- Preparation method of key intermediate of anti-hepatitis C drug ledipasvir
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The invention provides a preparation method of a key intermediate 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone. The method comprises the steps as follows: 2-amino-5-bromobenzoic acid is taken as a raw material, and subjected to diazotization, iodination,synthesis of 5-bromo-2-iodobenzoic acid, methylation, coupling reaction with phenylboronic acid, ester hydrolysis, acyl chlorination,intramolecular Friedel-Crafts alkylation, carbonyl reduction, iodization, fluorination and final reaction with 2-chloro-N-methoxy-N-methylacetamide to prepare the target product. The process adopts easily available starting raw materials, is low in price and free of hazardous process and has mild reaction conditions..
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- Preparation method of Ledipasvir key intermediate
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The invention provides a preparation method of a Ledipasvir key intermediate 7-bromo-2-(chloracetyl)-9,9-difluorofluorene. 4-bromaniline is used as an initial raw material, by virtue of aminoacetylation and benzyl-chlorophene alkylation, acetyl in the concentrated hydrochloric acid is removed, the diazotization coupling is performed under the catalysis of copper to obtain 2-bromofluorene, then the2-bromofluorene and a fluorine reagent react to obtain 7-bromo-9,9-difluorofluorene, finally the 7-bromo-9,9-difluorofluorene has Friedel-Crafts acylation reaction with chloroacetyl chloride to obtain an intermediate 7-bromo-2-(chloracetyl)-9,9-difluorofluorene. The preparation method of the invention is short in synthetic route, safe in process, simple and convenient in operation, low in raw material cost and capable of meeting the industrialized production requirement.
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- Anti-hepatitis c pharmaceutical intermediates
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The invention provided a compound represented by the formula I and a method utilizing the compound to prepare an anti hepatitis C drug. The preparation method is simple and economic, and is capable of being applying to industrial production, so the preparation of an anti hepatitis C drug may be achieved. The formula I is represented in the description, wherein the R represents fluorine or hydrogen, and the n is equal to 2 or 3.
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- Ledipasvir key intermediate and preparation method thereof
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The invention discloses a ledipasvir key intermediate LD-J, a structure of the ledipasvir key intermediate LD-J and a preparation method of the ledipasvir key intermediate LD-J. The preparation methodcomprises the following steps: (A1) preparing LD-G; (A2) preparing LD-H; (A3) preparing LD-I; (A4) preparing a Grignard reagent; and (A5) preparing LD-J. The ledipasvir key intermediate LD-J and thepreparation method thereof have the advantages that the process is mature and stable, the product is stable in quality, the production process is safe and reliable, and the preparation method is suitable for industrial production.
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- Ledipasvir preparation method
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The invention discloses a Ledipasvir preparation method. The Ledipasvir preparation method includes steps: (1) Ledipasvir intermediate product 1-LD-B preparation; (2) Ledipasvir intermediate product 2-LD-E preparation; (3) Ledipasvir intermediate product 3-LD-F preparation; (4) Ledipasvir intermediate product 4-LD-J preparation; (5) Ledipasvir intermediate product 5-LD-L preparation; (6) Ledipasvir-LD-Q preparation. The Ledipasvir preparation method has advantages of technical maturity and stability, product quality stability, safety and reliability in production process and suitableness for industrial production.
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Paragraph 0113; 0115; 0116; 0186; 0255
(2018/05/16)
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- Method for preparing [...] derivatives
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The present invention provides a preparation method of a fluorene ethyl ketone derivative, and particularly provides a preparation method of compounds of formula 1, definition of each group is as described in the specification. The compounds can be used as intermediates for preparation of ledipasvir, and used for the preparation of ledipasvir synthesis key intermediates and further preparation of ledipasvir. The method is low in cost, mild in reaction conditions, and suitable for industrialized production.
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- Preparation method of polysubstituted fluorene derivative
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The invention relates to the field of organic synthesis, and especially relates to a preparation method and a use of a polysubstituted fluorene derivative. The preparation method of the polysubstituted fluorene derivative comprises the steps of (1) a chlorination reaction, (2) a fluorination reaction, (3) an iodination reaction and (4) a Grignard reaction. The preparation method of the polysubstituted fluorene derivative has the advantages of easily available and cheap raw materials, low production cost, mild reaction conditions, few impurities, simple purification operation of the above product, and high purity and stable quality of the product, and the polysubstituted fluorene derivative purified in the invention has a content of above 99%, and is completely suitable for large-scale industrial production.
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- Hepatitis C virus inhibitor, medical composition and application thereof
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The invention provides a hepatitis C virus inhibitor, a medical composition and application thereof. The hepatitis C virus inhibitor is a compound as shown in a formula (I), or salt, hydrate or a solvent compound accepted in crystal forms and pharmacy. The compound disclosed by the invention has better hepatitis C viral protein NS5A restraining activity, has better pharmacodynamics/pharmacokinetics properties, is good in applicability and high in safety, can be used for preparing medicines for treating hepatitis C virus infection, and has favorable market development prospects.
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Paragraph 0062; 0064
(2017/04/18)
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- Discovery of ledipasvir (GS-5885): A potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection
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A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.
- Link, John O.,Taylor, James G.,Xu, Lianhong,Mitchell, Michael,Guo, Hongyan,Liu, Hongtao,Kato, Darryl,Kirschberg, Thorsten,Sun, Jianyu,Squires, Neil,Parrish, Jay,Keller, Terry,Yang, Zheng-Yu,Yang, Chris,Matles, Mike,Wang, Yujin,Wang, Kelly,Cheng, Guofeng,Tian, Yang,Mogalian, Erik,Mondou, Elsa,Cornpropst, Melanie,Perry, Jason,Desai, Manoj C.
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p. 2033 - 2046
(2014/04/03)
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- SYNTHESIS OF ANTIVIRAL COMPOUND
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The present disclosure provides processes for the preparation of a compound of formula I: which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates to compounds of formula I.
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Paragraph 0209; 0210
(2014/01/07)
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- SOLID FORMS OF AN ANTIVIRAL COMPOUND
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Amorphous and crystalline solid forms of the anti-HCV compound (1-{3-[6-(9,9-difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Compound I) were prepared and characterized in the solid state: Also provided are processes of manufacture and methods of using the amorphous and crystalline forms.
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Paragraph 0243-0244
(2014/01/07)
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