 2847 - 2852
(2007/10/03)
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