- A facile and efficient synthesis of d3-labelled Reyataz
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A facile and efficient synthesis of d3-labelled Reyataz is described. The key step of synthesis involved the coupling of N-(d 3-methoxycarbonyl)-L-tert-leucine 2b with an advanced chiral non-racemic building block 4. The latter was synthesized in 4 steps from the readily accessible hydrazine derivative 8. Copyright
- Zhang, Huiping,Bonacorsi Jr., Samuel J.,Chen, Bang-Chi,Leith, Leslie W.,Rinehart, J. Kent,Balasubramanian, Balu,Barrish, Joel C.
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- TABLETED COMPOSITIONS CONTAINING ATAZANAVIR
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Disclosed are compressed tablets containing atazanavir sulfate, optionally with another active agents, e.g., anti-HIV agents, granules that contain atazanavir sulfate and an intragranular lubricant that can be used to make the tablets, compositions comprising a plurality of the granules, processes for making the granules and tablets, and methods of treating HIV.
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Paragraph 0085; 0086; 0087; 0088; 0089; 0090-0094
(2018/06/01)
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- Method for synthesis of atazanavir
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The invention discloses a method for synthesis of atazanavir. The method comprises that a compound methyl (S)-1-((S)-2-ethoxyethyl-1-phenylethane-2-yl-amino)-3, 3-dimethyl-1-carbonylbutane-2-yl-carbamate shown in the formula V and a compound N-1-[N-(methoxycarbonyl)-L-tertiary leucine]-N-2-[4-(2-pyridyl)-benzyl]hydrazine shown in the formula VIII undergo a nucleophilic substitution reaction in anorganic solvent to produce a compound 1-[4-(2-pyridyl)phenyl]-5(S)-2, 5-bis{[N-(methoxycarbonyl)-L-tertiary leucine]amino}-4(S)-hydroxy-6-phenyl-2-azahexane VIII shown in the formula IX, wherein the compound shown in the formula IX is atazanavir. The method utilizes raw materials having a wide raw material source, the product is easy to purify, a cost is low, the synthesis processes are simple, the operation is simple, the process is simple, special requirement on equipment is avoided and large-scale production feasibility is realized.
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- A process for preparing Atazanavir monomer
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The invention discloses a method for preparing an atazanavir monomer. The method is applied to the technical field of medicines and comprises steps as follows: at the proper temperature, weak base is used as an acid-binding agent, under a certain organic solvent condition, N-methoxycarbonyl-L-tert-leucine firstly reacts with thionyl chloride to produce N-methoxycarbonyl-L-tert-leucine acyl chloride, then the N-methoxycarbonyl-L-tert-leucine acyl chloride and 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-diamino-6-phenyl-2-azahexane have an amide formation reaction at the room temperature, and the atazanavir monomer is obtained. The method has the advantages as follows: (1), the thionyl chloride is cheap, so that the costs of raw materials are effectively reduced, and the method is suitable for industrialization; (2), the produced pollution is less and is converted into soluble effluent brine after after-treatment, so that the method is relatively environment-friendly; (3), the operation is simple, the product yield is high, separation and purification are easy, and the method is suitable for industrial production.
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Paragraph 0020-0022
(2017/08/25)
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- Method for preparing anti-AIDS drug-Atazanavir monomer
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The invention discloses a method which is used for preparing an Atazanavir monomer and applied in the technical field of drug synthesis. The method comprises the steps that N-methoxycarbonyl-L-tertiary leucine and 1-[4-(pyridine-2-yl)-phenyl]-4(S)-hydroxyl-5(S)-2,5-diamido-6-phenyl-2-aza-hexane are subjected to an amidation reaction by taking HATU as a condensing agent under the condition of organic alkali and an organic solvent, certain aftertreatment is conducted, and then the Atazanavir monomer is obtained. According to the method, the synthetic yield of Atazanavir is increased, the purity is high, and the cost of raw materials is effectively reduced; meanwhile, the reaction time is short, material putting is easy, nitrogen protection is not needed, the material putting temperature can be properly controlled, by-products of HATU can be washed off more easily, the preparation time is greatly shortened, the working efficiency is improved, and therefore the method is suitable for industrial production.
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Paragraph 0022; 0023; 0024; 0025
(2017/06/02)
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- Method for synthesizing atazanavir
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The invention discloses a method for synthesizing atazanavir. The method comprises the following steps: performing nucleophilic substitution reaction on N-1-(t-butyloxycarboryl)-N-2-[4-(2-pyridyl) benzylidene]-hydrazine and (3S)-3-(t-butyloxycarboryl) amino-1-chlorine-4-phenyl-2-butanone, so as to obtain a compound III; removing a protection group of the compound III, performing condensation reaction on N-methoxycarbonyl-L-tertiary leucine, so as to obtain a compound IV; performing reduction reaction on the compound IV, thereby obtaining a final product, namely atazanavir. The method disclosed by the invention has the advantages of being gentle in reaction condition, high in security, simple and convenient to operate, simple in purification treatment on final products, high in purity, stable in quality, easy in raw material obtaining, low in price, high in total yield and the like, the total cost is greatly lowered, and the method is applicable to large-scale industrial production requirements.
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Paragraph 0012; 0017
(2017/09/13)
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- PROCESS FOR THE PREPARATION OF ATAZANAVIR OR ITS BISULFATE SALT
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The present invention relates to an improved process for the preparation of atazanavir bisulfate, an inhibitor of retroviral aspartate protease. The process of the present invention comprises conversion of 1,1-dimethylethyl[(2S,3R)-4-chloro-3-hydroxy-phenylbutan-2-yl]carbamate (Formula II) into 1-[4-(pyridine-2-yl)-phenyl]-4(S)-5 hydroxy-2-N-tert-butoxycarbonylamino-5(S)—N—(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Formula VII) without isolating intermediate compounds formed therein, followed by its subsequent conversion to atazanavir or its bisulfate salt.
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- PROCESS FOR PREPARATION OF ATAZANAVIR OR ITS BISULFATE SALT
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The present invention relates to an improved process for the preparation of atazanavir bisulfate, an inhibitor of retroviral aspartate protease. The process of the present invention comprises conversion of 1,1-dimethylethyl[(2S,3R)-4-chloro-3-hydroxy- -phenylbutan-2-yl]carbamate (Formula II) into 1-[4-(pyridine-2-yl)-phenyl]-4(S)-5 hydroxy-2-N-tert-butoxycarbonylamino-5(S)-N-(N-methoxycarbonyl-(L)-tert- leucyl)amino-6-phenyl-2-azahexane (Formula VII) without isolating intermediate compounds formed therein, followed by its subsequent conversion to atazanavir or its bisulfate salt.
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- PROCESS FOR THE PREPARATION OF ATAZANAVIR SULFATE SUBSTANTIALLY FREE OF DIASTEREOMERS
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The present invention provides atazanavir sulfate substantially free of diastereomeric impurities. The present invention also provides atazanavir sulfate having D-tertiary leucine analogues less than 0.1%. The present invention further relates to an improved process for preparing atazanavir sulfate, substantially free of its diastereoisomeric impurities, which comprises of reacting diamino compound (IV) with N-methoxycarbonyl-(L)-tertiary-leucine (V) having D-isomer less than 0.1 % to obtain atazanavir base; conversion of atazanavir base to atazanavir sulfate by reacting with sulfuric acid and crystallization of atazanavir sulfate from suitable organic solvent(s).
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Page/Page column 16; 17
(2011/10/03)
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- Methods for predicting the response to statins
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The invention provides methods for optimizing therapeutic efficacy for treating hypercholesterolemia in a subject having a cardiovascular disease (CVD), comprising (a) determining subject characteristics that affect the likelihood of reaching a goal level of low density lipoprotein (LDL); and (b) obtaining success probabilities of a variety of statin treatments for reaching said goal level of LDL using said subject characteristics and a multivariate model; and (c) administrating the optimal statin treatment with the highest success probability of step (b) to said subject thereby optimizing therapeutic efficacy for treating hypercholesterolemia in said subject.
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- PREPARATION PROCESS OF AN ANTIVIRALLY HETEROCYCLIC AZAHEXANE DERIVATIVE
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A process for the preparation of atazanavir or its pharmaceutically salts, or its solvates, which comprises condensing N-(methoxycarbonyl)-L-tert-leucine and 1-[4-(piridyn-2-yl)phenyl-4(S)-hydroxy]-5-(S)-2,5-diamino-6-phenyl-2-azahexane or a salt thereof using N,N-diisopropylcarbodiimide or N,N-dicyclohexylcarbodiimide and a tertiary organic amine, being the condensation carried out in the absence of 1-hydroxy-benzotriazole.
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Page/Page column 9-11
(2010/12/31)
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- Process for Synthesizing Atazanavir
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This invention relates to a process for synthesizing Atazanvir, including novel intermediates and novel steps to various intermediates along the synthetic pathway.
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Page/Page column 19-20
(2009/10/31)
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- PROCESS FOR SYNTHESIZING ATAZANAVIR
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This invention relates to a process for synthesizing Atazanavir, Formula (I), including novel intermediates and novel steps to various intermediates along the synthetic pathway.
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Page/Page column 42; 34
(2009/12/05)
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- An efficient and practical synthesis of the HIV protease inhibitor atazanavir via a highly diastereoselective reduction approach
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An efficient and practical synthesis of the HIV-1 protease inhibitor Atazanavir was developed by employing the diastereoselective reduction of ketomethylene aza-dipeptide isostere 10 as the key and final step. The high diastereoselectivity of the amino ketone reduction by lithium tri-iert-butoxyaluminum hydride in diethyl ether to afford the desired svn-1,2-amino alcohol structure was achieved by Felkin- Anh control as a result of the bulky and chiral N-(methoxycarbonyl)-L-tert-leucinyl moiety as the nitrogen protecting group. The coupling of the two key intermediates, N-(methoxycarbonyl)-L-tert-leucine acylated benzyl hydrazine 7 and chloromethyl ketone 9, via an SN2 reaction furnished the amino ketone 10 in high yield under our optimized conditions. Our new methodology features the late introduction of the S-hydroxyl group and the early acylation of benzyl hydrazine and chloromethyl ketone with N-(methoxycarbonyl)-L-tert-leucine, respectively, which confers high efficiency and easy purification.
- Fan, Xing,Song, Yan-Li,Long, Ya-Qiu
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- Process for the preparation of atazanavir
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The invention relates to a process for the preparation of Atazanavir, which comprises reacting the hydrochloride salt of compound (6) with N-methoxycaxbonyl-L-tert-leucine, the removal of the benzyloxycarbonyl group and the reaction with methoxycarbonyl chloride. The process is particularly advantageous in that it allows to use reduced amounts of N-methoxycarbonyl-L-tert-leucine and avoids the use of unstable intermediates.
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Page/Page column 7
(2008/12/06)
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- Process for preparing atazanavir bisulfate and novel forms
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A process is provided for preparing the HIV protease inhibitor atazanavir bisulfate wherein a solution of atazanavir free base is reacted with concentrated sulfuric acid in an amount to react with less than about 15% by weight of the free base, seeds of Form A crystals of atazanavir bisulfate are added to the reaction mixture, and as crystals of the bisulfate form, additional concentrated sulfuric acid is added in multiple stages at increasing rates according to a cubic equation, to effect formation of Form A crystals of atazanavir bisulfate. A process is also provided for preparing atazanavir bisulfate as Pattern C material. A novel form of atazanavir bisulfate is also provided which is Form E3 which is a highly crystalline triethanolate solvate of the bisulfate salt from ethanol.
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Page/Page column 10
(2008/06/13)
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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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- Intermediates for the preparation of peptide analogues
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The invention relates to a novel process for the preparation of compounds of formula I STR1 wherein R1 is hydrogen or a suitable amino-protecting group, R2 is unsubstituted or substituted alkyl, R3 is hydrogen, aryl, heterocyclyl, unsubstituted or substituted alkyl or unsubstituted or substituted cycloalkyl, R4, independently of R1, is hydrogen or a suitable amino-protecting group and m is a number from 1 to 7; and wherein further suitable protecting groups for functional groups may be present; which compounds are antivirally active or can be used as starting materials for pharmaceutically active, especially antiviral compounds. The precursor is an oxo compound, which is in turn prepared by hydrogenation with a suitable complex hydride or with hydrogen in the presence of a suitable catalyst and acyl migration starting from a hydrazone, which is in turn preferably prepared from a nitrile via an imino compound by means of hydrogenation and reaction with a hydrazine derivative, which is prepared from an aldehyde by reaction with a reactive derivative of a carboxylic acid in the presence of a cyanide salt; and the novel intermediates required therefor.
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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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- ANTIVIRALLY ACTIVE HETEROCYCLIC AZAHEXANE DERIVATIVES
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There are described compounds of formula I*, STR1 wherein R. sub.1 is lower alkoxycarbonyl,R 2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, R. sub.3 is phenyl that is unsubstituted or substituted by one or more lower alkoxy radicals, or C 4-C 8 cycloalkyl,R. sub.4 is phenyl or cyclohexyl each substituted in the 4-position by unsaturated heterocyclyl that is bonded by way of a ring carbon atom, has from 5 to 8 ring atoms, contains from 1 to 4 hetero atoms selected from nitrogen, oxygen, sulfur, sulfinyl (--SO--) and sulfonyl (--SO 2--) and is unsubstituted or substituted by lower alkyl or by phenyl-lower alkyl,R 5, independently of R 2, has one of the meanings mentioned for R 2, andR 6, independently of R. sub.1, is lower alkoxycarbonyl,or salts thereof, provided that at least one salt-forming group is present. The compounds are inhibitors of retroviral aspartate protease and can be used, for example, in the treatment of AIDS. They exhibit outstanding pharmacodynamic properties.
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