- Coupled fermentation-bioconversion process for production of chiral α-chlorohydrin with recombinant ketoreductase
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Enzymatic production of chemicals typically includes fermentation of engineered bacteria, preparation of enzymes, and bioconversion processes. Here coupled fermentation-bioconversion process for production of chiral atazanavir intermediate α-chlorohydrin
- Yang, Zhongyi,Li, Xin,Cai, Ganghua,Peng, Chunlong,Zhong, Yongjun,Luo, Xi
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Read Online
- Synthesis method of (2S, 3S)-3-(t-butyloxycarboryl amino)-1, 2-epoxy-4-phenylbutane
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The invention relates to the technical field of synthesis of drug intermediates, in particular to a synthesis method of (2S, 3S)-3-(t-butyloxycarboryl amino)-1, 2-epoxy-4-phenylbutane. The method comprises the following steps: condensing N-t-butyloxycarboryl-L-phenylalanine serving as a raw material with substituted phenol under the action of a condensing agent to obtain active ester 15; reacting the active ester 15 with a ylide reagent and alkali to obtain a sulfoxide ylide intermediate 16; reacting the sulfoxide ylide intermediate 16 with halide salt under the action of a catalyst to obtain a halogenated ketone intermediate 6; reducing the halogenated ketone intermediate 6 through a reducing agent under the action of a catalyst to obtain a halogenated methanol intermediate 7; and removing halogen acid from the halogenated methanol intermediate 7 under the action of alkali, and carrying out condensation cyclization to obtain the target product (2S, 3S)-3-(t-butyloxycarboryl amino)-1, 2-epoxy-4-phenylbutane. The synthesis method of the (2S, 3S)-3-(t-butyloxycarboryl amino)-1, 2-epoxy-4-phenylbutane, provided by the invention, has the characteristics of cheap and easily available initial raw materials, safe and controllable process and easiness in operation.
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Paragraph 0043; 0048; 0049; 0054
(2021/06/23)
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- Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D
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Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P. falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.
- Zogota, Rimants,Kinena, Linda,Withers-Martinez, Chrislaine,Blackman, Michael J.,Bobrovs, Raitis,Pantelejevs, Teodors,Kanepe-Lapsa, Iveta,Ozola, Vita,Jaudzems, Kristaps,Suna, Edgars,Jirgensons, Aigars
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supporting information
p. 344 - 352
(2018/12/11)
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- A process for the preparation method of the sulfuric acid [...] intermediates
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The invention discloses a method for preparing sulfuric acid [...] intermediate (2 R, 3 S) - 1, 2 - epoxy - 3 - tert-butoxycarbonyl amino - 4 - phenyl butane of the method, the method cheap L - phenylalanine as the starting material, by with the di-T-n-butyl reaction for protecting amino group, with acetic anhydride condensation, with hydrochloric acid after the occurrence of the chloro in the chiral catalyst under the effects of the asymmetric hydrogenation reduction, finally cyclization under basic conditions to obtain the target product. The present invention provides of sulfuric acid is an important intermediate [...] (2 R, 3 S) - 1, 2 - epoxy - 3 - tert-butoxycarbonyl amino - 4 - phenyl butane preparation method of the raw material is cheap, mild reaction conditions, the synthesis efficiency is high, it is suitable for industrial production, in order to prepare sulfuric acid [...] and intermediate provides a highly efficient way.
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- A method of preparing intermediates of luck sha neiwei
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The invention provides a preparation method for a fosamprenir intermediate. The preparation method comprises the following steps: taking benzyl cyanide as a raw material, and performing steps of nitrile hydrolysis, acylation, reaction with a Grignard reagent, ammonization, cyclizing and the like for synthesizing (2R,3S)-1,2-epoxy-3-t-butyloxycarborylamino-4-phenyl butane. The method is reasonable in process, simple to operate, low in cost and high in yield; with the method, industrialization can be well realized and the production efficiency is improved.
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Paragraph 0045; 0051; 0058; 0065
(2018/03/26)
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- A synthetic zara Wei intermediates (by machine translation)
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The invention discloses a method for synthesizing zara Wei intermediate (1S, 2R) - 1 - epoxy ethyl - 2 - phenylethyl amino acid tert-butyl, comprises the following steps: step 1, the 1 - phenyl - 3 - butene - 2 - one in the chiral amino alcohol catalyst 1 under the action of the 2 - nitro-benzylamine generating asymmetric reduction ammoniation reaction, to obtain (S)- 3 - amino - 4 - phenyl - 1 - butene; step 2, will (S)- 3 - amino - 4 - phenyl - 1 - butene with di-T-n-butyl reaction for protecting amino group to obtain (S)- 3 - N - tert-butoxycarbonyl amino - 4 - phenyl - 1 - butene; step 3, will be (S)- 3 - N - tert-butoxycarbonyl amino - 4 - phenyl - 1 - butene in the hand natural spiral alkene phenolalkone iron complex catalyst 2 under the action of the air oxygen in the epoxidation reaction, to obtain (1S, 2R) - 1 - epoxy ethyl - 2 - phenylethyl amino acid tert-butyl. The present invention provides of the important intermediate zara Wei (1S, 2R) - 1 - epoxy ethyl - 2 - phenylethyl amino acid tert-butyl synthetic method of the raw material is cheap, mild reaction conditions, the operation is simple, the synthesis efficiency is high, it is suitable for industrial production, in order to prepare zara Wei and intermediate provides a new way. (by machine translation)
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Paragraph 0014; 0030-0031
(2017/07/22)
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- A saquinavir intermediate preparation method
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The invention discloses a preparation method of a saquinavir intermediate. The preparation method comprises the steps of: enabling (1S, 2S)-(1-benzyl-3-chloro-2-hydroxypropyl) tert-butyl carbamate and methylsulfonyl chloride to be subjected to methyl sulfonylation in triethylamine and methylbenzene and in the nitrogen environment so as to obtain (1S, 2S)-(1-benzyl-3-chloro-2-methanesulfonic acid propyl) tert-butyl carbamate; enabling (1S, 2S)-(1-benzyl-3-chloro-2-methanesulfonic acid propyl) tert-butyl carbamate to react with metallic acetate at the presence of 18-crown ether-6 and methylbenzene to obtain (1S, 2R)-(1-benzyl-3-chloro-2-acetic acid propyl) tert-butyl carbamate; mixing (1S, 2R)-(1-benzyl-3-chloro-2- acetic acid propyl) tert-butyl carbamate with KOH, THF and ethanol, and reacting to obtain (2R, 3S)-1,2-epoxy-3-tert-butyloxycarboryl amino-4-phenyl butane. The preparation method of the saquinavir intermediate is short in reaction time and high in yield.
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Paragraph 0030; 0038; 0040
(2017/08/25)
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- Preparation method for amprenavir intermediate
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The invention relates to a synthesis method for an amprenavir intermediate, an anti-AIDS drug, in particular to a synthesis method for (2R,3S)-1,2-epoxy-3-(tert-butoxycarbonylamino)-4-phenylbutane. The synthesis method comprises the following steps: reacting L-phenylalanine, as a raw material, with acetic anhydride to generate N-acetyl-L-phenylalanine, and then carrying out a Mannich reaction, an Appel reaction and olefin epoxidation to obtain an intermediate. The method for preparing the (2R,3S)-1,2-epoxy-3-(tert-butoxycarbonylamino)-4-phenylbutane is reasonable in route, high in operability and high in yield, and facilitates industrial production.
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Paragraph 0052; 0053
(2016/10/08)
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- Synthetic method for chiral epoxy compound of anti-HIV drug intermediate
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The invention belongs to the field of chemical synthesis and particularly relates to a preparation method for a chiral epoxy compound of an anti-HIV drug intermediate. The method provided by the invention synthesizes the chiral epoxy compound by using a special ligand according to a route represented by the formula. L-phenylalanine used for synthesizing the anti-HIV drug intermediate is low in price and is easily available. The synthetic method is simple and feasible, the yield of the chiral epoxy compound is high, and the synthetic cost of the chiral epoxy compound is obviously lowered compared with that in an existing process.
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Paragraph 0043; 0044; 0045
(2016/10/10)
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- Thionyl Chloride-Mediated Synthesis of tert-Butyl ((S)-1-((R)-Oxiran-2-yl)-2-phenylethyl)carbamate with Boc-Involved Neighboring Group Participation
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A convenient, high-yielding preparation of tert-butyl ((S)-1-((R)-oxiran-2-yl)-2-phenylethyl)carbamate is described. An efficient chiral inversion as the key step is furnished via Boc-involved neighboring group participation mediated by thionyl chloride. This preparation has significant advantages over the previously reported methods with respect to simplicity, cost efficiency, yield, and purification procedure as well as industry reliability.
- Li, Tao,Mei, Mei,Gao, Hongjun,Li, Yuanqiang,Yan, Yongliang,Che, Daqing
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p. 1183 - 1189
(2015/03/18)
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- Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit
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Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.
- Jaudzems, Kristaps,Tars, Kaspars,Maurops, Gundars,Ivdra, Natalija,Otikovs, Martins,Leitans, Janis,Kanepe-Lapsa, Iveta,Domraceva, Ilona,Mutule, Ilze,Trapencieris, Peteris,Blackman, Michael J.,Jirgensons, Aigars
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supporting information
p. 373 - 377
(2014/05/06)
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- PROCESS FOR REDUCTION OF ALPHA-ACYLOXY SULFIDE DERIVATIVES
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The present invention provides an efficient and scalable process to prepare the compound of formula 4 by reduction of the corresponding α-acyloxy sulfides.
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Page/Page column 9
(2012/09/10)
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- New Cathepsin D inhibitor library utilizing hydroxyethyl isosteres with cyclic tertiary amines
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The design and synthesis of hydroxyethylamine isosteres as inhibitors of cathepsin D based on SAR data have been accomplished. A library of 96 of these hydroxyethylamine isosteres are described and many have proven to be very potent inhibitors of human cathepsin D activity as measured using a fluorometric assay technique, via peptide substrate Ac-Glu-Glu(Edans)-Lys-Pro-Ile-Cys-Phe-Phe-Arg- Leu-Gly-Lys(Methyl Red)-Glu-NH2. Compounds showing strongest inhibition of cathepsin D activity were those that contain a hydroxyethyl-N'-2- or N'-(4-chlorophenyl)piperazine moiety (IC50 values range from 0.55 to 8.5 nM), with N'-(2-pyrimidyl)piperizine (IC50 values range from 0.5 to 21.6 nM), with NN'- L-piperazinocolinamide (IC50 values range from 0.001 - 0.25 nM), or N-N'-L-piperazinocolin-N-methylamide (IC50 values range from 0.015 - 7.3 nM) .
- McConnell, Rose M.,Inapudi, Kalyani,Kadasala, Naveen,Yarlagadda, Karthika,Velusamy, Priya,McConnell, James S.,McConnell, Matthew S.,Trana, Carol,Green, Adam,Sayyar, Kelley
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p. 1146 - 1154,9
(2012/12/12)
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- From L-ascorbic acid to protease inhibitors: Practical synthesis of key chiral epoxide intermediates for aspartyl proteases
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Efficient synthetic routes were developed to prepare a sizable amount (4-15 grams) of the chiral epoxides 4-6 as versatile intermediates for the synthesis of aspartyl protease inhibitors of therapeutic interest such as HIV protease and β-secretase. Oxidative cleavage of the C(2)-C(3) double bond of L-ascorbic acid followed by functional group manipulation led to the preparation of the epoxide 10, which was opened with an azide to yield a common aziridine intermediate 12. Through opening of the aziridine ring of 12 with either a carbon or a sulfur nucleophile, chiral epoxide precursors 4-6 could be prepared for various HIV protease inhibitors. Except for the final low melting epoxides 5 and 6, all intermediates were obtained as crystalline solids, thus the synthetic pathway can be easily applied to a large-scale synthesis of the chiral epoxides.
- Chang, Sun Ki,So, Soon Mog,Lee, Sang Min,Kim, Min Kyu,Seol, Kyoung Mee,Kim, Sung Min,Kang, Jae Sung,Choo, Dong Joon,Lee, Jae Yeol,Kim, B. Moon
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p. 2213 - 2218
(2012/09/21)
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- Design, synthesis, and biological evaluation of novel fluorinated ethanolamines
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The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)-type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA-derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed compounds with remarkable BACE1 inhibitory activity. Docking studies revealed the influence of the fluorine atoms in the binding mode of the synthesized ligands. Furthermore, the biological evaluation of our final products and synthesis intermediates led to the discovery of compounds with antimicrobial activity against Mycobacterium and Nocardia species.
- Fustero, Santos,Cunat, Ana C.,Flores, Sonia,Baez, Claribel,Oliver, Judit,Cynamon, Michael,Guetschow, Michael,Mertens, Matthias D.,Delgado, Oscar,Tresadern, Gary,Trabanco, Andres A.
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scheme or table
p. 14772 - 14784
(2012/02/03)
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- Synthesis of chiral iodo-N,O-acetonide aminal scaffolds via an efficient cascade reaction of amino acid-derived epoxides
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Novel amino acid-derived iodo-N,O-acetonide aminals were developed as chiral, non-epimerizable scaffolds to facilitate complex molecule synthesis. These scaffolds are readily prepared from commercially available amino acid derivatives in ≤6 steps, contain an orthogonally-protected β-hydroxy amine moiety, and feature a directly reactive alkyl-iodide group for facile substitution chemistry. Further, a novel ring opening/cyclization cascade reaction was developed to prepare these compounds efficiently (59-72%) from readily available epoxide derivatives.
- Paige Souder,Evans, Zachary M.,Driver, Joshua A.,Pozzo, Eric J.,Lampkins, Andrew J.
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scheme or table
p. 6908 - 6910
(2012/02/15)
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- Convenient method for synthesis of N-protected α-amino epoxides: Key intermediates for HIV protease inhibitors
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A convenient method for synthesis of 2R,3S and 2S,3S N-Boc phenylalanine epoxides using readily available allylamine is described. Previous methods employed multistep synthetic routes from l-phenyl alanine that include use of m-chloroperbenzoic acid (m-CPBA) and a chromatographic method for purification of the desired diastereomers. Column purification could be eliminated by bringing in much improvement in the existing process. The process was further enhanced by replacing m-CPBA with oxone, an ecofriendly reagent advantageous for commercial application. The overall green process discussed involves the recovery and recycling of enantiomers of chiral allyl amines and judicial separation of diastereomers of the epoxides using simple economical methods.
- Blacker, A. John,Roy, Mita,Hariharan, Sivaramkrishanan,Headley, Catherine,Upare, Abhay,Jagtap, Ashutosh,Wankhede, Karuna,Mishra, Sushil Kumar,Dube, Dagadu,Bhise, Sanjay,Vishwasrao, Sandesh,Kadam, Nitin
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p. 331 - 338
(2013/01/10)
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- Synthesis of deuterium-labelled fosamprenavir calcium
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This study describes the synthesis of deuterium-labelled fosamprenavir calcium. The stable isotopic-labelled compound was prepared starting from L-phenylalanine in 18 steps with a 9% overall yield. Copyright
- Shi, Lei,Chen, Liping,Chen, Ryan,Chen, Liqin
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experimental part
p. 148 - 152
(2011/07/31)
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- Expedient asymmetric synthesis of (2S,3S)-Boc-phenylalanine epoxide, a key intermediate for the synthesis of biologically active compounds
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The asymmetric synthesis of (2S,3S)-3-(tert-butoxycarbonyl)amino-1,2-epoxy-4-phenylbutane [(2S,3S)-Boc-phenylalanine epoxide] has been achieved in six steps and in 55% overall yield from the N-benzylimine derived from (R)-2,3-O-isopropylidene-glyceraldehy
- Badorrey, Ramon,Diaz-de-Villegas, Maria D.,Galvez, Jose A.
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experimental part
p. 2226 - 2229
(2010/03/03)
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- Stereoselective synthesis of anti-N-protected 3-amino-1,2-epoxides by nucleophilic addition to N-tert-butanesulfinyl imine of a glyceraldehyde synthon
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(Chemical Equation Presented) A di-O-TBS protected glyceraldehyde synthon was condensed with Ellman's reagent to form a bench-stable N-tert-butanesulfinyl imine 6, which served as a common intermediate for the stereoselective introduction of various R groups. The Ellman adducts were converted to useful multifunctional intermediates 18a-i in one pot. The alcohols 18a-i were efficiently elaborated to both known and novel anti-N-protected-3-amino-1,2- epoxides in two steps. Compound 2a is a key intermediate toward HIV protease inhibitors.
- Harried, Scott S.,Croghan, Michael D.,Kaller, Matthew R.,Lopez, Patricia,Zhong, Wenge,Hungate, Randall,Reider, Paul J.
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experimental part
p. 5975 - 5982
(2009/12/24)
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- Amino acid derived epoxide ring opening under microwave irradiation
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A solvent-free microwave-assisted methodology for the obtainment of the hydroxyethylamine (HEA) isostere is described. A phenylalanine derived aminoalkyl epoxide is allowed to react with a dipeptide amine using basic alumina partially deactivated with water under microwave irradiation. The HEA is obtained in very short time (3 min). This methodology is amenable to application in a parallel or automatic sequential format. Copyright
- Vaiana, Nadia,Rizzi, Luca,Romeo, Sergio
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p. 648 - 649
(2008/02/07)
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- Unnatural amino acid-substituted (hydroxyethyl)urea peptidomimetics inhibit γ-secretase and promote the neuronal differentiation of neuroblastoma cells
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γ-Secretase, exhibiting characteristics of aspartyl protease, mediates the intramembranous proteolysis of β-amyloid precursor protein (APP) and Notch, and it is considered to be a prime pharmacological target in the development of therapeutics for Alzheimer's disease (AD). To identify compounds that block γ-secretase-mediated proteolysis, we used a highly sensitive cell-based reporter gene assay for γ-secretase in which Gal4/VP16-tagged C99-APP was expressed as the immediate substrate of γ-secretase, and Gal4/VP16-tagged APP intracellular domain released by the γ-secretase cleavage then activated the expression of the Gal4-driven luciferase reporter gene. Using this reporter assay, we demonstrated that the newly synthesized (hydroxyethyl)urea peptidomimetics, which contain unnatural amino acid moieties at positions P1′ and/or P3′, can effectively inhibit γ-secretase activity and significantly reduce Aβ production. The γ-secretase-dependent S3 cleavage of Notch was also consistently blocked by these (hydroxyethyl) ureas as evidenced by the decreased generation of the Notch intracellular domain, a prerequisite for the activation of Notch signaling. The inhibition of Notch signaling by active Jia compounds efficiently promotes the neuronal differentiation of neuroblastoma cells, intervening in tumorigenesis and the malignancy of neuroblastomas. Our results suggest that (hydroxyethyl) urea peptidomimetics containing unnatural amino acid substitutions could represent a novel class of γ-secretase inhibitors with enhanced stability, providing the basis for the further development of effective therapeutics for AD and neuroblastomas. Copyright
- Liao, Yung-Feng,Wang, Bo-Jeng,Hsu, Wen-Ming,Lee, Hsinyu,Liao, Chia-Yin,Wu, Shin-Ying,Cheng, Hui-Ting,Hu, Ming-Kuan
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p. 588 - 601
(2008/02/03)
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- Production method of aminochlorohydrin sulfate
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Highly pure (2R,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane or (2S,3R)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane may be conveniently produced in high yield by: (a) reacting compound (1) with lithiumchloromethane to give compound (2) and at least a byproduct; (b) dissolving compound (2) and the byproduct in a polar solvent and adding water to the solution to precipitate compound (2) as crystals; (c) reducing the crystals of compound (2) to give compound (3) and at least its diastereomer as an impurity; (d) adding sulfuric acid thereto to give compound (4) and at least its diastereomer as an impurity; and (e) precipitating compound (4) as crystals from a solution containing acetic acid ester or acetic acid ester.
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Page/Page column 21
(2010/11/26)
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- OXIME DERIVATIVE HYDROXYETHYLAMINE ASPARTYL-PROTEASE INHIBITORS
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The invention relates to novel compounds and methods of treating diseases, disorders, and conditions associated with amyloidosis. Amyloidosis refers to a collection of diseases, disorders, and conditions associated with abnormal deposition of A-beta protein.
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Page/Page column 128-129
(2010/02/15)
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- NOVEL SULFONE AMIDE DERIVATIVES CAPABLE OF INHIBITING BACE
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The present invention relates to novel derivatives of sulfone amide of Formula 1 as defined in this disclosure which inhibit the activity of BACE (or beta-secretase). These sulfone amide derivatives are useful for the treatment and prevention of Alzheimer's disease and related diseases caused by production of beta-amyloid, by inhibiting the activity of BACE.
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Page/Page column 158
(2010/02/11)
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- An efficient synthesis of N-protected threo (2R,3S)-3-amino-1,2-epoxy phenylbutane
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A precise and versatile method was developed for the synthesis of threo amino epoxide derivatives, which are useful intermediates for protease inhibitors. It involves the diastereoselective reduction of the carbonyl group of γ-N,N-dibenzyl amino α-hydroxy β-keto sulfide prepared from an amino acid, and its subsequent stereospecific conversion to an amino epoxide via acetoxy halogenation in high yield.
- Suzuki, Takayuki,Honda, Yutaka,Izawa, Kunisuke
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p. 5811 - 5814
(2007/10/03)
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- Asymmetric transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones with chiral Rh complexes
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Asymmetric transfer hydrogenation of N-substituted (3S)-3-amino-1-chloro-4- phenyl-2-butanones in the presence of Cp*RhCl[(R,R)-Tsdpen] (S/C = 1000) with a mixture of formic acid/triethylamine gave N-substituted (2R,3S)-3-amino-1-chloro-2-hydroxy-4-phenylbutanes with up to 93% de in a quantitative yield, and reduction with the enantiomeric catalyst Cp*RhCl[(S,S)-Tsdpen] gave (2S.3S)-diastereomeric alcohol with up to 96% de.
- Hamada, Takayuki,Torii, Takayoshi,Onishi, Tomoyuki,Izawa, Kunisuke,Ikariya, Takao
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p. 7391 - 7394
(2007/10/03)
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- One-Carbon Chain Extension of Esters to α-Chloroketones: A Safer Route without Diazomethane
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The reaction of a variety of methyl esters with dimethylsulfoxonium methylide at 0-25 °C affords the chain-extended β-keto dimethylsulfoxonium ylides. Subsequent treatment with hydrogen chloride in THF proceeds with loss of DMSO to afford the corresponding α-chloroketones. This sequence has been utilized to convert the methyl esters of CBZ-protected alanine and valine to the anti N-protected α-amino epoxides, which are important pharmaceutical intermediates. When the same protocol is applied to BOC-protected phenylalanine methyl ester, epimerization occurs so that the use of a more reactive aryl ester is required. This chemistry provides a practical route to α-chloroketones that avoids the use of toxic and explosive diazomethane.
- Wang, Dengjin,Schwinden, Mark D.,Radesca, Lilian,Patel, Bharat,Kronenthal, David,Huang, Ming-Hsing,Nugent, William A.
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p. 1629 - 1633
(2007/10/03)
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- Stereoselective synthesis of photoreactive peptidomimetic γ-secretase inhibitors
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The first asymmetric synthesis of novel, potent photoreactive γ-secretase inhibitors 2 and 3 has been accomplished. Two Stereoselective methods for the preparation of lactone 9 are described. Protected benzophenone intermediate 19 is prepared via an aldol-elimination reaction followed by a PtO2-catalyzed asymmetric hydrogenation. Two routes leading from 19 to compounds 2 and 3 are evaluated. The application of 3 as an activity-based probe has been demonstrated by localizing γ-secretase activity in the plasma membrane of intact cells.
- Chun, Jiong,Yin, Ye Ingrid,Yang, Guangli,Tarassishin, Leonid,Li, Yue-Ming
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p. 7344 - 7347
(2007/10/03)
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- Probing pockets S2-S4′ of the γ-secretase active site with (hydroxyethyl)urea peptidomimetics
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(Hydroxyethyl)urea peptidomimetics are potent inhibitors of γ-secretase that are accessible in a few synthetic steps. Systematic alteration of P2-P4′ revealed that the corresponding S2-S4′ active site pockets accommodate a variety of substituents, consistent with the fact that this protease cleaves a variety of single-pass membrane proteins; however, phenylalanine is not well tolerated at P2′. A compound spanning P2-P3′ was identified as a low nM inhibitor of γ-secretase activity both in cells and under cell-free conditions.
- Esler, William P.,Das, Chittaranjan,Wolfe, Michael S.
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p. 1935 - 1938
(2007/10/03)
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- NOVEL GAMMA-LACTAMS AS BETA-SECRETASE INHIBITORS
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There is provided a series of novel substituted gamma-lactams of Formula (I) wherein R1, R2, R3, R4 and R5 are defined herein, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of aβ-peptide. The present invention is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.
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- Enantiodivergent, catalytic asymmetric synthesis of γ-amino vinyl sulfones
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A set of diversely substituted N-Boc-γ-amino vinyl sulfones has been prepared by a four-step procedure from readily available, highly enantiopure anti-N-Boc-3-amino-1,2-alkanediols. This new route, which does not depend on the accessibility of α-amino acids as starting materials, is noteworthy for its efficiency, for its generality, and for the fact that both enantiomers of a given γ-amino vinyl sulfone can be obtained with equal ease.
- Pico, Anna,Moyano, Albert,Pericas, Miquel A.
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p. 5075 - 5083
(2007/10/03)
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- Application of the lewis acid-lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: Stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and β3- adenergic receptor agonist
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Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97:3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of β3-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to β-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.
- Nogami, Hiroyuki,Kanai, Motomu,Shibasaki, Masakatsu
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p. 702 - 709
(2007/10/03)
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- Process for producing alpha-aminoketones
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A process for producing α-aminohalomethyl ketones or N-protected α-aminohalomethyl ketones from specified 3-oxazolidin-5-one derivatives via 5-halomethyl-5-hydroxy-3-oxazolidine derivatives. By this process, α-aminohalomethyl ketones and compounds relating to them can be obtained efficiently and economically in industrial scale.
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- Process for producing alpha-aminoketones
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An amino group of an α-amino acid ester is protected as an imine, and it is then reacted with a halomethyllithium to obtain an N-protected-α-aminohalomethylketone. Further, this N-protected-α-aminohalomethylketone is treated with an acid to obtain an α-aminohalomethylketone. This process is suited for industrial production, and can produce an α-aminohalomethylketone and its related compounds economically and efficiently.
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- Production method of beta-amino-alpha-hydroxycarboxylic acid
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The present invention provides a production method of an optically active β-amino-α-hydroxycarboxylic acid, which includes the following steps (a)-(c): (a) treating an optically active N-carbamate protected β-amino epoxide with an acid to give an optically active 5-hydroxymethyl-2-oxazolidinone; (b) oxidizing the resulting compound in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy and hypochlorite to give an optically active 4-benzyl-2-oxo-5-oxazolidinecarboxylic acid; and (c) treating the 4-benzyl-2-oxo-5-oxazolidinecarboxylic acid with a base, and a production method of an optically active N-carbamate protected β-amino-α-hydroxycarboxylic acid which includes protection of the amino group with a carbamate type protecting group. The industrial production method of the present invention can produce these compounds efficiently.
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- Process research and development for an efficient synthesis of the HIV protease inhibitor BMS-232632
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Development of an efficient and scalable process for the human immunodeficiency virus (HIV) protease inhibitor BMS-232632 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)L-tert- leucinyl]-amino}-4(S)-hydroxy-6-phenyl-2-azahexane, is described. The key step in the synthesis of the intermediate N-1-(tert-butyloxycarbonyl)-N-2-[4-(pyridin-2-yl)benzylidene]hydrazone (11) was the Pd-mediated coupling of boronic acid 9 with 2-bromopyridine. An efficient procedure was developed for the chemoselective reduction of hydrazone 11 to hydrazine carbamate 4. The key intermediate N-(tert-butyloxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxy-butane (6) was prepared stereoselectively from chiral diol 10. The subsequent union of 4 and 6 followed by coupling with N-methoxycarbonyl-L-tert-leucine provided the free base BMS-232632 in high yield. Evaluation of a variety of salts and identification of bisulfate salt 19 with enhanced bioavallability are also described.
- Xu, Zhongmin,Singh, Janak,Schwinden, Mark D.,Zheng, Bin,Kissick, Thomas P.,Patel, Bharat,Humora, Michael J.,Quiroz, Fernando,Dong, Lin,Hsieh, Dau-Ming,Heikes, James E.,Pudipeddi, Madhusudhan,Lindrud, Mark D.,Srivastava, Sushil K.,Kronenthal, David R.,Mueller, Richard H.
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p. 323 - 328
(2013/09/06)
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- Process for producing optically active threo-3-amino-1,2-epoxy compounds
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Highly pure optically active threo-3-amino-1,2-epoxy compounds appropriate for materials for manufacturing drugs and a process for producing the same on an industrial scale. An optically active threo-3-amino-1,2-diol derivative is subjected in an organic solvent in the presence of a base to alkylsufonylation or arylsulfonylation to thereby give the corresponding optically active threo-3-amino-2-hydroxy-1-sulfonyloxy compound. Next, the resultant product is subjected to epoxidation in the presence of a base to give the corresponding optically active threo-3-amino-1,2-epoxy compound. The thus obtained epoxy compound is purified by using an organic solvent and water, thus giving a highly pure epoxy compound.
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- Method for producing epoxide crystal
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The invention relates to a method for industrially producing highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoepoxide (crystal) or (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoalcohol. The method for producing N-carbamate-protected β-aminoepoxide crystal, includes one or more of the following steps (a) to (d): (a) dissolving (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoalcohol containing at least the diastereomer as an impurity in a solvent including at least one or more selected from aromatic hydrocarbon solvent, saturated hydrocarbon solvent, aqueous mixture solvent, acetone and 2-propanol, to remove insoluble matters; (b) treating the (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoalcohol with a base, thereby converting the N-carbamate-protected β-aminoalcohol to (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoepoxide; (c) treating the (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoepoxide containing at least the diastereomer as an impurity with an acid, thereby converting the diastereomer as an impurity to (4S, 5R) or (4R, 5S) oxazolidin-2-one derivative, and optionally separating and removing the resulting oxazolidin-2-one derivative in water or an aqueous mixture solvent; and (d) crystallizing the (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoepoxide in a mixture solvent of water and water-miscible organic solvent. By the methods of the present invention, highly pure (2R, 3S)- or (2S, 3R)-N-carbamate-protected β-aminoepoxide or (2R, 3S) or (2S, 3R)-N-carbamate-protected β-aminoalcohol can be efficiently produced.
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- Process for producing (2R, 3S)-3-amino-1, 2-oxirane
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A process for producing (2R, 3S)-3-amino-4-phenylbutane-1,2-epoxide compounds which comprises treating a (2S, 3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound or a (2S, 3S)-3-amino-4-phenylbutane-1,2-epoxide with a carboxylic acid quaternary ammonium salt or a carboxylic acid metal salt a quaternary ammonium salt and a quaternary ammonium salt, to give a (2S, 3S)-1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound, further treating the same with a sulfonic acid halide in the presence of an organic base to give a (2S, 3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound, furthermore treating said compound with an inorganic base. An intermediate for the production of an HIV protease inhibitor can be produced from L-phenylalanine.
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Page column 6-7
(2008/06/13)
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- Method for the production of a crystalline epoxide
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The present invention provides a production method including adding water to a solution of (2R,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane(1)((2R,3S)-epoxide compound) or (2S,3R)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane(2)((2S,3R)-epoxide compound) in a polar solvent to allow crystallization, whereby to produce crystals of the (2R,3S)-epoxide compound or the (2S,3R)-epoxide compound conveniently in a high yield by an industrial production method without requiring an extremely low temperature.
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- Processes for the preparation of threo-1,2-epoxy-3-amino-4-phenylbutane derivatives
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The present invention provides a production method of high quality threo-1,2-epoxy-3-amino-4-phenylbutane derivatives (1) on a commercial scale in a simple, easy and efficient manner and with very high productivity, which comprises treating a threo-1-halo-2-hydroxy-3-amino-4-phenylbutane derivative (2) with a base in a polar organic solvent or a solvent composed of a polar organic solvent and water, and adding the resulting reaction mixture to water to thereby cause the resulting threo-1,2-epoxy-3-amino-4-phenylbutane derivative (1) to crystallize out.
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Page column 10-11
(2008/06/13)
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- METHOD FOR PURIFYING AND ISOLATING (2S,3S)- OR (2R,3S)-HALOHYDRIN DERIVATIVES
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The present invention has for its object to provide a practical method for the purification and isolation on a commercial scale of said compound (1) or compound (2) in good yield and with high quality. The present invention provides a purification/isolation method of a (2S,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (1) or a (2R,3S)-1-halo-2-hydroxy-3-N-(tert-butoxycarbonyl)amino-4-phenylbutane (2) which comprises, for the purpose of removing contaminant impurity from a mixture containing at least one of said compounds(1) and (2), causing the objective compound (1) or compound (2) to be crystallized in the presence of a solvent comprised of a hydrocarbon solvent and then collecting the obtained crystals.
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- Synthesis of a chiral aziridine derivative as a versatile intermediate for HIV protease inhibitors.
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[reaction: see text] Chiral aziridine derivative 1 was prepared from D-tartaric acid. This compound could be utilized as a common intermediate for the synthesis of hydroxyethylamine class HIV protease inhibitors such as saquinavir, amprenavir, or nelfinavir.
- Kim,Bae,So,Yoo,Chang,Lee,Kang
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p. 2349 - 2351
(2007/10/03)
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- Synthesis of N-BOC-3-amino-1,2-epoxy-4-phenylbutane from (3S)-hydroxy-γ-butyrolactone by means of the Hofmann rearrangement
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The stereocontrolled synthesis of the title alkylaminoepoxide was achieved starting from (3S)-hydroxy-γ-butyrolactone by efficient utilization of the Hofmann rearrangement followed by intramolecular oxazolidinone ring formation as a key step.
- Murakami, Masahiro,Hinoue, Kazumasa,Nakagawa, Kazuya,Monden, Yoshiko,Furukawa, Yoshiro,Katsumura, Shigeo
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- Process for the preparation of (2r,3s)-3-amino-1,2-oxirane
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A process for producing (2R,3S)-3-amino-4-phenylbutane-1,2-epoxide compounds which comprises treating a (2S,3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane compound or a (2S,3S)-3-amino-4-phenylbutane-1,2-epoxide with a carboxylic acid quaternary ammonium salt or a carboxylic acid metal salt a quaternary ammonium salt and a quaternary ammonium salt, to give a (2S,3S)-1-acyloxy-3-amino-2-hydroxy-4-phenylbutane compound, further treating the same with a sulfonic acid halide in the presence of an organic base to give a (2S,3S)-1-acyloxy-3-amino-2-sulfonyloxy-4-phenylbutane compound, furthermore treating said compound with an inorganic base.
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- Process for the reduction of carbonyl compounds
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PCT No. PCT/JP97/00189 Sec. 371 Date Dec. 29, 1997 Sec. 102(e) Date Dec. 29, 1997 PCT Filed Jan. 29, 1997 PCT Pub. No. WO97/28105 PCT Pub. Date Aug. 7, 1997The present invention provides a process for reducing carbonyl compounds to hydroxy compounds, in particular stereoselectively reducing alpha -aminohaloketone derivatives, under mild conditions in an easy and simple manner, which comprises reacting a carbonyl compound of the general formula (1) with an organoaluminum compound of the general formula (4) to provide the corresponding alcohol compound of the general formula (5).
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- A convergent, stereocontrolled synthesis of C2-symmetrical and pseudosymmetrical sulfur-tethered bis(amino alcohols)
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The totally enantiocontrolled preparation of C2-symmetrical and pseudosymmetrical sulfur-tethered bis(amino alcohols) from anti-3-amino-1,2- alkane diols is described. The key step in the synthetic procedure involves the use of triphenylsilanethiol as a sulfide or hydrogenosulfide equivalent in the regioselective nucleophilic ring opening of both anti- and syn- aminoalkyl epoxides.
- Aguilar, Nuria,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 3913 - 3916
(2007/10/03)
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- A totally stereocontrolled route to N-methyl-γ-amino-β-hydroxy acids: Asymmetric synthesis of the amino acid component of hapalosin
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A new approach to the synthesis of N-methyl-γ-amino-β-hydroxy acids, compounds that are essential components of several depsipeptides exhibiting highly interesting therapeutic profiles, is presented. Relevant steps in the synthetic sequence involve the totally stereoselective preparation of a protected aminoalkyl epoxide from a highly enantiopure 2,3-epoxy alcohol, efficient N-methylation and three-step conversion to the desired N-methyl amino acid. The method is exemplified by the enantioselective synthesis of (3R,4S)-4-(N-methylamino)-3-hydroxy-5-phenylpentanoic acid in two differently protected forms.
- Catasus, Monica,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 9309 - 9312
(2007/10/03)
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