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US 6,555,665 B1Granted
Glycosidation of 4,5-epoxymorphinan-6-ols
AssigneeCeNes Limited
InventorsArie Gutman, Genadi Nisnevitch, Lev Yudovitch, Igor Rochman
Life of this patent
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Abstract
Glycosidation of 4,5-Epoxymorphinan-6-ols with a Thioglycoside as a glycoside donor is disclosed. The process comprises reacting a 4,5-Epoxymorphinan-6-ol and a Thioglycoside in the presence of a thiophilic promoter under conditions capable of forming 4,5-Epoxymorphinan-6-glycosides. This novel approach was used for preparation of pharmaceutically important 4,5-Epoxymorphinan-6-β-D-glucuronides. The process provides both high stereo-selectivity and high yields.
Claims18
A process for glycosidation of a 4,5-Epoxymorphinan-6-ol, or a salt or complex thereof, comprising reacting said 4,5-Epoxymorphinan-6-ol, or a salt or complex thereof, with a thioglycoside.
A process for glycosidation of a 4,5-Epoxymorphinan-6-ol, or a salt or complex thereof, comprising reacting a 4,5-Epoxymorphinan-6-ol selected from compounds of formula [3]:
- wherein:
- said ----- bond between 7 and 8 is either olefin or dihydro adduct;
- R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- and
- R4 is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- with a glycoside donor selected from thioglycosides of formula [2]:
- wherein:
- R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R1 is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R2 is alkyl, haloalkyl, or aralkyl;
- and
- R5 is alkyl or aryl;
- and
- wherein said reacting is performed under conditions capable of forming a protected 4,5-Epoxymorphinan-6-β-D-glucuronide of formula [1], or a salt or complex thereof:
- wherein:
- said ----- bond between 7 and 8 is either olefin or dihydro adduct;
- R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R1 is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R2 is alkyl, haloalkyl, or aralkyl;
- R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- and
- R4 is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl.
19 more elements
A protected 4,5-Epoxymorphinan-6-β-D-glucuronide of formula [1], or a salt or complex thereof:
- wherein:
- said ----- bond between 7 and 8 is either olefin or dihydro adduct;
- R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R1 is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R2 is alkyl, haloalkyl, or aralkyl;
- R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- and
- R4 is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl, and
- provided that:
- (1) when R and R1 are isobutyryl and R2 is methyl, then R4 is not acetyl, benzoyl, isobutyryl, or pivalyl,
- (2) when R and R1 are pivalyl and R2 is methyl, then R4 is not pivalyl,
- (3) the protected 4,5-Epoxymorphinan-6-β-D-glucuronide is not the chlorohydrate hemihydrate of [acetyl-3 (triacetyl-2,3,4-β-D-glucopyranoside)-6 yl-6 morphine] methyl uronate, and
- (4) the protected 4,5-Epoxymorphinan-6-β-D-glucuronide is not:
- wherein Ac is acetyl.
11 more elements
A process for preparing Morphine-6-β-D-glucuronide (M6G), comprising:
- (i) reacting a 4,5-Epoxymorphinan-6-ol, or a salt or complex thereof, with a thioglycoside to prepare a protected 4,5-Epoxymorphinan-6-β-D-glucuronide;
- and
- (ii) hydrolyzing said protected 4,5-Epoxymorphinan-6-β-D-glucuronide to prepare Morphine-6-β-D-glucuronide (M6G).
A process for preparing Morphine-6-β-D-glucuronide (M6G) comprising:
- (i) reacting a 4,5-Epoxymorphinan-6-ol selected from compounds of formula [3]:
- wherein:
- said ----- bond between 7 and 8 is either olefin or dihydro adduct;
- R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- and
- R4 is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- with a glycoside donor selected from thioglycosides of formula [2]:
- wherein:
- R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R1 is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R2 is alkyl, haloalkyl, or aralkyl;
- and
- R5 is alkyl or aryl;
- and
- wherein said reacting is performed under conditions capable of forming a protected 4,5-Epoxymorphinan-6-β-D-glucuronide of formula [1], or a salt or complex thereof:
- wherein:
- said ----- bond between 7 and 8 is either olefin or dihydro adduct;
- R is acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R1 is alkyl, arylmethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- R2 is alkyl, haloalkyl, or aralkyl;
- R3 is alkyl, arylmethyl, allyl, cyclopropylmethyl, cyclobutylmethyl, hydrogen, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- and
- R4 is alkyl, arylmethyl, 2-(4-morpholinyl)ethyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, haloalkoxycarbonyl, vinyloxycarbonyl, or allyloxycarbonyl;
- and
- (ii) hydrolyzing said protected 4,5-Epoxymorphinan-6-β-D-glucuronide to prepare Morphine6-β-D-glucuronide (M6G).
22 more elements
Dependencies are inferred from the claim text.