- A route to dipeptides containing β-amino-α-hydroxy acid fragments by coupling of N-boc-β-lactams with α-amino esters. Application to the synthesis of (-)-bestatin
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α-Amino esters are smoothly acylated by N-Boc-3-alkoxy-4-alkyl-β-lactams in DMF under the influence of sodium azide, giving a novel dipeptide coupling reaction.
- Palomo,Aizpurua,Cuevas
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Read Online
- A ubenimex in the synthesis of the impurity and its preparation method (by machine translation)
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The invention provides a bestatin the impurities in the raw material, the impurity of the structure has been confirmed, is ubenimex quality control in order to obtain high-quality ubenimex bulk drug. The invention also provides a preparation method of the impurity, the preparation method of the high purity of the product, can be used as the raw materials of the bestatin quality research process impurities to the use of the reference substance. (by machine translation)
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Paragraph 0028-0035
(2019/05/16)
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- Preparation method of ubenimex
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The invention provides a preparation method of ubenimex. The preparation method comprises that L-leucine benzyl ester p-toluenesulfonate and HOBt undergo a condensation reaction to produce an activated ester solution, (2S, 3R)-3-benzyloxyformamido-2-hydroxy-4- phenylbutyric acid and a weak acid strong alkali inorganic salt are mixed, the activated ester solution is added into the mixture drop by drop and undergoes a reaction to produce N-[(2S, 3R)-3-benzoylformamido-2-hydroxy-4-phenylbutyryl]-L-leucine, and N-[(2S, 3R)-3-benzoylformamido-2-hydroxy-4-phenylbutyryl]-L-leucine is reduced into ubenimex through hydrogen gas. The preparation method utilizes ethyl acetate as an organic solvent, saves tetrahydrofuran-caused potential safety hazard, utilizes the weak acid strong alkali inorganic salt as a base catalyst, saves a cost, is free of an organic solvent and is easy to operate.
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Paragraph 0041; 0042; 0043; 0049; 0050; 0051; 0058-0060
(2017/10/27)
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- A synthesis method of ubenimex
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The invention discloses a method for synthesizing ubenimex. The method comprises the following steps: by taking D-Boc-phenyl alaninal as a raw material, sequentially preparing hydroxynitrile, carrying out a nitrile hydrolysis reaction, performing amino protection, performing chiral resolution on (2RS,3R)-3-tert-butoxyacylamino-2-hydroxy-4-phenylbutyric acid, and synthesizing (S)-phenyl-2-((2S,3R)-3-(tert-butoxyacylamino)-2-hydroxy-4-phenylbutyramide)-4-mevalonate, thereby synthesizing the ubenimex. According to the synthetic method disclosed by the invention, the defect that the resolving agent used in the conventional synthetic method is high in toxicity (such as strychnine) or high in price (such as alpha-phenylethylamine) is overcome, the synthetic method is simple in steps and low in cost, and use of reagents such as strychnine is avoided; and moreover, a dextro-amino compound is taken as the chiral resolution agent, the price is low, the operation is simple, the stirring and recrystallization time is shortened, and the synthetic efficiency is greatly improved.
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Paragraph 0016; 0033; 0034; 0044; 0045; 0055; 0056
(2017/05/19)
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- A Ubenimex the asymmetric synthesis of the method of
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The invention relates to an ubenimex synthesis method which is simple and convenient in operation. The method comprises the steps: (S1) catalyzing nitrobenzene ethane and glyoxylic acid, which serve as raw materials, by a catalyst, so as to obtain (2S,3R)-2-hydroxy-3-nitro-4-phenyl-butyric acid; (S2) catalyzing (2S,3R)-2-hydroxy-3-nitro-4-phenyl-butyric acid and L-leucine, which serve as raw materials, by a condensation agent and an activator, so as to obtain N-[(2S,3R)-4-phenyl-3-nitro-2-hydroxy butyryl]-L-leucine; (S3) reducing nitro of N-[(2S,3R)-4-phenyl-3-nitro-2-hydroxy butyryl]-L-leucine, which serves as a raw material, into amino, thereby obtaining ubenimex. By adopting the method to asymmetrically synthesize ubenimex, the steps are simple, subsequent resolution is avoided, the utilization ratio of atoms is high, and the production cost is low.
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Paragraph 0066-0069
(2017/02/09)
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- Common precursor strategy for the synthesis of bestatin, amprenavir intermediate and syn-4-hydroxy-5-phenyl-γ-lactam
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A common precursor strategy for the synthesis of bestatin hydrochloride, an anticancer agent, 1,3-diaminoalcohol, an amprenavir intermediate, and a syn-4-hydroxy-5-phenyl-γ-lactam intermediate of various bioactive molecules using an α,β-unsaturated ester as a common precursor is described. The protocol offers mild reaction conditions, good yields and excellent stereoselectivity.
- Kumar, Brijesh,Aga, Mushtaq A.,Rouf, Abdul,Shah, Bhahwal A.,Taneja, Subhash C.
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p. 17206 - 17209
(2014/05/06)
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- Synthesis of new (-)-bestatin-based inhibitor libraries reveals a novel binding mode in the S1 pocket of the essential malaria M1 metalloaminopeptidase
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The malarial PfA-M1 metallo-aminopeptidase is considered a putative drug target. The natural product dipeptide mimetic, bestatin, is a potent inhibitor of PfA-M1. Herein we present a new, efficient, and high-yielding protocol for the synthesis of bestatin derivatives from natural and unnatural N-Boc-d-amino acids. A diverse library of bestatin derivatives was synthesized with variants at the side chain of either the α-hydroxyβ-amino acid (P1) or the adjacent naturalα-amino acid (P1′). Surprisingly, we found that extended aromatic side chains at the P1 position resulted in potent inhibition against PfA-M1. To understand these data, we determined the X-ray cocrystal structures of PfA-M1 with two derivatives having either a Tyr(OMe) 15 or Tyr(OBzl) 16 at the P1 position and observed substantial inhibitor-induced rearrangement of the primary loop within the PfA-M1 pocket that interacts with the P1 side chain. Our data provide important insights for the rational design of more potent and selective inhibitors of this enzyme that may eventually lead to new therapies for malaria.
- Velmourougane, Geetha,Harbut, Michael B.,Dalal, Seema,McGowan, Sheena,Oellig, Christine A.,Meinhardt, Nataline,Whisstock, James C.,Klemba, Michael,Greenbaum, Doron C.
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experimental part
p. 1655 - 1666
(2011/05/16)
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- A short enantioselective synthesis of (-)-bestatin via l-proline-catalyzed α-amination of an aldehyde
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A short and high yielding enantioselective synthesis of (-)-bestatin, a naturally occurring aminopeptidase inhibitor, is described via l-proline-catalyzed asymmetric α-amination of 3-phenylpropionaldehyde as the key reaction. The methodology also involves a Pd-catalyzed intramolecular cyclization of an allylic acetate giving a trans-oxazoline in a highly diastereoselective manner (dr > 14:1).
- George, Shyla,Suryavanshi, Gurunath S.,Sudalai, Arumugam
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scheme or table
p. 6791 - 6793
(2009/04/06)
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- A total synthesis of (-)-bestatin using Shibasaki's asymmetric Henry reaction
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A total synthesis of the potent aminopeptidase inhibitor (-)-bestatin has been achieved using Shibasaki's asymmetric Henry reaction catalyzed by an optically active rare earth lanthanum-(R)-binaphthol complex in 26% overall yield.
- Gogoi, Naminita,Boruwa, Joshodeep,Barua, Nabin C.
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p. 7581 - 7582
(2007/10/03)
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- New stereoselective synthesis of the peptidic aminopeptidase inhibitors bestatin, phebestin and probestin
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Peptidic aminopeptidase inhibitors, bestatin, phebestin and probestin have been prepared by stereo- and regiocontrolled reactions from a common α,β-epoxy ester precursor.
- Righi, Giuliana,D'Achille, Claudia,Pescatore, Giovanna,Bonini, Carlo
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p. 6999 - 7002
(2007/10/03)
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- Diastereoselective synthesis of syn-aminoalcohols via contributing CH-π interaction: Simple synthesis of (-)-bestatin
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1H NMR and X-ray crystallography studies revealed that a CH-π and chelation control in aromatic aminoaldehydes (1-6) effects a highly diastereoselective addition to afford optically active syn-aminoalcohols (1a-6a). This methodology was applied to the synthesis of (-)-bestatin.
- Lee, Byong Won,Lee, Jin Hwan,Jang, Ki Chang,Kang, Jae Eun,Kim, Jin Hyo,Park, Ki-Min,Park, Ki Hun
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p. 5905 - 5907
(2007/10/03)
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- Chirospecific synthesis of the (2S,3R)- and (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acids from sugar: Application to (-)-bestatin
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The enantiomerically pure (2S,3R)- and (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acids (AHPBA) were first obtained from sugar in a chirospecific manner. Additionally, the obtained (2S,3R)-AHPBA 1 was easily applied to the synthesis of (-)-bestatin.
- Lee, Jin Hwan,Lee, Byong Won,Jang, Ki Chang,Jeong, Ill-Yun,Yang, Min Suk,Lee, Sang Gyeong,Park, Ki Hun
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p. 829 - 836
(2007/10/03)
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- New synthetic technology for efficient construction of α-hydroxy-β-amino amides via the passerini reaction
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The Passerini reaction of N-protected amino aldehydes, isonitriles, and TFA using pyridine-type bases proceeds under mild conditions and directly affords α-hydroxy-β-amino amide derivatives in moderate to high yields. These adducts are readily hydrolyzed to αhydroxy-β-amino carboxylic acids. Application of these key intermediates to concise syntheses of P1-α-ketoamide protease inhibitors is illustrated.
- Semple, J. Edward,Owens, Timothy D.,Nguyen, Khanh,Levy, Odile E.
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p. 2769 - 2772
(2007/10/03)
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- Synthesis of the peptidic α-hydroxy amides phebestin, probestin, and bestatin from α-keto amide precursors
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Aminopeptidase inhibitors, phebestin, probestin and bestatin have been prepared by stereospecific reduction of α-keto amide precursors using zinc borohydride.
- Wasserman, Harry H.,Xia, Mingde,Petersen, Anders K.,Jorgensen, Michael R.,Curtis, Erin A.
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p. 6163 - 6166
(2007/10/03)
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- Synthesis of Bestatin, a Potent Inhibitor of Leukotriene A4 Hydrolase, by an N3 Nucleophile Reaction to a Non-protected Diol
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The synthesis of bestatin (1), based on the regio-selective introduction of a nitrogen function to a non-protected diol 9, is described.
- Koseki, Koshi,Ebata, Takashi,Matsushita, Hajime
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p. 534 - 536
(2007/10/03)
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- A STEREOCONTROLLED SYNTHESIS OF (-)-BESTATIN FROM AN ACYCLIC ALLYLAMINE BY IODOCYCLOCARBAMATION
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1,2-Asymmetric induction of iodocyclocarbamation is described by using allylamines 2 and 6 and the method has been succesfully applied to a stereocontrolled synthesis of bestatin.
- Kobayashi, Susumu,Isobe, Toshiyuki,Ohno, Masaji
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p. 5079 - 5082
(2007/10/02)
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- BESTATIN
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Bestatin, which is (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl!-L-leucine, and related compounds which inhibit aminopeptidase B, leucino aminopeptidase and Bleomycin hydrolase, enhance the anti-tumor effect of Bleomycin and exhibit an antifertility effect were synthesized and tested.
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- Biologically active substance, bestatin, and production thereof
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This invention provides a new chemical named bestatin which inhibits aminopeptidase B, leucine aminopeptidase and bleomycin hydrolase, enhances the antitumor effect of bleomycin, has the chemical name [(2S,3R)-3-amino-2-hydroxy-4-phenylbutanoyl]-L-leucine and has the following structure: STR1 and also provides a process for the production thereof which comprises cultivating a strain of streptomyces which produces bestatin in a nutrient medium under aerobic conditions until substantial activity inhibitory to aminopeptidase B is imparted to said cultured medium and then recovering said bestatin from said cultured medium. A preferred strain is Streptomyces olivoreticuli FERM-P No. 2590 (A.T.C.C. 31159).
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