Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III
View Patent ↗A method is provided for the semi-synthesis of taxane intermediates useful in the preparation of paclitaxel and docetaxel from 9-dihydro-13-acetylbaccatin III. The preparation of a suitably protected baccatin III backbone from 9-dihydro-13-acetylbaccatin III, and the insertion of the phenylisoserine side chain onto the protected baccatin III from 9-dihydro-13-acetylbaccatin III to form the taxane derivatives, paclitaxel and docetaxel is disclosed.
1. A compound of the formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent hydrogen or a hydroxyl protecting group, independently selected at each location.
2. The compound of claim 1 wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent a hydroxyl protecting group.
3. The compound of claim 1 wherein each of R 1 , R 2 , R 4 , R 5 and R 6 is, independently at each location, formyl, acetyl, dichloroacetyl, propionyl, isopropionyl, pivalyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, dimethylphenylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, trichloroethoxycarbonyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, benzoyl, t-butyloxycarbonyl, benzyloxycarbonyl, methoxymethyl, methoxyethyl, ethoxyethyl, para-methoxyphenyl, tetrahydropyranyl, tetrahydrofuranyl, alkylsulfonyl or arylsulfonyl.
4. The compound of claim 1 wherein R 1 is acetyl, R 2 is acetyl, R 4 is a hydroxyl protecting group, R 5 is acetyl, and R 6 is benzoyl.
5. A method comprising reacting a compound of the formula
by a Mitsunobu displacement reaction using an azide compound, so as to provide a compound of the formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent hydrogen or a hydroxyl protecting group, independently selected at each location.
6. A process comprising oxidizing a compound of the formula
to provide a compound of the formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent a hydroxyl protecting group, independently selected at each location.
7. The process of claim 6 wherein the azide is converted to a carbonyl compound by using an alkoxide in THF, most preferably either LiOMe or NaOMe followed by acidic hydrolysis.
8. A compound of the formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent hydrogen or a hydroxyl protecting group, independently selected at each location.
9. The compound of claim 8 wherein R 1 , R 2 , R 5 and R 6 each represent a hydroxyl protecting group, and R 4 is hydrogen.
10. The compound of claim 8 wherein each of R 1 , R 2 , R 5 and R 6 is, independently at each location, formyl, acetyl, dichloroacetyl, propionyl, isopropionyl, pivalyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, dimethylphenylsilyl, tert-butyidiphenylsilyl, tribenzylsilyl, triphenylsilyl, trichloroethoxycarbonyl, benzyl, para-nitrobenzyl, para-methoxybenzyl, benzoyl, t-butyloxycarbonyl, benzyloxycarbonyl, methoxymethyl, methoxyethyl, ethoxyethyl, para-methoxyphenyl, tetrahydropyranyl, tetrahydrofuranyl, alkylsulfonyl or arylsulfonyl.
11. The compound of claim 8 wherein R 1 is acetyl, R 2 is acetyl, R 4 is hydrogen, R 5 is acetyl, and R 6 is benzoyl.
12. A process comprising bromination of a compound of the formula
to provide a compound of the formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent hydrogen or a hydroxyl protecting group, independently selected at each location.
13. The process of claim 12 wherein the bromination comprises use of a brominating agent.
14. The process of claim 12 wherein the compound of the formula
is in admixture with a compound of formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent hydrogen or a hydroxyl protecting group, independently selected at each location.
15. A process comprising oxidation of a compound of the formula
to provide a compound of the formula
wherein R 1 , R 2 , R 4 , R 5 and R 6 each represent hydrogen or a hydroxyl protecting group, independently selected at each location.
16. The process of claim 15 wherein a bromide is converted to an azide and the azide is converted to a carbonyl.
17. A process comprising treating a starting compound of the formula
wherein R 13 represents hydrogen or an amine protecting group, under diazotiation conditions, to provide a product compound of the formula
wherein BAC is
wherein R 4 is a hydrogen protecting group,
wherein R 2 is a hydroxyl protecting group, preferably acetyl, and R 8 and R 9 represent alkyl groups, e.g., C1–C10 alkyl groups such as methyl and ethyl, or
wherein R 4 represents a hydroxyl protecting group, preferably dichloroacetyl, and R 10 and R 11 represent alkyl groups, e.g., C1–C10 alkyl groups such as methyl and ethyl, wherein the diazotiation conditions comprise tosyl azide and at least base selected from triethylamine and diazobicycloundecane.
18. A process comprising treating a compound of the formula
where R 13 is hydrogen or an amine protecting group, under conditions that convert a diazo group to an acetate group, to provide a compound of the formula
19. A process comprisina enolate oxidation of a starting compound of the formula
to provide a product compound of the formula
wherein R 2 is a hydroxyl protecting group, R 4 is hydrogen or a hydroxyl protecting group, R 5 is a hydroxyl protecting group, R 6 is a hydroxyl protecting group, and R 7 is hydrogen or a hydroxyl protecting group, wherein the starting compound is exposed to oxidizing conditions comprising potassium hexamethyldisilazide and a molybdenum compound.