- A scalable synthesis of biaryl unit of the HIV protease inhibitor atazanavir
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Atazanavir is one of the most prescribed HIV-1 protease inhibitors approved by the FDA. It was the first protease inhibitor approved for once-a-day dosing to treat AIDS due to good oral bioa-vailability and favorable pharmacokinetic profile. This research aims to develop a new synthetic cost effective process for biaryl-hydrazine unit {tert-butyl 2-[4-(2-pyridinyl)benzyl]hydrazinecarboxylate} of atazanavir on a large scale. The synthesis involved palladium catalyzed Suzuki-Miyaura coupling of 2-chloropyridine and (4-cyanophenyl)boronic acid followed by DIBAL-H reduction of cyano group to aldehyde which is then treated with tert-butyl carbazate to furnish hydrazone subsequently in situ reduction with NaBH4. A large scale synthesis of biaryl-hydrazine unit of atazanavir was accomplished in three steps with 71% overall yield. We have developed a short and efficient synthesis of atazanavir key intermediate biaryl-hydrazine unit. The process does not require the usage of Grignard reagent, expensive catalyst, protection/deprotection of aldehyde moiety and catalytic hydrogenation.
- Katari, Naresh K.,Prasad, Malavattu G.,Reddy, Pedavenkatagari N.,Vijayalakshmi, Chapala
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- Industrial production method of atazanavir intermediate tert-butyl 2-[4-(2-pyridyl)benzyl]-carbazate
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The invention relates to the technical field of biological industry, in particular to an industrial production method of atazanavir intermediate tert-butyl 2-[4-(2-pyridyl)benzyl]-carbazate. The industrial production method includes: subjecting p-chlorobenzaldehyde as a raw material to aldolization, carrying out Grignard coupling reaction, carrying out reductive amination to generate phenylhydrazone, and carrying out hydrogenation to obtain the target product tert-butyl 2-[4-(2-pyridyl)benzyl]-carbazate. Compared with the prior art, the industrial production method has the advantages of high efficiency, good stability, low cost, good operational convenience and the like, and is suitable for continuous production of high-quality products, with product purity reaching 99% and above and unknow impurity content less than 0.3%.
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Paragraph 0035; 0045-0047; 0048; 0058-0060
(2019/04/17)
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- Preparation method of tert-butyl 2-(4-(pyridin-2-yl)benzyl)hydrazinecarboxylate
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The invention discloses a preparation method of tert-butyl 2-(4-(pyridin-2-yl)benzyl)hydrazinecarboxylate. The preparation method comprises the steps that 1, 4-(2-pyridyl)benzaldehyde, ethyl alcohol and tert-butyl carbazate are put into a reaction kettle, and stirring is started; 2, tert-butyl 2-2-[4-(2-pyridyl)benzal]hydrazinecarboxylate is obtained; 3, tert-butyl 2-2-[4-(2-pyridyl)benzal]hydrazinecarboxylate, ethyl alcohol and palladium carbon are put into the reaction kettle, and stirring is started; 4, a sodium formate solution is dropwise added into a solution obtained in the step 3; 5, after a reaction is completed, a finished product is obtained. The preparation method has the following advantages that the production steps are greatly reduced compared with the prior art, and meanwhile a produced by-product is single and easy to separate; absolute ethyl alcohol serving as a solvent can be recycled repeatedly, palladium carbon serving as a catalyst can be used multiple times through recycling and draining, the production cost is lowered, and the production benefit of an enterprise is improved.
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Paragraph 0042; 0043
(2017/05/23)
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- Synthesis and biological evaluation of Hydrazone derivatives as antifungal agents
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Emerging yeasts are among the most prevalent causes of systemic infections with high mortality rates and there is an urgent need to develop specific, effective and non-Toxic antifungal agents to respond to this issue. In this study 35 aldehydes, hydrazones and hydrazines were obtained and their antifungal activity was evaluated against Candida species (C. parapsilosis, C.Tropicalis, C. krusei, C. albicans, C. glabrata and C. lusitaneae) and Trichosporon asahii, in an in vitro screening. The minimum inhibitory concentrations (MICs) of the active compounds in the screening was determined against 10 clinical isolates of C. parapsilosis and 10 of T. asahii. The compounds 4-pyridin-2-ylbenzaldehyde] (13a) and tert-butyl-(2Z)-2-(3,4,5-Trihydroxybenzylidine)hydrazine carboxylate (7b) showed the most promising MIC values in the range of 16-32 μg/mL and 8-16 μg/mL, respectively. The compounds' action on the stability of the cell membrane and cell wall was evaluated, which suggested the action of the compounds on the fungal cell membrane. Cell viability of leukocytes and an alkaline comet assay were performed to evaluate the cytotoxicity. Compound 13a was not cytotoxic at the active concentrations. These results support the discovery of promising candidates for the development of new antifungal agents.
- Casanova, Bruna B.,Muniz, Mauro N.,De Oliveira, Thayse,De Oliveira, Luís Flavio,Machado, Michel M.,Fuentefria, Alexandre M.,Gosmann, Grace,Gnoatto, Simone C. B.
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p. 9229 - 9241
(2016/08/31)
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- Reductive alkylation of hydrazine derivatives with α-picoline-borane and its applications to the syntheses of useful compounds related to active pharmaceutical ingredients
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An efficient method for the direct reductive alkylation of hydrazine derivatives with α-picoline-borane has been developed to synthesize a variety of N-alkylhydrazine derivatives. This method provided N,N-dialkylhydrazine derivatives and N-monoalkylhydrazine derivatives upon fine-tuning of the substrates and the reagent equivalency in a one-pot manner. The method was applied to the synthesis of active pharmaceutical ingredients of therapeutic drugs such as isocarboxazid.
- Kawase, Yasushi,Yamagishi, Takehiro,Kato, Jun-Ya,Kutsuma, Teruo,Kataoka, Tadashi,Iwakuma, Takeo,Yokomatsu, Tsutomu
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p. 455 - 464
(2014/03/21)
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- A three step continuous flow synthesis of the biaryl unit of the HIV protease inhibitor Atazanavir
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The development of multistep continuous flow reactions for the synthesis of important intermediates for the pharmaceutical industry is still a significant challenge. In the present contribution the biaryl-hydrazine unit of Atazanavir, an important HIV protease inhibitor, was prepared in a three-step continuous flow sequence in 74% overall yield. The synthesis involved Pd-catalyzed Suzuki-Miyaura cross-coupling, followed by hydrazone formation and a subsequent hydrogenation step, and additionally incorporates a liquid-liquid extraction step.
- Dalla-Vechia, Luciana,Reichart, Benedikt,Glasnov, Toma,Miranda, Leandro S. M.,Kappe, C. Oliver,De Souza, Rodrigo O. M. A.
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p. 6806 - 6813
(2013/10/01)
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- PROCESS FOR THE PREPARATION OF ARYLPYRIDINYL COMPOUNDS
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A process is described for the preparation of arylpyridine compounds by aryl-aryl cross-coupling reactions between a halopyridine and an arylmagnesium halide carried out in the presence of a catalytic amount of a zinc salt and a catalytic amount of palladium complex with a bidentate phosphine. The zinc salt is preferably selected from ZnCl2, ZnBr2 and/or Zn(OAc)2, while the palladium complex with a bidentate phosphine is preferably selected from the group of (1,2-Bis(diphenylphosphino)ethane)palladium(II) chloride, (1,3-Bis(diphenylphosphino)propane) palladium(II) chloride and (1,4-Bis(diphenylphosphino)butane)palladium(II) chloride. Most preferred is (1,2-Bis(diphenylphosphino)ethane)palladium(II) chloride. It is thus possible to obtain molar yields higher than 95% calculated on the arylmagnesium halide and a catalyticity less than 1 : 1500. The process is particularly suitable for the preparation of 4-(2'-pyridyl)benzaldehyde which can then effectively been converted to N1-(t-butoxycarbonyl)-N2-(4-(2'pyridyl)benzyl)hydrazine.
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Page/Page column 15
(2011/01/12)
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- Azapeptide derivatives as HIV protease inhibitors
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This invention relates to novel compounds of the Formula Ib: that are azapeptides, and pharmaceutically acceptable salts thereof. More specifically, the invention relates to novel azapeptide compounds that are derivatives of the HIV protease inhibitor atazanavir sulfate. This invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are treated by administering HIV protease inhibitors. The invention also relates to the use of one or more of the disclosed compounds as reagents in analytical studies involving atazanavir.
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Page/Page column 33
(2009/01/24)
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- HIV PROTEASE INHIBITING COMPOUNDS
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A compound of the formula (I) is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 113
(2010/02/12)
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- HIV PROTEASE INHIBITING COMPOUNDS
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A compound of the formula is disclosed as an HIV protease inhibitor. Methods and compositions for inhibiting an HIV infection are also disclosed.
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Page/Page column 58
(2010/02/12)
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- Process for the preparation of aryl-pyridinyl compounds
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A process is described for the preparation of arylpyridine compounds by aryl-aryl cross-coupling reactions between a halopyridine and an arylmagnesium halide carried out in the presence of a catalytic amount of a zinc salt and a catalytic amount of palladium. The zinc salt is preferably selected from ZnCl2, ZnBr2 and/or Zn(OAc)2, while the palladium is preferably used in the form of Pd(PPh3)4 or Pd(OAc)2 +4 PPh3. The reaction can also be carried out in the presence of bidentate phosphines, such as, for example, 1,3-bis(diphenylphosphine)propane or 1,4-bis(diphenylphosphine)-butane. It is thus possible to obtain molar yields higher than 97% (calculated relative to the halopyridine) and a catalyticity of more than 2000.
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Page column 15
(2010/02/07)
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- Production method of hydrazine derivative
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A production method of hydrazine derivative having a group of the formula (II) which comprises subjecting a hydrazone derivative having a group of the formula (I) to catalytic reduction and deactivating the reduction catalyst contained in the reaction mixture thereof. According to the production method of the present invention, which is industrially superior, hydrazine derivative (II) stable even in a solution state can be produced
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- Method for producing hydrazine derivative
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The present invention provides a method for producing a hydrazine derivative of the formula [2]: wherein R1 is alkyl group having 1-12 carbon atoms and the like, R2 is alkyl group having 1-12 carbon atoms and the like, and Ar is phenylene group and the like, from a hydrazone derivative of the formula [1] wherein R1, R2 and Ar are as defined above, in the presence of at least one base selected from the group consisting of an organic base and an inorganic base, and a metal hydrogenating catalyst. By this method, reduction proceeds selectively and a hydrogenolysis reaction (side reaction) can be suppressed.
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- Method for producing hydrazine derivative
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The present invention provides a method for producing a hydrazine derivative of the formula [2]: wherein R1is alkyl group having 1-12 carbon atoms and the like, R2is alkyl group having 1-12 carbon atoms and the like, and Ar is phenylene group and the like, from a hydrazone derivative of the formula [1] wherein R1, R2and Ar are as defined above, in the presence of at least one base selected from the group consisting of an organic base and an inorganic base, and a metal hydrogenating catalyst. By this method, reduction proceeds selectively and a hydrogenolysis reaction (side reaction) can be suppressed.
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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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- New aza-dipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: Candidates for clinical development
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On the basis of previously described X-ray studies of an enzyme/aza- dipeptide complex, aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis (L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
- Bold, Guido,F?ssler, Alexander,Capraro, Hans-Georg,Cozens, Robert,Klimkait, Thomas,Lazdins, Janis,Mestan, Jürgen,Poncioni, Bernard,R?sel, Johannes,Stover, David,Tintelnot-Blomley, Marina,Acemoglu, Figan,Beck, Werner,Boss, Eugen,Eschbach, Martin,Hürlimann, Thomas,Masso, Elvira,Roussel, Serge,Ucci-Stoll, Katharina,Wyss, Dominique,Lang, Marc
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p. 3387 - 3401
(2007/10/03)
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