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US 2005/0033046 A1Published application
Regioselective synthesis of CCI-779
AssigneeWyeth
InventorsWarren Chew, Chia-Cheng Shaw
Life of this patent
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Abstract
A method for regioselective synthesis of CCl-779 based on boronate chemistry is provided. Also provided are novel intermediates useful in this method.
Claims48
A process for preparing a 42-ester of rapamycin, which comprises:
- (a) acylating a rapamycin 31-silyl ether with a compound of formula
- HOOC.CR7R8R9
- or a mixed anhydride thereof,
- wherein:
- R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl-of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, chloroethyl, or tetrahydropyranyl;
- R8 and R9 are taken together to form X;
- X is a 2-phenyl-1,3,2-dioxaborinan-5-yl or a 2-phenyl-1,3,2-dioxaborinan-4-yl,
- wherein the phenyl may be optionally substituted;
- R12 and R13 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
- and
- f=0-6;
- to give a 42-ester boronate 31-silyl ether of rapamycin;
- (b) selectively hydrolyzing the 42-ester boronate 31-silyl ether in mild acidic conditions to provide a rapamycin 42-ester boronate;
- and
- (c) treating the rapamycin 42 ester boronate with a suitable diol to provide a 42-ester of rapamycin.
13 more elements
A process for preparing a compound of formula:
- which comprises treating a 31-silyl ether, rapamycin 42-boronate ester with a suitable diol.
A process for preparing 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid, which comprises:
- reacting 2,2-bis(hydroxymethyl)propionic acid with phenylboronic acid.
The process as claimed in 36, which is carried out in the presence of tetrahydrofuran solvent.
A process for increasing the purity of a compound of formula
- in a solution containing isomers B and C in a ratio of <about 10:1
- comprising the step of adjusting the pH of the solution to a pH of about 5 to about 6.
A compound of formula (I):
- in which R is selected from:
- —O—C═O.CR7R8R9 wherein:
- R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, chloroethyl, or tetrahydropyranyl;
- R8 and R9 are taken together to form X;
- X is 2-phenyl-1,3,2-dioxaborinan-5-yl or 2-phenyl-1,3,2-dioxaborinan-4-yl, wherein the phenyl may be optionally substituted;
- R12 and R13 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
- and
- f=0-6.
6 more elements
A compound of formula:
- in which R is selected from:
- —O—C═O.CR7R8R9 wherein:
- R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, chloroethyl, or tetrahydropyranyl;
- R8 and R9 are taken together to form X;
- X is 2-phenyl-1,3,2-dioxaborinan-5-yl or 2-phenyl-1,3,2-dioxaborinan-4-yl,
- wherein the phenyl may be optionally substituted;
- R12 and R13 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
- and
- f=0-6;
- and wherein R′, R″, and R′″ are the same or different selected from alkyl of 1-6 carbon atoms, phenyl and benzyl.
8 more elements
A compound which is rapamycin 42-ester with 5-methyl-2-phenyl-1,3,2-dioxaborinane-5-carboxylic acid.
A compound in which is rapamycin 31-O-trimethylsilyl ether, 42-ester with 5-methyl-2-phenyl-1, 3, 2-dioxaborinane-5-carboxylic acid.
A compound of formula:
- HO—C═O.CR7R8R9
- R7 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, —(CR12R13)fOR10, —CF3, —F, or —CO2R10;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, triphenylmethyl, benzyl, alkoxymethyl of 2-7 carbon atoms, chloroethyl, or tetrahydropyranyl;
- R8 and R9 are taken together to form X;
- X is a 2-phenyl-1,3,2-dioxaborinan-5-yl or a 2-phenyl-1,3,2-dioxaborinan-4-yl,
- wherein the phenyl may be optionally substituted;
- R12 and R13 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, or —F;
- and
- f=0-6;
- or a mixed anhydride derivative thereof.
7 more elements
Dependencies are inferred from the claim text.