Stereoselective reduction of a morphinone
View Patent ↗A synthetic method is provided, wherein the method comprises stereoselectively reducing a ketone of a morphinone to form a reduced morphinone and optionally covalently attaching a water soluble polymer to the reduced morphinone.
1. A synthetic method comprising:
stereoselectively reducing a ketone of a morphinone to form a reduced morphinone by contacting the morphinone with a stereoselective reducing agent,
wherein the morphinone has the following structure
wherein:
R 1 is H or a hydroxyl protecting group;
wherein the stereoselective reducing agent is a single agent or combination of agents selected from the group consisting of lithium triethylborohydride, sodium triethylborohydride, potassium triethylborohydride, sodium triacetoxyborohydride, potassium triacetoxyborohydride, lithium tri-sec-butylborohydride, sodium tri-sec-butylborohydrid, potassium tri-sec-butylborohydride, lithium 9-borabicyclo[3.3.1]-nonane hydride, lithium hexylborohydride, lithium trisiamylborohydride, lithium triethylborodeuteride, and LiA1H(Cet 2 CMe 2 ) 3 ; and
wherein the molar amount of the reduced morphinone in an α epimer form is at least 65% of the molar amount of morphinone contacted with the stereoselective reducing agent; and
covalently attaching a water-soluble polymer to the reduced morphinone.
2. The method of claim 1 , wherein R 1 is H.
3. The method of claim 1 , wherein R 1 is a hydroxyl protecting group selected from the group consisting of alkanoyl having 2 to 5 carbons; aryloyl having 7 to 11 carbons, benzyl, 1-ethoxyethyl, methoxymethyl, 4-methoxyphenylmethyl, methoxyethoxymethyl (“MEM”), 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2,-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
4. The method of claim 3 , wherein R 1 is MEM.
5. The method of claim 1 , wherein at least 90% of the molar amount of morphinone contacted with the stereoselective reducing agent forms the reduced morphinone having the following structure:
wherein R 1 is H or a hydroxyl protecting group.
6. The method of claim 5 , wherein R 1 is H.
7. The method of claim 5 , wherein R 1 is a hydroxyl protecting group selected from alkanoyl having 2 to 5 carbons; aryloyl having 7 to 11 carbons, benzyl, 1-ethoxyethyl, methoxymethyl, 4-methoxyphenylmethyl, methoxyethoxymethyl (“MEM”), 1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2,-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
8. The method of claim 7 , wherein R 1 is MEM.
9. The method of claim 5 , wherein the step of covalently attaching a water-soluble polymer to the reduced morphinone is effected by causing the reduced morphinone to be reacted with a halogen-terminated, water-soluble polymer.
10. The method of claim 9 , wherein the halogen-terminated, water-soluble polymer has the following structure:
CH 3 O—(CH 2 CH 2 O) n′ —CH 2 CH 2 -halo
wherein: subscript n′ is an integer from 1 to 14; and halo is selected from the group consisting of fluoro, bromo, chloro and iodo.
11. The method of claim 10 , wherein subscript n′ is an integer from 2 to 9, and halo is bromo.
12. The method of claim 1 , wherein the stereoselective reducing agent is sodium triethylborohydride, sodium tri-sec-butylborohydride or potassium tri-sec-butylborohydride.
13. The method of claim 1 , wherein the reduction is performed at a reaction temperature from about −50° C. to about 20° C.
14. The method of claim 1 , wherein the reduction is performed in a solvent chosen from toluene, methyl t-butyl ether, tetrahydrofuran, hexane, cyclohexane, diethylether, and 2-methyl tetrahydrofuran or a combination thereof.
15. The method of claim 1 , wherein the water-soluble polymer is a methoxy-polyethylene glycol (“methoxy-PEG”) polymer.
16. The method of claim 5 , wherein at least 99% of the molar amount of morphinone contacted with the stereoselective reducing agent forms the reduced morphinone having the following structure:
wherein R 1 is H or a hydroxyl protecting group.
17. The method of claim 15 , wherein the water-soluble polymer is covalently attached to the reduced morphinone by contacting the reduced morphinone with water-soluble polymer having a sulfonate-based leaving group selected from the group consisting of mesylate, tosylate and tresylate.
18. The method of claim 16 , wherein the sulphonate-based leaving group is mesylate.
19. The method of claim 16 , wherein the sulphonate-based leaving group is tosylate.