- 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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- 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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Page/Page column 4-6
(2019/05/04)
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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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- 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 0016; 0017; 0023; 0024
(2018/09/11)
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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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p. 1874 - 1880
(2016/05/09)
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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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Page/Page column 23
(2017/04/21)
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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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p. 1615 - 1620
(2016/09/23)
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- swiss that Wei method for the preparation of intermediates (by machine translation)
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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).
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Paragraph 0066 - 0669
(2016/10/10)
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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 0171-0173
(2015/07/02)
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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 31
(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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- PROCESS FOR THE PREPARATION OF (3R,3AS,6AR)-HEXAHYDROFURO [2,3-B] FURAN-3-YL (1S,2R)-3-[[(4-AMINOPHENYL) SULFONYL] (ISOBUTYL) AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE
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The present invention relates to a process for the preparation of (3R,3a S,6aR)-hexa-hydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate as well as novel intermediates for use in said process. (3R,3a S,6aR)-hexahydrofuro [2,3-b] furan-3-yl (1S,2R)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate is particularly useful as an HIV protease inhibitor.
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Page/Page column 29
(2010/04/06)
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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 3
(2010/11/30)
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- METHOD AND COMPOSITIONS FOR TREATING HIV INFECTIONS
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Described herein are compounds and compositions that are useful in the treatment of HIV, AIDS, and AIDS-related diseases. In addition, compounds are described herein that are capable of inhibiting the dimerization of HIV proteases.
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Page/Page column 28-29
(2008/12/08)
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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 41
(2008/06/13)
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- Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor
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The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2′ substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.
- Surleraux, Dominique L. N. G.,Tahri, Abdellah,Verschueren, Wim G.,Pille, Geert M. E.,De Kock, Herman A.,Jonckers, Tim H. M.,Peeters, Anik,De Meyer, Sandra,Azijn, Hilde,Pauwels, Rudi,De Bethune, Marie-Pierre,King, Nancy M.,Prabu-Jeyabalan, Moses,Schiffer, Celia A.,Wigerinck, Piet B. T. P.
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p. 1813 - 1822
(2007/10/03)
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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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