Preparation of saturated ketone morphinan compounds
Inventors
Wang, Peter X. • Jiang, Tao • Gurusamy, Narayanasamy • Jung, Catherine K.
Assignees
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Publication Number
US-9040705-B2
Publication Date
2015-05-26
Expiration Date
Abstract
The present invention provides processes for the preparation of saturated ketone morphinan compounds. In particular, the invention provides processes for the conversion of a morphinan comprising an allyl alcohol ring moiety into a morphinan comprising a saturated ketone ring moiety by an isomerization reaction catalyzed by an inorganic salt of a late transition metal.
Core Innovation
The invention relates to a one-pot process for the preparation of a morphinan comprising a saturated ketone ring moiety. The process contacts a morphinan comprising an allyl alcohol ring moiety with an inorganic salt of a late transition metal in the presence of a protic solvent, and the allyl alcohol ring moiety is catalytically isomerized to the saturated ketone ring moiety.
The process is constrained by a weight:weight ratio of the protic solvent to the morphinan comprising an allyl alcohol ring moiety from 2:1 to 4:1. The late transition metal can be group VIIIB metals, and the inorganic salt is specified by anion classes including halide, sulfate, phosphate, or nitrate.
The invention further includes preparation of compounds of Formula (III) by contacting a compound of Formula (II) with an inorganic salt of a late transition metal in the presence of a protic solvent. The contacting step uses a weight:weight ratio of the protic solvent to the compound of Formula (II) from 2:1 to 4:1, and the process is described with stereochemical and optical-activity constraints for selected configurations and products isolated in forms such as free base for the compound of Formula (IV).
Claims Coverage
Two independent claims are represented. The claim coverage centers on catalytic isomerization or conversion using an inorganic salt of a late transition metal in the presence of a protic solvent, with the protic-solvent to substrate weight:weight ratio constrained to 2:1 to 4:1.
One-pot morphinan isomerization using late transition metal inorganic salt in protic solvent
A one-pot process for the preparation of a morphinan comprising a saturated ketone ring moiety, comprising contacting a morphinan comprising an allyl alcohol ring moiety with an inorganic salt of a late transition metal in the presence of a protic solvent, wherein the allyl alcohol ring moiety is catalytically isomerized to the saturated ketone ring moiety, and wherein the weight:weight ratio of the protic solvent to the morphinan comprising an allyl alcohol ring moiety is from 2:1 to 4:1.
Formula (II) to Formula (III) preparation by contacting with late transition metal inorganic salt in protic solvent
A process for the preparation of a compound of Formula (III), comprising contacting a compound of Formula (II) with an inorganic salt of a late transition metal in the presence of a protic solvent to form the compound of Formula (III), wherein Z is an anion, and wherein the weight:weight ratio of the protic solvent to the compound of Formula (II) is from 2:1 to 4:1.
The independent claims cover preparation of a morphinan saturated ketone ring moiety and preparation of a compound of Formula (III) by contacting the stated substrates with an inorganic salt of a late transition metal in a protic solvent, with the same 2:1 to 4:1 protic-solvent ratio. Dependent limitations include late transition metal and anion classes, yield thresholds, stereochemical and optical-activity constraints, and free base isolation.
Stated Advantages
Yield exceeding 85% and, in some embodiments, exceeding 95%.
Documented Applications
Preparation of a morphinan comprising a saturated ketone ring moiety.
Preparation of compounds of Formula (III).
Isolation of the compound of Formula (IV) in free base form.
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