Method for preparation of taxol using an oxazinone

Claim 2

An oxazinone of the formula: wherein R₁ is aryl, substituted aryl, alkyl, alkenyl, or alkynyl; R₈ is hydrogen, ethoxyethyl, 2,2,2-trichloroethoxy­methyl or other hydroxyl protecting group; and R₃ is aryl, substituted aryl, alkyl, alkenyl, or alkynyl.

Claim 3

An oxazinone according to claim 1, wherein the hydroxyl protecting group is selected from the group consisting of acetals, ethers, esters, and carbonates.

Claim 4

An oxazinone according to claim 1 or claim 2, wherein R₁ is aryl; R₈ is ethoxyethyl, or 2,2,2-­trichloroethoxymethyl; and R₃ aryl.

Claim 5

An oxazinone according to any one of claims 1 to 3, wherein R₁ and R₃ are phenyl.

Claim 6

The enantiomers and diastereomers of an oxazinone according to any one of claims 1 to 4.

Claim 7

A process for the preparation of a taxol intermediate comprising contacting an alcohol with an oxazinone having the formula: wherein R₁ is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR₇ wherein R₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₂ and R₅ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and OR₈ wherein R₈ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R₃ and R₆ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl, the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a p-amido ester which is suitable for use as an intermediate in the synthesis of taxol.

Claim 8

A process for the preparation of a taxol intermediate comprising contacting an alcohol with an oxazinone having the formula: wherein R₁ is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR₇ wherein R₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₂ and R₅ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and OR₈ wherein R₈ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R₃ and R₆ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl, the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a p-amido ester which is suitable for use as an intermediate in the synthesis of taxol.

Claim 9

A process for the preparation of a taxol having the formula: wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo; L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or; E and F together form an oxo; G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane; J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or P and Q together form an oxo; and S and T are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or S and T together form an oxo; and U and V are independently hydrogen or lower alkyl, alkenyl, alkynyl, aryl, or substituted aryl; and W is aryl, substituted aryl, lower alkyl, alkenyl, or alkynyl, comprising: contacting an oxazinone of the formula: wherein R ₁ is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR₇ wherein R₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₂ and R₅ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and OR₈ wherein R₈ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R₃ and R₆ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl; with an alcohol of the formula: wherein said A, B, D, E, F, G, I, J, K, L, M, P and Q are as defined above, the contacting of said oxazinone and said alcohol being carried out in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.

Claim 10

A process for the preparation of a taxol having the formula: wherein A and B are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or A and B together form an oxo; L and D are independently hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; E and F are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or; E and F together form an oxo; G is hydrogen or hydroxy or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or G and M together form an oxo or methylene or G and M together form an oxirane or M and F together form an oxetane; J is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or I is hydrogen, hydroxy, or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; or I and J taken together form an oxo; and K is hydrogen, hydroxy or lower alkoxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy; and P and Q are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or P and Q together form an oxo; and S and T are independently hydrogen or lower alkanoyloxy, alkenoyloxy, alkynoyloxy, or aryloyloxy or S and T together form an oxo; and U and V are independently hydrogen or lower alkyl, alkenyl, alkynyl, aryl, or substituted aryl; and W is aryl, substituted aryl, lower alkyl, alkenyl, or alkynyl, comprising: contacting an oxazinone of the formula: wherein R ₁ is aryl, heteroaryl, alkyl, alkenyl, alkynyl or OR₇ wherein R₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₂ and R₅ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and OR₈ wherein R₈ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or hydroxyl protecting group; and R₃ and R₆ are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl; with an alcohol of the formula: wherein said A, B, D, E, F, G, I, J, K, L, M, P and Q are as defined above, the contacting of said oxazinone and said alcohol being carried out in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.

Claim 11

A process according to claim 6 or claim 7, wherein R₁ is aryl, R₂ is OR₈ with R₈ being ethoxyethyl or 2,2,2-­trichloroethoxymethyl, and R₃ is aryl.

Claim 12

A process according to any one of claims 6 to 8, wherein R₁ and R₃ are phenyl, R₅ and R₆ are hydrogen, and R₂ is OR₈ with R₈ being a hydroxyl protecting group.

Claim 13

A process for the preparation of taxol which comprises contacting an alcohol with an oxazinone of the formula: wherein R₁ is aryl, heteroaryl, aryl, alkyl, alkenyl, alkynyl or OR₇ wherein R₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₈ is hydrogen, ethoxyethyl, 2,2,2-­trichloroethoxymethyl or other hydroxyl protecting group; and R₃ is aryl, substituted aryl, alkyl, alkenyl, or alkynyl; the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.

Claim 14

A process for the preparation of taxol which comprises contacting an alcohol with an oxazinone of the formula: wherein R₁ is aryl, heteroaryl, aryl, alkyl, alkenyl, alkynyl or OR₇ wherein R₇ is alkyl, alkenyl, alkynyl, aryl or heteroaryl; R₈ is hydrogen, ethoxyethyl, 2,2,2-­trichloroethoxymethyl or other hydroxyl protecting group; and R₃ is aryl, substituted aryl, alkyl, alkenyl, or alkynyl; the contacting of said alcohol and oxazinone being carried out in the presence of a sufficient amount of an activating agent to cause the oxazinone to react with the alcohol to form a β-amido ester which is suitable for use as an intermediate in the synthesis of taxol, and converting said intermediate to taxol.

Claim 15

A process according to any one of claims 6 to 10, wherein aryl is C₆₋₁₅ aryl, alkyl is C₁₋₁₅ alkyl, alkenyl is C₂₋₁₅ alkenyl and alkynyl is C₂₋₁₅ alkynyl.

Claim 16

A process according to any one of claims 6 to 11, wherein the hydroxyl protecting group is selected from acetals, ethers, esters, and carbonates.

Claim 17

A process according to any one of claims 6 to 11, wherein the alcohol has the formula: wherein R₄ is a hydroxyl protecting group.

Claim 18

A process according to claim 13, wherein R₄ is selected from ethers, esters, carbonates and silyl groups.

Claim 19

A process according to any one of claims 6 to 14, wherein the activating agent is a tertiary amine.

Claim 20

A process according to claim 15, wherein the activating agent is triethyl amine, diisopropyl ethyl amine, pyridine, N-methyl imidazole, or 4-dimethylaminopyridine.