- Everolimus intermediate, and preparation method and application thereof
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The invention discloses an everolimus intermediate, and a preparation method and an application of the everolimus intermediate. A structure of the everolimus intermediate C is shown as formula (1) asshown in the specification. The preparation method comprises the following step: allowing 28-monosilicon protected rapamycin (an everolimus intermediate B) to react with trifluoromethanesulfonic acidsingle-protection glycol ester in the presence of organic base. The invention further discloses the application of the everolimus intermediate C. The preparation method of the everolimus intermediateis simple and high in yield; everolimus prepared from the intermediate can reduce side reactions; a technical operation procedure is simplified; the total yield is increased; the product quality is ensured; and therefore, the preparation method has better industrial application and popularization prospects.
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- Preparation method of everolimus
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The invention discloses a preparation method of everolimus. The preparation method comprises the following step of performing deprotection reaction on an everolimus intermediate C. The preparation method of everolimus adopts a manner of regioselective protection of rapamycin 28-hydroxyl, so that the selectivity of a 40-hydroxyl alkylation reaction is improved; side reactions are reduced; a total yield of everolimus calculated from rapamycin can reach above 70%; compared with yields reported in available literatures, the yield is greatly increased; a technical operation procedure is simplified;the product quality is ensured; and the preparation method has better industrial application and popularization prospects.
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- METHOD FOR PREPARING 42-(DIMETHYLPHOSPHINATE) RAPAMYCIN
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A method for preparing 42-(dimethylphosphinate) Rapamycin (Ridaforolimus) (I) is provided, which has advantages of high conversion rate and no 31,42-bis(dimethyl phosphinate) Rapamycin (III) generated. In the method of the present invention, Rapamycin (II) is firstly reacted with triethyl chlorosilane in a base condition to form 31,42-bis(triethylsilylether) Rapamycin (IV-b), followed by a selective deprotection process to obtain 31-triethylsilylether Rapamycin (V-b). Next, a phosphorylation reaction is performed by using dimethylphosphinic chloride under a base solution to obtain a crude product. Finally, a deprotection reaction is performed in a diluted sulfuric acid solution to obtain a crude product of Ridaforolimus (I). Since the conversion rate of each step of the method of the present invention is higher than 98%, it indicates that the method of the present invention is suitable for industrial production.
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- Process for preparation of temsirolimus
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The present invention provides two synthetic routes for the preparation of Temsirolimus (compound 1b and analog of Temsirolimus 1a). The first route includes the synthesis of CCI-779 by directly reacting rapamycin (4b) or Prolyl-rapamycin (4a) with substituent-2,2-bis(methoxy) propionic acid anhydride(11) in the presence of an organic base, followed by deprotection to give CCI-779 or Proline CCI-779. The second route includes a process involving a reaction of rapamycin-OH-31-sily ether (4d) or Prolyl-rapamycin-OH-31-sily ether (4c) with substituent-2,2-bis(methoxy) propionic acid anhydride(11) in the presence of an organic base and followed by subsequent hydrolysis step to obtain the desired CCI-779 or Proline CCI-779. Compound 11, as described in this invention, is stable at room temperature, cost effective and ease of processing.
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Page/Page column 13
(2010/10/19)
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- Cleavage of the cyclohexyl-subunit of rapamycin results in loss of immunosuppressive activity
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The cyclohexyl-subunit of rapamycin was cleaved by a sequence involving a Baeyer-Villiger reaction and acid hydrolysis of the resulting lactone- acetal as key steps. Binding of this new rapamycin derivative to FKBP12 was only slightly reduced by this modi
- Sedrani, Richard,Jones, Lyn H.,Jutzi-Eme, Anne-Marie,Schuler, Walter,Cottens, Sylvain
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p. 459 - 462
(2007/10/03)
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