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Details for Patent: 6,187,916

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Details for Patent: 6,187,916

Title: Process for the preparation of taxane derivatives and .beta.-lactam intermediates therefor
Abstract:A process for the preparation of a taxane derivative of the formula ##STR1## in which R.sub.2 represents an RO--, RS-- or RR'N-- in which R represents an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl, or cycloalkyl, saturated heterocyclic, cycloalkenyl, unsaturated heterocyclic, aryl or heterocyclic aromatic; R' is a hydrogen or R defined above; R and R' can be connected to form together with the nitrogen a cyclic structure; Y is oxygen or sulfur; R.sub.3 represents an unsubstituted or substituted straight chain or branched alkyl, alkenyl or alkynyl radical, an unsubstituted or substituted cycloalkyl, cycloalkenyl or an unsubstituted or substituted aryl; which comprises reacting a .beta.-lactam of the formula ##STR2## in which R.sub.311 represents a radical R.sub.3 defined above or a protected R.sub.3 whenever R.sub.3 includes one or more active hydrogens; with a baccatin III derivative of the formula: ##STR3## in which M is an alkali metal or alkaline earth metal atom (ion).
Inventor(s): Ojima; Iwao (Stony Brook, NY)
Assignee: Research Foundation of State University of New York (Stony Brook, NY)
Filing Date:Jun 07, 1995
Application Number:08/481,205
Claims:1. A .beta.-lactam of the formula I: ##STR19##

in which:

R.sub.2' represents RO--, RS--, or RR'N-- in which R represents a cycloalkyl, cycloalkenyl, or unsaturated or saturated heterocyclic radical containing 3 to 15 carbon atoms, wherein said heterocyclic radical contains at least one oxygen, nitrogen, or sulfur atom. R' is hydrogen or R as defined above, or R and R' are together an alkylene, alkenylene, or alkynylene of 2 to 10 carbons;

R.sub.3' represents a straight-chain or branched alkyl, alkenyl, or alkynyl radical, or a cycloalkyl, cycloalkenyl, or aryl radical; wherein R and R.sub.3' are unsubstituted or substituted with one or more halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto, alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonyl, wherein the alkyl portion contains 1 to 15 carbon atoms, aryloxycarbonyl, wherein the aryl portion contains 6 to 20 carbon atoms, or heteroaryloxycarbonyl radicals, wherein the heteroaryl portion contains 3 to 15 carbon atoms;

G.sub.1 represents a hydrogen or a hydroxyl protecting group; and

Y is oxygen.

2. A .beta.-lactam of the formula I: ##STR20##

in which:

R.sub.2' represents RO--, RS--, or RR'N-- in which R represents a straight-chain or branched alkyl, alkenyl, or alkynyl radical, a cycloalkyl, cycloalkenyl, aryl, or unsaturated or saturated heterocyclic radical containing 3 to 15 carbon atoms, wherein said heterocyclic radical contains at least one oxygen, nitrogen, or sulfur atom, R' is hydrogen or R as defined above, or R and R' are together an alkylene, alkenylene, or alkynylene of 2 to 10 carbons;

R.sub.3' represents a cycloalkyl or cycloalkenyl radical;

wherein R and R.sub.3' are unsubstituted or substituted with one or more halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto, alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonyl, wherein the alkyl portion contains 1 to 15 carbon atoms, aryloxycarbonyl, wherein the aryl portion contains 6 to 20 carbon atoms, or heteroaryloxycarbonyl radicals, wherein the heteroaryl portion contains 3 to 15 carbon atoms;

G.sub.1 represents a hydrogen or a hydroxyl protecting group; and

Y is oxygen.

3. A .beta.-lactam of the formula I: ##STR21##

in which:

R.sub.2' represents RO--, RS--, or RR'N-- in which R represents a straight-chain or branched alkyl, alkenyl, or alkynyl radical, a cycloalkyl, cycloalkenyl, aryl, or unsaturated or saturated heterocyclic radical containing 3 to 15 carbon atoms, wherein said heterocyclic radical contains at least one oxygen, nitrogen, or sulfur atom, R' is hydrogen or R as defined above, or R and R' are together an alkylene, alkenylene, or alkynylene of 2 to 10 carbons;

R.sub.3' represents a straight-chain or branched alkyl, alkenyl, or alkynyl radical, or a cycloalkyl, cycloalkenyl, or aryl radical;

wherein R and R.sub.3' are unsubstituted or substituted with one or more halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto, alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonyl, wherein the alkyl portion contains 1 to 15 carbon atoms, aryloxycarbonyl, wherein the aryl portion contains 6 to 20 carbon atoms, or heteroaryloxycarbonyl radicals, wherein the heteroaryl portion contains 3 to 15 carbon atoms;

G.sub.1 represents a hydrogen or a hydroxyl protecting group; and

Y is sulfur.

4. The .beta.-lactam according to claim 1, 2, or 3 in which R.sub.2, represents RO--, RS--, or RR'N--, wherein when R is:

an alkyl radical, it contains 1 to 10 carbon atoms;

an alkenyl radical, it contains 2 to 10 carbon atoms;

an alkynyl radical, it contains 2 to 10 carbon atoms;

a cycloalkyl radical, it contains 3 to 10 carbon atoms;

a cycloalkenyl radical, it contains 3 to 10 carbon atoms;

a heterocyclic radical, it contains 3 to 10 carbon atoms;

a polycycloalkyl radical, it contains 6 to 20 carbon atoms;

an aryl radical, it contains 6 to 20 carbon atoms or a heterocyclic aromatic radical, it contains 3 to 15 carbon atoms;

and R' is hydrogen or R as defined above;

and when R.sub.31 represents:

an alkyl radical, it contains 1 to 10 carbon atoms;

an alkenyl radical, it contains 2 to 10 carbon atoms;

an alkynyl radical, it contains 2 to 10 carbon atoms;

a cycloalkyl radical, it contains 3 to 10 carbon atoms;

a cycloalkenyl radical, it contains 3 to 10 carbon atoms; or

an aryl radical, it contains 6 to 20 carbon atoms.

5. The .beta.-lactam according to claim 2 or 3 in which R.sub.2' represents RO--, RS--, RR'N--, wherein R is:

an alkyl radical selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-methylpentyl, heptyl, 2-methylhexyl, octyl, and 2-methylheptyl;

a cycloalkyl radical selected from cyclopropyl, cyclobutyl, cyclopentyl, cylcohexyl, cycloheptyl, adamantyl, and cyclooctyl;

an alkenyl radical selected from vinyl and allyl;

an aryl radical selected from phenyl and naphthyl;

a heterocyclic aromatic radical selected from furyl, pyrrolyl, and pyridyl;

a cycloalkenyl radical selected from cyclohexenyl, and cycloheptenyl;

a 9-fluoroenylmethyl radical;

a benzyl radical;

a saturated heterocyclic radical selected from oxiranyl, tetrahydrofuryl, prrolidinyl, piperidinyl, tertrahydropyranyl; or

an unsaturated heterocyclic radical selected from dihydrofuryl, dihydropyrrolyl, dihydropyranyl, or dihydropyrridyl;

R' is hydrogen or R as defined above, and the cyclic RR'N-- radical is selected from aziridino, azetidino, pyrrolidino, piperidino, and morpholino.

6. The .beta.-lactam according to claim 1 or 3 in which R.sub.3' is:

an alkyl radical selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, 2-methylpentyl, heptyl, 2-methylhexyl, octyl, and 2-methylheptyl;

a 9-fluoroenylmethyl radical;

a cyclohexylmethyl radical, a cyclohexylethyl radical, a benzyl radical, a tolyl radical, a 2-phenylethenyl, or a phenylethyl radical;

a cycloalkenyl radical selected from cyclopropyl, cyclobutyl cyclohexyl, cycloheptyl, adamantyl, and cyclootyl;

an alkenyl radical selected from vinyl and allyl;

an alkynyl radical selected from ethynyl and propargyl;

an aryl radical selected from phenyl and naphthyl; or

a cycloalkenyl radicalselected from cyclohexenyl and cyloheptenyl.

7. The .beta.-lactam according to claim 1, 2, or 3 in which G.sub.1 represents a methoxymethyl, methoxyethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilyl-ethoxyl)methyl, tetrahydropyranyl, 2,2,2-trichloro-ethoxycarbonyl, benzyloxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxymethyl, trimethylsilyl, triethylsilyl, tripropylsilyl, dimethylethylsilyl, dimethyl(t-butyl)silyl, diethyl-methylsilyl, dimethylphenylsilyl, diphenylmethylsilyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, or trifluoroacetyl group.

8. The .beta.-lactam according to claim 1 wherein R is substituted and the substituents are one or more halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto, alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl radicals.

9. The .beta.-lactam according to claim 2 wherein R is substituted and the substituents are one or more halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto, alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl radicals.

10. The .beta.-lactam according to claim 3 wherein R is substituted and the substituents are one or more halogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, mercapto, alkylthio, arylthio, heteroarylthio, cyano, carboxyl, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl radicals.

11. The .beta.-lactam according to claim 8 wherein the alkyl portion of the alkoxycarbonyl radical contains 1 to 15 carbon atoms and the aryl portion of the aryloxycarbonyl radical contains 6 to 20 carbon atoms.

12. The .beta.-lactam according to claim 9 wherein the alkyl portion of the alkoxycarbonyl radical contains 1 to 15 carbon atoms and the aryl portion of the aryloxycarbonyl radical contains 6 to 20 carbon atoms.

13. The .beta.-lactam according to claim 10 wherein the alkyl portion of the alkoxycarbonyl radical contains 1 to 15 carbon atoms and the aryl portion of the aryloxycarbonyl radical contains 6 to 20 carbon atoms.
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