- Comparison of a Batch and Flow Approach for the Lipase-Catalyzed Resolution of a Cyclopropanecarboxylate Ester, A Key Building Block for the Synthesis of Ticagrelor
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In this study a batch reactor process is compared to a flow chemistry approach for lipase-catalyzed resolution of the cyclopropanecarboxylate ester (±)-3. (1R,2R)-3 is a precursor of the amine (1R,2S)-2 which is a key building block of the API ticagrelor. For both flow and batch operation, the biocatalyst could be recycled several times, whereas in the case of the flow process the reaction time was significantly reduced.
- Hugentobler, Katharina G.,Rasparini, Marcello,Thompson, Lisa A.,Jolley, Katherine E.,Blacker, A. John,Turner, Nicholas J.
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Read Online
- Controllable stereoinversion in DNA-catalyzed olefin cyclopropanationviacofactor modification
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The assembly of DNA with metal-complex cofactors can form promising biocatalysts for asymmetric reactions, although catalytic performance is typically limited by low enantioselectivities and stereo-control remains a challenge. Here, we engineer G-quadruplex-based DNA biocatalysts for an asymmetric cyclopropanation reaction, achieving enantiomeric excess (eetrans) values of up to +91% with controllable stereoinversion, where the enantioselectivity switches to ?72% eetransthrough modification of the Fe-porphyrin cofactor. Complementary circular dichroism, nuclear magnetic resonance, and fluorescence titration experiments show that the porphyrin ligand of the cofactor participates in the regulation of the catalytic enantioselectivityviaa synergetic effect with DNA residues at the active site. These findings underline the important role of cofactor modification in DNA catalysis and thus pave the way for the rational engineering of DNA-based biocatalysts.
- Cheng, Yu,Hao, Jingya,Jia, Guoqing,Li, Can,Lu, Shengmei,Miao, Wenhui
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p. 7918 - 7923
(2021/06/16)
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- Preparation method of phenyl-containing compound
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The present invention discloses a method for preparing an phenyl-containing compound. The present invention provides a method for preparing a compound shown in formula I, comprising the following steps: in the presence of formamide or acetamide, in the pr
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- Preparation method of chiral aromatic cyclopropylamine and salt thereof and intermediate used in preparation method
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The embodiment of the invention provides a preparation method of a compound as shown in a formula I or salt thereof, which comprises the following steps: (1) reacting a compound as shown in a formulaVI with a compound as shown in a formula VII in a first
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Paragraph 0076-0078
(2020/06/20)
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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; 0040; 0044; 0084; 0125
(2018/04/21)
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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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- Development of a Practical Enzymatic Process for Preparation of (S)-2-Chloro-1-(3,4-difluorophenyl)ethanol
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(S)-2-Chloro-1-(3,4-difluorophenyl)ethanol (1) is a vital chiral intermediate for the synthesis of Ticagrelor - an effective treatment for acute coronary syndromes. A ketoreductase (KRED) KR-01 in our KRED library was screened to transform 2-chloro-1-(3,4
- Guo, Xiang,Tang, Jia-Wei,Yang, Jiang-Tao,Ni, Guo-Wei,Zhang, Fu-Li,Chen, Shao-Xin
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p. 1595 - 1601
(2017/10/25)
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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 0115-0118
(2018/02/04)
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- Intermediate for standard auspicious Luo river (1R, 2S) - 2 - (2,3-difluorophenyl) method for the preparation of cyclopropylamines (by machine translation)
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The invention discloses a method for preparing ticagrelor midbody (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine, belonging to the technical fields of organic synthesis route design and preparation of raw material medicines and midbodies. The method comprises the following steps: performing alcoholysis on succinic anhydride, thereby obtaining mono-methyl succinate, performing acylating chlorination reaction on mono-methyl succinate, thereby obtaining a compound methyl 4-chloro-4-oxobutyrate, performing Fridel-Crafts reaction on methyl 4-chloro-4-oxobutyrate and o-difluorobenzene, thereby obtaining a compound methyl 4-ketone-4-(3,4-difluorophenyl) butyrate (IV), and further performing asymmetric reduction reaction, cyclization reaction and Hoffman degradation on the compound IV, thereby obtaining the compound (1R,2S)-2-(2,3-difluorophenyl) cyclopropylamine. Initial raw materials used in the method are low in cost and easy to obtain, the reaction condition is gentle, the operation is safe, simple and convenient, the environment pollution is small, and the key ticagrelor midbody prepared by using the method is simple and convenient in after treatment, and is beneficial to on-scale production.
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Paragraph 0038; 0043
(2017/03/23)
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- Gram-Scale Synthesis of Chiral Cyclopropane-Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity
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Engineered hemoproteins have recently emerged as promising systems for promoting asymmetric cyclopropanations, but variants featuring predictable, complementary stereoselectivity in these reactions have remained elusive. In this study, a rationally driven strategy was implemented and applied to engineer myoglobin variants capable of providing access to 1-carboxy-2-aryl-cyclopropanes with high trans-(1R,2R) selectivity and catalytic activity. The stereoselectivity of these cyclopropanation biocatalysts complements that of trans-(1S,2S)-selective variants developed here and previously. In combination with whole-cell biotransformations, these stereocomplementary biocatalysts enabled the multigram synthesis of the chiral cyclopropane core of four drugs (Tranylcypromine, Tasimelteon, Ticagrelor, and a TRPV1 inhibitor) in high yield and with excellent diastereo- and enantioselectivity (98–99.9% de; 96–99.9% ee). These biocatalytic strategies outperform currently available methods to produce these drugs.
- Bajaj, Priyanka,Sreenilayam, Gopeekrishnan,Tyagi, Vikas,Fasan, Rudi
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supporting information
p. 16110 - 16114
(2016/12/26)
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- HEMOPROTEIN CATALYSTS FOR IMPROVED ENANTIOSELECTIVE ENZYMATIC SYNTHESIS OF TICAGRELOR
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The present invention provides methods by which trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine and related cyclopropane compounds are prepared using synthetic strategies that include a biocatalytic cyclopropanation step.
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Paragraph 0211; 0212; 0221; 0222
(2016/12/22)
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- Biocatalytic approaches to a key building block for the anti-thrombotic agent ticagrelor
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Three complementary biocatalytic routes were examined for the synthesis of the cyclopropyl amine (1R,2S)-2, which is a key building block for the anti-thrombotic agent ticagrelor 1. By employing either a ketoreductase, amidase or lipase biocatalyst, the k
- Hugentobler, Katharina G.,Sharif, Humera,Rasparini, Marcello,Heath, Rachel S.,Turner, Nicholas J.
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supporting information
p. 8064 - 8067
(2016/09/09)
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- NOVEL PROCESSES FOR THE PREPARATION OF PHENYLCYCLOPROPYLAMINE DERIVATIVES AND USE THEREOF FOR PREPARING TICAGRELOR
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Provided herein are novel processes for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein are novel, commercially viable and industrially advantageous processes for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. Provided further herein are novel acid addition salts of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine, and process for their preparation. The intermediate and its acid addition salts are useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity.
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Paragraph 0278; 0279
(2013/07/05)
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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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p. 3598 - 3602
(2012/07/14)
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- NOVEL PROCESSES FOR THE PREPARATION OF PHENYLCYCLOPROPYLAMINE DERIVATIVES AND USE THEREOF FOR PREPARING TICAGRELOR
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Provided herein are novel processes for the preparation of phenylcyclopropylamine derivatives, which are useful intermediates in the preparation of triazolo[4,5-d]pyrimidine compounds. Provided particularly herein are novel, commercially viable and industrially advantageous processes for the preparation of a substantially pure ticagrelor intermediate, trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine. Provided further herein are novel acid addition salts of trans-(1R,2S)-2-(3,4-difluorophenyl)-cyclopropylamine, and process for their preparation. The intermediate and its acid addition salts are useful for preparing ticagrelor, or a pharmaceutically acceptable salt thereof, in high yield and purity.
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Page/Page column 45
(2012/01/14)
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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 6-7
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE CYCLOPROPYLAMINES
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This invention relates to a process for the production of optically active 2-(disubstituted aryl) cyclopropylamine derivatives and optically active 2-(disubstituted aryl) cyclopropane carboxamide derivative which are useful intermediates for the preparati
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Page/Page column 30
(2008/06/13)
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