162635-03-2

The invention discloses a method for separating and purifying temsirolimus. The method comprises the following steps: (1) synthesis of a crude product; and (2) separation and purification. The specific separation and purification method has the advantages of great improvement of the purity and the yield of temsirolimus, reduction of the cost, and broad market application prospect.

The invention provides an intermediate of temsirolimus. The intermediate has better selectivity and higher yield when used for preparation of the temsirolimus. The intermediate provided by the invention has a structural formula which is described in the specification.

The invention provides a preparation method for temsirolimus. The preparation method comprises the following steps: step 1, dissolving 2,2,5-trimethyl-1,3-dioxane-5-carboxylic acid in a solvent underan alkaline condition, dropwise adding a solution of 2,4,6-trichlorobenzoyl chloride under stirring at a normal temperature, after a reaction is completed, carrying out cooling, adding a rapamycin double-protection compound, then dropwise adding an alkaline solution, and carrying out a reaction so as to obtain a coupled intermediate; and step 2, dissolving the coupled intermediate into a solvent,carrying out cooling, dropwise adding an inorganic acid solution, and carrying out deprotection so as to obtain the temsirolimus. The preparation method provided by the invention has the advantages ofsimple process, easy operation, high reaction yield, few by-products and applicability to industrial production.

The invention discloses a method for preparing temsirolimus. The method comprises the following steps: (1) preparing 2,2,5-trimethyl-5-carboxy-1,3-dioxane; (2) cooling the 2,2,5-trimethyl-5-carboxy-1,3-dioxane and dichloromethane to 0-5 DEG C under the protection of nitrogen, performing stirring for dissolving, adding DIPEA and 2,4,6-trichlorobenzoyl chloride, and carrying out a reaction to obtainan acid anhydride product; (3) adding the acid anhydride product to dichloromethane containing rapamycin and 4-(N,N-dimethylamino)pyridine, and carrying out a reaction; and (4) mixing a product obtained in step (3) with tetrahydrofuran containing p-toluenesulfonic acid, dropwise adding ethylene glycol at 0-5 DEG C, adding water after the reaction is finished, performing extraction by using ethylacetate, and washing and drying the extracted product to prepare the temsirolimus. The method has the advantages of simple preparation process, high yield, high purity and low cost, and is suitable for industrialized production.

The invention refers to the selective acylation of Rapamycin at the 42-position (I) with an acylating agent of the formula (II) wherein R4 and R5 are the same or different, individually the rest of an acetal, especially tetrahydropyran, or of a carbonate or the rest of a silyl ether or taken together are the rest of a boronate, an acetal or ketal.

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.

(Chemical Equation Presented) A lipase-catalyzed acylation of the immunosuppressant rapamycin with complete regioselectivity is described. The method was successfully applied to the synthesis of 42-hemiesters and temsirolimus (CCI-779), an investigational oncology drug.

A compound of structure (I) wherein R1 and R2 are each, independently, hydrogen or -CO(CR3R4)b(CR5R6)dCR7R8R9 ; R3 and R4 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, or -F; R5 and R6 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11, or R5 and R6 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with -(CR3R4)fOR10; R7 is hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11; R8 and R9 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11, or R8 and R9 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with -(CR3R4)fOR10; R10 is hydrogen, alkyl, alkenyl, alkynyl, tri-(alkyl)silyl, tri-(alkyl)silylethyl, triphenylmethyl, benzyl, alkoxymethyl, tri-(alkyl)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; R11 is hydrogen, alkyl, alkenyl, alkynyl, or phenylalkyl; X is 5-(2,2-dialkyl)[1,3]dioxanyl, 5-(2,2-dicycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]-dioxanyl, 4-(2,2-dicycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]dioxalanyl, or 4-(2,2-dicycloalkyl)[1,3]dioxalanyl; b = 0-6; d = 0-6; and f = 0-6 with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one -(CR3R4)fOR10, X, or -(CR3R4)fOR10 substituted cycloalkyl group, or a pharmaceutically acceptable salt thereof which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.