- PROCESS FOR PREPARING BORTEZOMIB, INTERMEDIATES, AND CRYSTALLINE FORMS THEREOF
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The present disclosure provides a process for preparing Bortezomib, intermediates, and crystalline forms thereof.
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Paragraph 0043
(2020/05/29)
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- Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo
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Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.
- Ju, Yuan,He, Lihui,Zhou, Yuanzheng,Yang, Tao,Sun, Ke,Song, Rao,Yang, Yang,Li, Chengwei,Sang, Zitai,Bao, Rui,Luo, Youfu
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p. 3104 - 3119
(2020/03/04)
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- Asymmetric Synthesis of α-Aminoboronates via Rhodium-Catalyzed Enantioselective C(sp3)-H Borylation
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α-Aminoboronic acids, isostructural boron analogues of α-amino acids, have received much attention because of the important biomedical applications implicated for compounds containing this structure. Additionally, the inherent versatility of α-aminoboronic acids as synthetic intermediates through diverse carbon-boron bond transformations makes the efficient synthesis of these compounds highly desirable. Here, we present a Rh-monophosphite chiral catalytic system that enables a highly efficient enantioselective borylation of N-adjacent C(sp3)-H bonds for a range of substrate classes including 2-(N-alkylamino)heteroaryls and N-alkanoyl- or aroyl-based secondary or tertiary amides, some of which are pharmaceutical agents or related compounds. Various stereospecific transformations of the enantioenriched α-aminoboronates, including Suzuki-Miyaura coupling with aryl halides and the Rh-catalyzed reaction with an isocyanate derivative of α-amino acid, affording a new peptide chain elongation method, have been demonstrated. As a highlight of this work, the borylation protocol was successfully applied to the catalyst-controlled site-selective and stereoselective C(sp3)-H borylation of an unprotected dipeptidic compound, allowing remarkably streamlined synthesis of the anti-cancer drug molecule bortezomib and offering a straightforward route for the synthesis of privileged molecular architectures.
- Reyes, Ronald L.,Sato, Miyu,Iwai, Tomohiro,Sawamura, Masaya
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supporting information
p. 589 - 597
(2020/01/22)
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- Virtues of Volatility: A Facile Transesterification Approach to Boronic Acids
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Boronic acids are an increasingly important compound class for many applications, including C-C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic and inefficient step in boronic acid syntheses. We describe an approach that highly facilitates this transformation by leveraging the volatility of methylboronic acid and its diol esters. The method is performed under mild conditions, provides high yields, and eliminates cumbersome and problematic purification steps.
- Hinkes, Stefan P.A.,Klein, Christian D.P.
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p. 3048 - 3052
(2019/05/10)
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- Rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides
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Chiral α- and β-aminoboronic acids exhibit unique biological activities. General methods for the synthesis of these bioisosteres of amino acids are highly desirable. We report a facile preparation of these compounds through rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides. Catalytic asymmetric synthesis of α- and β-aminoboronic esters with high regio-, diastereo-, and enantioselectivities were achieved through effective catalyst control and tuning substrate geometry. Starting from easily available materials this strategy provides a unified synthetic access to both enantioenriched α-boration and β-boration products. The synthetic utility of these methods was demonstrated by efficient synthesis of an anticancer drug molecule and diverse transformations of the boration products.
- Bai, Xiao-Yan,Zhao, Wei,Sun, Xin,Li, Bi-Jie
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p. 19870 - 19878
(2019/12/25)
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- Preparation method of bortezomib synthesis intermediate
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The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation process of a bortezomib synthesis intermediate (R) 1-amino-3-methylbutyl boronic acid pinacol ester hydrochloride. The preparation
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- AN IMPROVED PROCESS FOR THE PREPARATION OF BORONIC ACID ESTERS
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The present invention relates to an improved process for the preparation of a compound of formula (I), wherein PG1 may be independently selected from tert-butyloxycarbonyl (Boc), phthaloyl, 9-fluorenylmethyloxycarbonyl (Fmoc), triphenylmethyl (Trityl), carboxybenzyl (Cbz), trifluoroacetyl, benzyl (Bn), benzylidene, methanesulfonyl (Mesyl), toluene sulfonyl (Tosyl) or acyl; its isolation as solid and use for the preparation of the compound of formula (IV), in particular the compound of formula (IV) i.e. [(1R)-3-methyl-1[[(2S)-1-oxo-3-phenyl-2- [(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid with more than 99.95% chiral purity, as measured by HPLC.
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- A solid-phase approach for the synthesis of α-Aminoboronic acid peptides
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A solid-phase synthesis of α-Aminoboronic acid peptides using a 1-glycerol polystyrene resin is described. Standard Fmoc solid-phase peptide chemistry is carried out to construct bortezomib and ixazomib. This approach eliminates the need for liquid-liquid extractions, silica gel column chromatography, and HPLC purifications, as products are isolated in high purity after direct cleavage from the resin.
- Daniels, Blake E.,Stivala, Craig E.
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p. 3343 - 3347
(2018/02/06)
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- Proteasome inhibitor delanzomib for use in the treatment of lupus
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The present invention provides a method for treating lupus in a subject, comprising the step of administering to the subject Compound A.
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- Novel Boronic Acid Compound Preparation
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The purpose of the present invention is to avoid side effects from contained medicines. Provided are: a preparation obtained by mixing a boronic acid compound and a block copolymer represented by general formula (I); and a production method therefor.
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- Method for preparing chiral amino acid ester and the boron for assists meters with the application in the synthesis of
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The present invention discloses intermediates of chiral alpha-amino boric acid esters, chiral alpha-amino boric acid esters and salts thereof, and key intermediates for the synthesis of bortezomib. The invention also discloses a preparation method for the intermediates of the alpha-amino boric acid esters, and a method for synthesis of the bortezomib by using chiral alpha-amino boric acid esters and salts thereof and using a convergent strategy. According to the present invention, the bortezomib synthesis process route is low in cost, key intermediates are low in production cost, and operations are simple, very easy for industrial production.
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- Manufacturing method for Bortezomib and new intermediate thereof
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The present invention relates to bortezomib and a manufacturing method of a novel intermediate thereof and, more specifically, to a manufacturing method of bortezomib with high yield and purity by using a novel intermediate through a simple manufacturing process, which is a highly appropriate in industrial fields. The manufacturing method of bortezomib represented by chemical formula I according to the present invention comprises the steps of: preparing a boronic acid ester compound represented by chemical formula II by reacting a compound represented by chemical formula III with a compound represented by chemical formula VII; and preparing bortezomib by performing boronic acid deprotection reaction on the compound represented by the chemical formula II.COPYRIGHT KIPO 2015
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- CRYSTALLINE BORTEZOMIB PROCESS
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The present invention provides process for preparation of crystalline Bortezomib (Ia) as its monohydrate which is designated as crystalline Form-SB and characterized by having water content ranging between 3.5-6.0% w/w; X-ray powder diffraction pattern co
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Paragraph 0082; 0083; 0084; 0085
(2015/10/06)
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- PROCESS FOR PREPARING OF BORTEZAMIB
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The present invention provides improved processes for the preparation of Bortezomib, tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) and N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6- methano-1,3,2-benzodioxaborol-2-yl]butyl} phenylalanine of formula (V). Compound (IV) is prepared by coupling (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethyl- hexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine of formula (II) or its salt with N-(tert-butoxycarbonyl)-L-phenylalanine of formula (III) in a first solvent in the presence of a first coupling agent and a first base, wherein the coupling process does not comprise solvent exchange. Compound (V) is prepared by deprotecting compound (IV) using an alcoholic solution of an inorganic acid.
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- PROCESS FOR THE PREPARATION OF BORTEZOMIB
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The present invention relates to a process for the preparation of bortezomib (Formula I) and its intermediates.
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Paragraph 0048
(2013/04/13)
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- Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein
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The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid β-peptide (Aβ) by Amyloid-β Precursor Protein (APP) expressing HEK293 cells by affecting the γ-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent γ-secretase complex but more likely interfere with an upstream target involved in γ-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for Aβ-lowering activity and supported the involvement of a serine protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 μM. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular Aβ production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives.
- Peuchmaur, Marine,Lacour, Marie-Agnes,Sevalle, Jean,Lisowski, Vincent,Touati-Jallabe, Youness,Rodier, Fabien,Martinez, Jean,Checler, Frederic,Hernandez, Jean-Francois
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p. 1018 - 1029
(2013/03/14)
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- Process for Preparing and Purifying Bortezomib
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The present invention provides a synthetic process for producing bortezomib using a novel intermediate. The present invention also provides a process for purifying bortezomib anhydride, and a new crystalline polymorph of bortezomib anhydride.
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Page/Page column 10
(2012/12/13)
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- PROTEASOME INHIBITORS AND PROCESSES FOR THEIR PREPARATION, PURIFICATION AND USE
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The invention provides boronic esters of Formula (I) wherein R1, R2, R3, and R4 are as described herein, and methods for the preparation and purification thereof.
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Page/Page column 123
(2011/08/04)
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- NITRIC OXIDE DONATING PROSTAMIDES
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Nitroderivatives of prostaglandins having improved pharmacological activity and enhanced tolerability are described. They can be employed for the treatment of glaucoma and ocular hypertension.
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Page/Page column 41; 42-44; 47-48
(2009/04/25)
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- Design, synthesis, biological evaluation, and Structure-Activity Relationship (SAR) discussion of dipeptidyl boronate proteasome inhibitors, Part I: Comprehensive understanding of the SAR of α-amino acid boronates
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New series of dipeptidyl boronate inhibitors of 20S proteasome were designed and synthesized. The comprehensive understanding of the SAR was obtained by utilizing the variation of four substituents. From the screened compounds in enzyme, novel inhibitors 49 and 50 were identified to be highly potent druglike candidates with IC50 values of 1.2 and 1.6 nM, respectively, which showed better activities than the drug bortezomib on the market. Two hematologic human tumor cell lines, HL-60 and U266, were significantly sensitive to both candidates and showed nearly the same potency as the standard bortezomib with IC50 values less than 10 nM. But as for most of the eight human solid tumor cell lines, both candidates were more potent than the standard with the IC50 value range of 9.8-70 nM. The activity evaluation of the stereoisomers showed that changing R-isomers to S-isomers greatly reduced the potency and even induced inactivity.
- Zhu, Yongqiang,Zhao, Xin,Zhu, Xinrong,Wu, Gang,Li, Yuejie,Ma, Yuheng,Yuan, Yunxia,Yang, Jie,Hu, Yang,Ai, Li,Gao, Qingzhi
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experimental part
p. 4192 - 4199
(2010/01/16)
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- Asymmetric copper-catalyzed synthesis of α-amino boronate esters from N-tert-butanesulfinyl aldimines
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A general and efficient new method for the asymmetric synthesis of α-amino boronate esters has been developed. The key step is the Cu(I)-catalyzed addition of bis(pinacolato)diboron to N-tert-butanesulfinyl aldimines, which proceeds in good yields (52-88%) and with very high diastereoselectivities (>96:2) for a variety of aldimine substrates. This method was applied to an efficient synthesis of bortezomib, a potent α-amino boronic acid inhibitor of the proteasome that is in clinical use for the treatment of multiple myeloma and mantle cell lymphoma. Copyright
- Beenen, Melissa A.,An, Chihui,Ellman, Jonathan A.
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p. 6910 - 6911
(2008/12/22)
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