Process for preparation of chiral 3-amino-pyrrolidine and analogous bicyclic compounds
AssigneeAbbott Laboratories
InventorsQun Li, Wei-Bo Wang, Daniel T. Chu, Lisa Anne Hasvold
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Abstract
A process for the preparation of chiral 3-aminopyrrolidine and analogous bicyclic derivatives from dihydroxy olefins by treatment with titanium isopropoxide, an optically active tartrate ester and tert-butyl hydroperoxide, followed by subsequent alkylation of the intermediate with an alkyl or alkenyl magnesium halide, then pyrrolidine ring formation by condensation with an arylmethylamine, subsequent chiral replacement of a ring hydroxyl group with an amino group with further protection thereof, optional additional substitution closing of the second ring, and hydrogenolysis to remove a ring-nitrogen protecting group.
Claims8
A process for the preparation of chiral 3-aminopyrrolidine compounds having the formula:
- ##STR25## wherein R is C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, or C.sub.3 -C.sub.6 -cycloalkyl, and R.sup.1 is hydrogen, C.sub.1 -C.sub.6 -alkyl or an amino-protecting group;
- comprising:
- (a) protecting a single hydroxyl group of selected positional isomer of 2-butene-1,4-diol, by stepwise treatment with a base, an arylmethyl halide and a tetraalkylammonium halide, and isolating a monoprotected hydroxy-olefin having the formula:
- HO--CH.sub.2 --CH.dbd.CH--CH.sub.2 --OAr,
- wherein Ar represents the aryl moiety;
- (b) chirally oxidizing the monoprotected hydroxy-olefin with titanium isopropoxide, an optically active chiral tartrate ester and t-butyl hydroperoxide, and isolating an epoxy compound having the formula:
- ##STR26## (c) reacting the epoxy compound with an R--Mg--X compound, wherein R is as defined above, and X is halogen, under Grignard Reaction conditions, and isolating the chiral third intermediate compound having the formula:
- ##STR27## (d) removing the protecting group from the chiral third intermediate compound, and isolating the chiral fourth intermediate compound having the formula:
- ##STR28## (e) sulfonylating the chiral fourth intermediate compound by treatment with a substituted sulfonyl chloride, and isolating the chiral diprotected triol compound having the formula:
- ##STR29## wherein L represents the substituted sulfonyl moiety;
- (f) cyclizing the chiral diprotected triol compound by treatment with an arylmethylamine compound, and isolating the chiral pyrrolidine intermediate having the formula:
- ##STR30## (g) replacing the hydroxyl group of the chiral pyrrolidine intermediate with an amino group by an amination reaction that inverts the chiral center, and isolating the chiral aminopyrrolidine compound having the formula:
- ##STR31## (h) derivatizing the amino group of the chiral aminopyrrolidine compound, and isolating the chiral substituted-aminopyrrolidine compound having the formula:
- ##STR32## wherein R.sup.1 is as defined above;
- (i) deprotecting the ring nitrogen of the chiral substituted-aminopyrrolidine compound, and isolating the desired product.
Dependencies are inferred from the claim text.