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US 6,472,534 B2Granted
Methods for the preparation of intermediates in the synthesis of HIV-protease inhibitors
AssigneeAgouron Pharmaceuticals, Inc.
InventorsBennett C. Borer, Scott E. Zook, Juliette K. Busse
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Abstract
Methods for the preparation of chemical intermediates in the synthesis of HIV-protease inhibitors related to and including nelfinavir mesylate are disclosed. The method of this invention comprises converting tetrohydran derivatives into oxazolines to provide key reaction intermediates for the preparation of nelfinavir. Also disclosed is a method for the preparation of a chiral amino alcohol from an epoxy-tetrahydrofuran.
Claims20
A method for the preparation of an oxazoline,
- from a tetrahydrofuran
- comprising treating the tetrahydrofuran, wherein Ra is —COR(1) and Rb is hydrogen, —COR(3), —SO2R(2) or a suitable hydroxyl protecting group with an oxophilic electrophilic reagent in a manner that is effective to provide the oxazoline, wherein Rb is hydrogen, —COR(3), —SO2R(2) or a suitable hydroxyl protecting group and Rc is hydrogen, —COR(3) or —SO2R(2);
- wherein R(1), R(2) and R(3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group.
A method for the preparation of an oxazoline having the formula:
- wherein R(1), R(2) and R(3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, said method comprising the steps of:
- (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:
- in a manner that is effective to convert said amino-tetrahydrofuran, or a salt thereof, to a tetrahydrofuran-amide, having the formula:
- (2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent to convert said tetrahydrofuran-amide to an tetrahydrofuran amide-sulfonate having the formula:
- comprising the step-wise treatment of the tetrahydrofuran-amide with at least one molar equivalent amount of the sulfonylating reagent, followed by treatment with a base, wherein the molar equivalent amount of base used in the treatment is less than the molar equivalent amount of the sulfonylating reagent, and
- (3) treating the tetrahydrofuran amide-sulfonate with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran amide-sulfonate to said oxazoline.
3 more elements
A method for the preparation of an oxazoline diol having the formula:
- said method comprising the steps of:
- (1) treating an amino-tetrahydrofuran, or a salt thereof, having the formula:
- in a manner that is effective to convert the amino-tetrahydrofuran, or a salt thereof, to a tetrahydrofuran-amide having the formula:
- (2) treating the tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to an oxazoline diester having the formula:
- (3) hydrolyzing the oxazoline diester to said oxazoline diol;
- wherein R(1) and R(3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
3 more elements
A method for the preparation of an oxazoline diol having the formula:
- comprising the steps of:
- (1) treating an amino-tetrahydrofuran or a salt thereof, having the formula:
- in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-amide having the formula:
- (2) treating the tetrahydrofuran-amide with a substituted or unsubstituted alkyl or aryl sulfonylating reagent, in a manner effective to convert said tetrahydrofuran-amide to a fused tetrahydrofuranyloxazoline having the formula:
- (3) hydrolyzing the fused tetrahydrofuranyloxazoline to a tetrahydrofuran-amide having the formula:
- (4) treating the tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to an oxazoline diester having the formula:
- (5) hydrolyzing the oxazoline diester to said oxazoline diol,
- wherein R(1) and R(3) independently represent substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl.
5 more elements
A method for the preparation of an oxazoline having the formula:
- wherein R(1) is substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl, R(10) is a suitable hydroxyl protecting group and R(11) is H or substituted alkyl sulfonyl, comprising the steps of
- (1) treating an amino-tetrahydrofuran or a salt thereof, having the formula:
- in a manner that is effective to convert the amino-tetrahydrofuran or a salt thereof, to a tetrahydrofuran-hydroxy-amide having the formula:
- (2) treating the tetrahydrofuran-hydroxy-amide in a manner effective to protect the hydroxyl moiety of the hydroxy-amide to form a protected tetrahydrofuran-amide, having the formula:
- (3) treating the protected tetrahydrofuran-amide with an oxophilic electrophilic reagent in a manner that is effective to convert said tetrahydrofuran-amide to said protected oxazoline;
- wherein said oxophilic electrophilic reagent is selected from an oxophilic Lewis acid, an oxophilic protic acid, or triflic anhydride.
3 more elements
Dependencies are inferred from the claim text.