- Stereoselective synthesis of the key intermediate of ticagrelor and its diverse analogs using a new alcohol dehydrogenase from Rhodococcus kyotonensis
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Bioreduction catalyzed by alcohol dehydrogenase/reductase is one of the most valuable biotransformation processes widely used in industry. The (S)-2-Chloro-1-(3, 4-difluorophenyl) ethanol is a key chiral synthon for synthesizing the antithrombotic agent ticagrelor. Herein, a new alcohol dehydrogenase (named Rhky-ADH) identified from Rhodococcus kyotonensis by an enzyme promiscuity-based genome mining method was successfully cloned and functionally expressed in Escherichia coli. The whole cell biocatalyst harboring Rhky-ADH was biochemically characterized and was shown to be able to convert 2-Chloro-1-(3, 4-difluorophenyl) ethanone to (S)-2-Chloro-1-(3, 4-difluorophenyl) ethanol with more than 99 % enantiomeric excess (ee) and 99 % conversion. Our data showed that the optimum temperature and pH for Rhky-ADH were 25 °C and pH 8.0, respectively. The addition of NADH and an appropriate concentration of isopropanol enhanced the activity of Rhky-ADH, and 1 mM Mn2+ increased the enzyme activity by about 8 %. Substrate specificity experiments showed that Rhky-ADH had notable enzyme promiscuity and could reduce several ketones with high stereoselectivity. Our investigation on this novel enzyme adds another rare biocatalyst to the toolbox for producing chiral alcohols, which are widely used in the pharmaceutical industry.
- Hu, Junmei,Li, Gudong,Liang, Chaoqun,Shams, Saira,Zheng, Guojun,Zhu, Shaozhou
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- Method for preparing ticagrelor intermediate
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The invention discloses a method for preparing a ticagrelor intermediate. The method comprises the following steps: taking o-difluorobenzene and chloroacetyl chloride as initial raw materials, carrying out an F-K reaction, a bio-enzyme fermentation technology asymmetric reduction reaction, a ring-closure reaction and a cyclopropanation reaction, so as to obtain the key intermediate (1R, 2R)-2-(3,4-difluorophenyl) cyanocyclopropane carboxylate of the ticagrelor at high yield, high enantioselectivity and high purity. The method can realize industrialized production. The method is low in energy consumption, less in pollution, green, clean, high in yield and high in purity, the cost is reduced, the product quality is stable, and the method is suitable for large-scale stable industrial production.
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Paragraph 0021; 0026; 0030; 0031
(2018/03/06)
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- Preparation method of ticagrelor
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The invention discloses a preparation method of ticagrelor. The preparation method comprises the following steps: (1) preparation of ticagrelor intermediate product 1-TK acid; (2) preparation of ticagrelor intermediate product 2-TK-amide; (3) preparation of ticagrelor intermediate product 3-TK-amino compound hydrochloride; (4) preparation of ticagrelor intermediate product 4-TK-amino compound R-tartrate; ( 5) preparation of ticagrelor intermediate product 5-TK-amino compound L-mandelate; and (6) preparation of ticagrelor-TK. The preparation method has the advantages of cost advantage, mature and stable process, stable product quality, and safe and reliable production process.
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Paragraph 0035; 0037; 0039; 0042; 0082; 0123
(2018/04/21)
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- Ticagrelor key intermediate and preparation method thereof
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The invention discloses a ticagrelor key intermediate 1-TK-acid and a preparation method of the ticagrelor key intermediate 1-TK-acid. The ticagrelor key intermediate has a structure shown in a formula (D) which is shown in the description. The method comprises the following steps of (1) preparing 2-chloro-1-(3,4-difluorophenyl)ethanone; (2) preparing a methylbenzene solution of 2-chloro-1-S-(3,4-difluorophenyl)ethyl alcohol; (3) preparing the ticagrelor key intermediate 1-TK-acid. The ticagrelor key intermediate 1-TK-acid has the advantages that the technology is matured and stable, the product quality is stable, the production technology is safe and reliable, and the ticagrelor key intermediate 1-TK-acid is suitable for industrialized production.
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Paragraph 0020; 0022-0026
(2018/05/16)
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- (1 R, 2 S) - 2 - (3, 4 - difluorophenyl) amine ·D - mandelic acid salt preparation method
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The invention discloses a preparation method of (1R,2S)-2-(3,4-difluorophenyl) rolicyprine.D-mandelate. The preparation method comprises the following steps: carrying out cyclopropanation on a compound shown in a formula V to obtain a compound shown in a formula IV; carrying out amide generation and Hofmann degradation to obtain a compound shown in a formula II; and performing salification with D-mandelic acid to obtain a compound shown in a formula I. The compound shown in the formula V is prepared in a way that a compound shown in a structure formula VI is subjected to CBS asymmetric reduction reaction, wherein a catalyst for the CBS asymmetric reduction reaction is a compound shown in a structural formula VII, and a reduction agent for the CBS asymmetric reduction reaction can be borane-tetrahydrofuran or borane-N,N-diethyl phenylamine.
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Paragraph 0065-0068
(2018/02/04)
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- Preparation of (1R, 2S) - 2 - (3,4-difluorophenyl) method of cyclopropylamine (by machine translation)
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Preparation of (1R, 2S) - 2 - (3,4-difluorophenyl) method of cyclopropylamine, comprising 1,2-difluorobenzene as raw material is introduced to the reaction at benzene ring through acetyl; composition after reduction with borohydride, dead circulation of the reaction, the racemate 3,4-difluoro-phenyl oxirane; racemate 3,4-difluoro-phenyl oxirane under the action of a catalyst, and water undergo hydrolysis reactions to form a (s) - 3,4-difluoro-phenyl oxirane ; (s) - 3,4-difluoro-phenyl ethylene oxide and phosphorus acyl acetic acid three diethlyl reaction, and then carry on aminolysis and Hofmann degradation reaction, can obtain (1R, 2S) - 2 - (3,4-difluorophenyl) ring propylamine. This method can avoid the chiral oxidizing-reducing the use of expensive reagent; obtained by kinetic resolution of (s) - 3,4-difluoro-phenyl oxirane, its low cost of raw materials, the catalyst can be used repeatedly; the split configuration of R-configuration by-product can be obtained after transformation (s) - 3,4-difluoro-phenyl oxirane, intermediate cost can be reduced. (by machine translation)
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Paragraph 0050; 0051; 0052
(2016/10/20)
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- PREPARATION OF TICAGRELOR
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Provided are processes for preparing Ticagrelor and its intermediates that are useful in the processes. Also provided are salts of Ticagrelor, their processes and solid dispersion of Ticagrelor having Ticagrelor in amorphous form.
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Paragraph 0201
(2015/03/16)
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- Synthesis and biological evaluation of ticagrelor derivatives as novel antiplatelet agents
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Ticagrelor (1) is the first reversible P2Y12 receptor antagonist blocking adenine diphosphate (ADP)-induced platelet aggregation with rapid onset and offset of effects. In this study, synthesis of ticagrelor and its derivatives has been accomplished in a convergent way. The compound design was based on modifications of ticagrelor and its major metabolite (33) in order to ameliorate their pharmacokinetic properties and dosing profile. The final compounds (1a-g, 35a-g) were evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats. The assay results showed that some compounds (e.g., 1b, 1d, 33, 35b, 35f) exhibited comparable potency with that of ticagrelor.
- Zhang, Hao,Liu, Jun,Zhang, Luyong,Kong, Lingyi,Yao, Hequan,Sun, Hongbin
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supporting information; experimental part
p. 3598 - 3602
(2012/07/14)
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- Design, synthesis and evaluation of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents
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A series of clinafloxacin triazole hybrids as a new type of antibacterial and antifungal agents were synthesized for the first time and screened for their antimicrobial efficacy against four Gram-positive bacteria, four Gram-negative bacteria and two fungi by two fold serial dilution technique. The bioactive assay indicated that most of the target compounds displayed broad antimicrobial spectrum and good antibacterial and antifungal activities with low MIC values ranging from 0.25 to 2 μg/mL against all the tested strains which exhibited comparable or even better efficiency in comparison with the reference drugs Chloramphenicol, Clinafloxacin and Fluconazole, respectively. Notably, some synthesized clinafloxacin triazoles showed stronger efficacy against methicillin-resistant Staphylococcus aureus than their parent Clinafloxacin.
- Wang, Yan,Damu, Guri L.V.,Lv, Jing-Song,Geng, Rong-Xia,Yang, Da-Cheng,Zhou, Cheng-He
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scheme or table
p. 5363 - 5366
(2012/09/22)
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- CHEMICAL PROCESS FOR PREPARATION OF AROMATIC CYCLOPROPANE ESTERS AND AMIDES
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The present invention relates to compounds useful as pharmaceutical intermediates, to processes for preparing said intermediates, to intermediates used in said processes, and to the use of said intermediates in the preparation of pharmaceuticals. In particular, the present invention concerns enantiomerically pure trans-cyclopropane carboxylic acid derivatives, processes for preparing said carboxylic acid derivatives and their use in preparing pharmaceuticals.
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Page/Page column 5
(2008/06/13)
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- Method for preparing 2-(2-arylmorpholin-2-yl)ethanol derivatives and intermediates
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The invention relates to a process for the preparation of substituted 2-(2-arylmorpholin-2-yl)ethanol derivatives.
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Page/Page column 26-27
(2010/11/08)
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- Process for the preparation of fluorinated benzoic acids
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In the process for the preparation of fluorinated benzoic acids of the formula I STR1 in which X and Y, for example, independently of one another denote chlorine or fluorine and X moreover denotes bromine, a fluorinated chloroacetophenone of the formula II STR2 in which Z denotes chlorine or hydrogen, is reacted with a hypohalite.
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