Process for preparing taxol-type compound from beta-lactam precursors

Claim 2

The process of claim 1 wherein said β-lactam enantiomer is coupled to the C-13 hydroxyl group of a starting alcohol under liquid phase conditions in the presence of a sufficient amount of an activating agent, thereby to form an ester moiety at said C-13 position and produce a taxol-type compound, said starting alcohol having the generic structure: wherein: A is a radical selected from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, B and C are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy, aryloyloxy and cyclohexoyloxy, B and C taken together can form an oxo radical, D is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, D and E taken together can form a radical selected from the group consisting of oxo and methylene, E and F together with the carbon atoms between them can form an oxetane (i.e., an oxycyclobutyl) ring, F and G are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy, aryloyloxy and phen(lower alkan)oyloxy, F and G taken together can form an oxo radical, H and I are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoxyloxy and aryloyloxy, J and K are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, J and K taken together can form an oxo radical, L and M are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, and L and M together can form an oxo radical.

Claim 3

The process of claim 2 wherein said resulting taxol-type compound is purified.

Claim 4

The process of claim 2 wherein said starting alcohol includes at least one protective tri (lower alkyl) silyl group, and wherein, after said coupling, said resulting taxol-type compound is subjected to mild hydrolyzing conditions sufficient to remove said tri (lower alkyl) silyl group(s).

Claim 5

The process of claim 4 wherein said resulting hydrolyzed product is purified.

Claim 6

The process of claim 1 wherein said liquid phase is aqueous and said starting β-lactam and said lipase are each dissolved therein.

Claim 7

The process of claim 1 wherein said liquid medium is a non-lipase denaturing organic liquid in which said starting β-lactam and said lipase are each dissolved, and wherein a starting 1-(substituted) ethenyl acetate of the formula wherein R₇ is a radical selected from the group consisting of hydrogen and lower alkyl is additionally dissolved.

Claim 8

The process of claim 3 wherein the mole ratio of said starting β-lactam to said starting acetate is in the range of about 1 to about 3.

Claim 9

The process of claim 1 wherein said contacting is carried out at a temperature in the range of about 10°C to about 50°C.

Claim 10

The process of claim 1 wherein said contacting is carried out in said liquid phase at a pH that is in the range of about 3 to about 10.

Claim 11

The process of claim 1 wherein said starting β-lactam has a concentration in said liquid phase that is in the range of about 0.1 to about 1 M.

Claim 12

The process of claim 1 wherein said liquid phase is aqueous and is phosphate buffered.

Claim 13

The process of claim 1 wherein the weight ratio of said starting β-lactam to said lipase is in the range of about 1:1 in said liquid medium.

Claim 14

The process of claim 1 wherein said lipase is a member of the Pseudomonas genus.

Claim 15

The process of claim 14 wherein said starting β-lactam is hydrolyzed during said contacting under aqueous phase conditions in the presence of at least one lipase that is selected from the group consisting of P-30, K-10, AK, AP, PL, CCL, PPL and FAP, and wherein, in said starting β-lactam, R₁ is selected from the group consisting of lower alkanoyl and lower alkenoyl.

Claim 16

The process of claim 14 wherein said starting β-lactam is transesterified with a starting 1-(substituted) ethenyl acetate of the formula where R₇ is a radical selected from the group consisting of hydrogen and lower alkyl under organic phase conditions in the presence of at least one lipase that is selected from the group consisting of P-30 and AK.

Claim 17

The process of claim 1 wherein said contacting is carried out until at least about 50 weight percent of said starting β-lactam has been converted into a mixture of enantiospecific β-lactam products.

Claim 18

The process of claim 1 wherein said separating is carried out by the steps comprising: (a) removing said lipase from the liquid medium resulting from said contacting; and (b) subjecting the resulting liquid medium to chromatography with a non-miscible organic liquid eluent to separate said enantiospecific β-lactam.

Claim 19

The method of claim 1 wherein said liquid medium is aqueous and contains a phosphate buffer, and wherein, during said contacting, enantioselective hydrolysis is accomplished, such that one class of product enantiomers is produced wherein the members of such class have the (3S,4R) configuration.

Claim 20

The method of claim 1 wherein said liquid medium is organic and further includes a starting ester having the formula where R₇ is selected from the group consisting of hydrogen and lower alkyl, and wherein, during said contacting, enantioselective transesterification is accomplished, such that one class of product enantiomers is produced wherein R₁ is hydroxyl and wherein the members of said class have the (3R,4S) configuration.

Claim 21

The method of claim 1 wherein said lipase is characterized by the capacity to produce during said contacting an enantiomeric excess of said β-lactam enantiomer product which is at least about 100 times greater than the amount of other β-lactam compounds concurrently produced.

Claim 22

The method of claim 1 wherein said lipase is recycled.

Claim 23

3-Hydroxy substituted β-lactam enantiomers having the (3S,4R) structure and characterized by the formula: where R₂ is a radical selected from the group consisting of hydrogen, aryl, substituted aryl, aralkyl, lower alkyl and lower alkenyl, R₃ is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkenoyl and aryloyl, R₄ and R₅ are each independently selected from the group consisting of hydrogen, lower alkyl and lower alkenyl.

Claim 24

3-Hydroxy substituted β-lactam enantiomers having the (3R,4S) structure and characterized by the formula: where R₂ is a radical selected from the group consisting of hydrogen, aryl, substituted aryl, aralkyl, lower alkyl and lower alkenyl, R₃ is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkenoyl and aryloyl, and R₄ and R₅ are each independently selected from the group consisting of lower alkyl and lower alkenyl.

Claim 25

Taxol-type compounds of the formula: wherein: R₂ is a radical selected from the group consisting of hydrogen, aryl, substituted aryl, aralkyl, lower alkyl and lower alkenyl, R₃ is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkenoyl and aryloyl, R₄ and R₅ are each independently selected from the group consisting of hydrogen, lower alkyl and lower alkenyl, A is a radical selected from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, B and C are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy, aryloyloxy and cyclohexoyloxy, B and C taken together can form an oxo radical, D is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, D and E taken together can form a radical selected from the group consisting of oxo and methylene, E and F together with the carbon atoms between them can form an oxetane (i.e., an oxycyclobutyl) ring, F and G are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy, aryloyloxy and phen(lower alkan)oyloxy, F and G taken together can form an oxo radical, H and I are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoxyloxy and aryloyloxy, J and K are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, J and K taken together can form an oxo radical, L and M are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, and L and M together can form an oxo radical.

Claim 26

Taxol-type compounds of the formula: wherein: R₂ is a radical selected from the group consisting of hydrogen, aryl, substituted aryl, aralkyl, lower alkyl and lower alkenyl, R₃ is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkenoyl and aryloyl, R₄ and R₅ are each independently selected from the group consisting of lower alkyl and lower alkenyl, A is a radical selected from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkyl, lower alkenyl, lower alkoxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, B and C are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy, aryloyloxy and cyclohexoyloxy, B and C taken together can form an oxo radical, D is a radical selected from the group consisting of hydrogen, hydroxyl, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, D and E taken together can form a radical selected from the group consisting of oxo and methylene, E and F together with the carbon atoms between them can form an oxetane (i.e., an oxycyclobutyl) ring, F and G are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy, aryloyloxy and phen(lower alkan)oyloxy, F and G taken together can form an oxo radical, H and I are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoxyloxy and aryloyloxy, J and K are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, J and K taken together can form an oxo radical, L and M are each an independently selected radical from the group consisting of hydrogen, hydroxyl, triethylsilyloxy, lower alkanoyloxy, lower alkenoyloxy and aryloyloxy, and L and M together can form an oxo radical.