Chemistry: molecular biology and microbiology – Process of utilizing an enzyme or micro-organism to destroy... – Resolution of optical isomers or purification of organic...
Reexamination Certificate
1998-11-16
2003-04-01
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
C435S135000, C435S123000
Reexamination Certificate
active
06541242
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes, particularly for the preparati of taxanes bearing a C-13 sidechain containing a heterocyclic or cycloalkyl group.
BACKGROUND OF THE INVENTION
Taxanes are diterpene compounds which find utility in the pharmaceutical field. For example, taxol analogues containing heterocyclic or cycloalkyl groups on the C-13 sidechain find utility as anticancer agents. Such taxol analogues may be prepared through semi-synthetic routes, particularly by the coupling of &bgr;-lactam or open chain intermediates to the taxane core to form a sidechain at C-13. As the stereochemistry of these analogues may affect their pharmaceutical activity, methods allowing efficient stereospecific preparation of the intermediate &bgr;-lactam and open chain compounds, as well as the final taxane products, are sought in the art.
SUMMARY OF THE INVENTION
The present invention provides efficient methods for the resolution of enantiomeric mixtures, preferably racemic mixtures, of compounds useful as intermediates in the preparation of taxanes bearing a C-13 sidechain containing a heterocyclic or cycloalkyl group, and thus for the stereospecific preparation of these compounds.
Specifically, the present invention provides a method for the resolution of a mixture I comprising the enantiomers Ia and Ib, where R
1
is in the cis position relative to R
2
in both Ia and Ib, or where R
1
, is in the trans position relative to R
2
in both Ia and Ib:
where
R
1
is hydroxyl; halo; or —O—C(O)—R
4
, where R
4
is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo;
R
2
is heterocyclo or cycloalkyl; and
R
3
is hydrogen; R
4
; —C(O)—OR ; or —C(O)—R
4
, where R
4
is independently selected from those groups recited for R
4
above;
comprising the step of contacting said mixture I with an enzyme or microorganism capable of catalyzing the stereoselective conversion of one of said compounds Ia or Ib to a non-enantiomeric form, and effecting said conversion.
The present invention also provides a process for the resolution of a mixture IV comprising the enantiomers IVa an IVb:
R
2
—T
a
—C(O)—OR
6
(IVA)
and
R
2
—T
b
—C(O)—OR
6
(IVb)
where
R
1
is in the erythro position relative to the group W in both IVa and IVb, or where R
1
is in the threo position relative to the group W in both IVa and IVb;
W is —NHR or —N
3
;
R
1
is hydroxyl; halo; or —O—C(O)—R
4
, where R
4
is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo;
R
2
is heterocyclo or cycloalkyl;
R
3
is hydrogen; R
4
; —C(O)—OR
4
; or —C(O)—R
4
, where R
4
is independently selected from those groups recited for R
4
above; and
R
6
is hydrogen; or R
4
, where R
4
is independently selected from those groups recited for R
4
above;
comprising the step of contacting said mixture IV with an enzyme or microorganism capable of catalyzing the stereoselective conversion of one of said compounds IVa or IVb to a non-enantiomeric form, and effecting said conversion.
Exemplary embodiments for the aforementioned stereoselective conversions include stereoselective hydrolysis, stereoselective esterification, stereoselective transesterification and stereoselective dehalogenation, particularly stereoselective hydrolysis or esterification.
Groups, such as hydroxyl groups, on the compounds of formulae I or IV may optionally be protected for use in the resolution methods of the present invention; such groups may optionally be subsequently deprotected.
DETAILED DESCRIPTION OF THE INVENTION
The methods of the present invention are described further as follows.
Cis Enantiomers
The following pair of cis enantiomers may be separated by the enzymatic methods of the instant invention:
that is, enantiomers Ia and Ib where R
1
is in the cis position relative to R
2
in both Ia and Ib.
It is preferred to resolve a mixture of cis enantiomers as described above according to the methods of the instant invention.
Trans Enantiomers
The following pair of trans enantiomers may be separated by the enzymatic methods of the instant invention:
that is, enantiomers Ia and Ib where R
1
is in the trans position relative to R
2
in both Ia and Ib.
Erythro Enantiomers
The following pairs of erythro enantiomers may be separated by the enzymatic methods of the instant invention:
that is, enantiomers IVa and IVb where R
1
is in the erythro position relative to the group W in both IVa and IVb.
Threo Enantiomers
The following pairs of threo enantiomers may be separated by the enzymatic methods of the instant invention:
that is, enantiomers IVa and IVb where R
1
is in the threo position relative to the group W in both IVa and IVb.
Preferred Methods for the Resolution of Mixture I
Mixture I, comprising an enantiomeric mixture of &bgr;-lactams Ia and Ib, is preferably resolved by stereoselective hydrolysis, esterification or dehalogenation. A particularly preferred method for the resolution of a mixture I comprising the enantiomers Ia(1) and Ib(1):
to form a mixture II comprising the compounds IIa(1) and IIb(1):
where
R
2
is heterocyclo or cycloalkyl; and
R
3
is hydrogen; R
4
; —C(O)—OR ; or —C(O)—R
4
, where R
4
is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo;
comprises one of the following steps (i), (ii), or (iii):
(i) where
R
1
is —O—C(O)—R
4
, where R
4
is independently selected from those groups recited for R
4
above; and one of R
1a
or R
1b
is the same as R
1
and the other of R
1a
or R
1b
is hydroxyl;
the step of contacting said mixture I, in the presence of water and/or an organic alcohol, with an enzyme or microorganism capable of catalyzing the stereoselective hydrolysis of mixture I to provide said mixture II; or
(ii) where
R
1
is hydroxyl; and
one of R
1a
or R
1b
is hydroxyl and the other of R
1a
or R
1b
is R
4
—C(O)—O—, where R
4
is independently selected from those groups recited for R
4
above;
the step of contacting said mixture I, in the presence of a compound III:
R
4
—C(O)—L (III)
where R
4
is as defined above for R
1a
or R
1b
and L is a leaving group, with an enzyme or microorganism capable of catalyzing the stereoselective esterification of mixture I to provide said mixture II; or
(iii) where
R
1
is a halogen atom; and
one of R
1a
or R
1b
is halogen and the other of R
1a
or R
1b
is hydroxyl;
the step of contacting said mixture I, in the presence of a hydroxide ion donor, with an enzyme or microorganism capable of catalyzing the stereoselective dehalogenation of mixture I to provide said mixture II.
The above methods may be employed in the resolution of other enantiomeric mixtures of the instant invention, although resolution of the above cis enantiomers Ia(1) and Ib(1) is preferred.
Preferred Methods for the Resolution of Mixture IV
Mixture IV is preferably resolved by stereoselective hydrolysis, esterification, dehalogenation or transesterification. A particularly preferred method for the resolution of a mixture IV comprising the enantiamers IVa(l) and IVb(1):
to form a mixture V comprising compounds Va(1) and Vb(1);
where
R
2
is heterocyclo or cycloalkyl;
R
3
is hydrogen; R
4
; —C(O)—OR
4
; or —C(O)—R
4
, where R
4
is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo; and
R
6
is hydrogen; or R
4
, where R
4
is independently selected from those groups recited for R
4
above;
comprises one of the following steps (i), (ii), or (iii):
(i) where
R
1
is —O—C(O)—R
4
, where R
4
is independently selected from those groups recited for R
4
above; and one of R
1a
or R
1b
is the same as R
1
and the other of R
1a
or R
1b
is hydroxyl;
the step of contacting said mixture IV, in the presence of water and/or an organic alcohol, with an enzyme or microorganism capable of catalyzing the stereoselective hydrolysis of mixture IV to provide said mixture V; or
(ii) where
R
1
is hydroxyl; and
one of R
1a
or R
1b
is hydroxyl and the other of R
1a
or R
1b
is R
4
—C(O)—O—, w
Bristol--Myers Squibb Company
Marx Irene
Peist Kenneth W.
LandOfFree
Enzymatic processes for the resolution of enantiomeric... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Enzymatic processes for the resolution of enantiomeric..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Enzymatic processes for the resolution of enantiomeric... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3063702