Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-04-11
2001-10-23
Trinh, Ba K. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S023000, C560S024000, C560S029000
Reexamination Certificate
active
06307088
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns the synthesis production of taxol, taxol analogs and their intermediates. More particularly, the present invention concerns alkyl esters of &bgr;-amino acid derivatives, which are useful in the synthesis of taxol and analogs thereof.
BACKGROUND OF THE INVENTION
Taxol is a naturally occurring taxane diterpenoid that has exhibited significant clinical activity as an antineoplastic agent with considerable potential for further development. The widespread treatment of candidates for taxol therapy is limited by the current scarcity of the drug. The low abundance of taxol in its natural source, the bark of the slow-growing Pacific yew, makes the long term prospects for the availability of taxol through isolation discouraging. Taxol has the general formula and a corresponding numbering system, as shown below:
Among the solutions to the taxol supply problem addressable by organic chemists is the partial synthesis of the drug, or of clinically effective analogs, by the attachment to naturally derived substances like baccatin III of the A-ring side chain that protrudes from the C-13 position. The preparation of taxol and its analogs is known. For example, U.S. Pat. No. 4,924,011, issued May 8, 1990 to Denis et al discloses the process for preparing taxol by the condensation of a (2R, 3S) side chain acid with a taxane derivative, followed by the removal of various groups protecting the hydroxyl groups. U.S. Pat. No. 4,924,012, issued May 8, 1990 to Colin et al discloses a process for preparing derivatives of baccatin III and of 10-deacetyl-baccatin III, by condensation of an acid with a derivative of baccatin III or of 10-deacetylbaccatin III, with the subsequent removal of protecting groups by hydrogen. Several syntheses of TAXOTERE® (Registered to Rhone-Poulenc Sante) and related compounds have been reported in the
Journal of Organic Chemistry
: 1986, 51, 46; 1990, 55, 1957; 1991, 56, 1681; 1991, 56, 6939; 1992, 57, 4320; 1992, 57, 6387; and 993, 58, 255; also, U.S. Pat. No. 5,015,744 issued May 14, 1991 to Holton describes such a synthesis.
The most straightforward implementation of partial synthesis of taxol requires convenient access to chiral, non-racemic side chain and derivatives, an abundant natural source of baccatin III or closely related diterpenoid substances, and an effective means of joining the two. Of particular interest then is the condensation of Baccatin III and 10-deacetyl Baccatin III of the formula:
However, the esterification of these two units is difficult because of the hindered C-13 hydroxyl of baccatin III located within the concave region of the hemispherical taxane skeleton. For example, Greene and Gueritte-Voegelein reported only a 50% conversion after 100 hours in one partial synthesis of taxol.
J. Am. Chem. Soc
., 1988, 110, 5917. The Holten patent addresses one method of more efficient synthesis.
Still, a need exists for further efficient protocols for the attachment of the taxol A-ring side chain to the taxane skeleton (e.g., baccatin III) and for the synthesis of taxol, taxol analogs and their intermediates with variable A-ring side chain structures.
SUMMARY OF THE INVENTION
Accordingly, it is a general object of this invention to provide a new, useful and efficient protocol for the attachment of the taxol A-ring side chain to the taxane skeleton for the synthesis of taxol, taxol analogs and their intermediates with variable A-ring side chain structures which overcomes the disadvantages of the prior art.
Another object of the present invention is the attachment of the taxol A-ring side chain to baccatin III to synthesize taxol, taxol analogs and their intermediates with variable A-ring side chain structures.
It is a further object of this invention to provide a rapid and highly efficient esterification of O-protected isoserine and 3-phenylisoserine acids having N-benzyloxycarbonyl groups to the C-13 hydroxyl of 7-O-protected baccatin III.
It is another object of this invention to provide a deprotection-acylation sequence to the foregoing, to provide taxol, cephalomannine, 10-acetyl TAXOTERE® and various analogs, including photoaffinity labeling candidates.
It is a further object to provide intermediate compounds for use in the formation of variable A-ring side chain structures useful in the synthesis of taxol, taxol analogs and their intermediates.
Accordingly, the present invention provides a chemical compound useful in the production of taxol, taxol analogues and their intermediates having a formula:
wherein
R
1
=an olefinic group, an aromatic group or PhCH
2
R
2
=an alkyl group, an olefinic group, an aromatic group, hydrogen or Ph
R
3
=an alkyl group
P
1
=a hydroxyl protecting group or hydrogen.
The present invention further contemplates specific compounds according to the above general formula, including ones in which R
1
may be PhCH
2
, R
2
may be hydrogen or Ph, R
3
may be an ethyl group, and P
1
may be hydrogen, benzyloxymethyl, CO
2
CH
2
CCl
3
and CH
2
OCH
2
CCl
3
.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns a chemical process for the efficient production of taxol, taxol analogs and their intermediates. This can be accomplished by the attachment of the taxol A-ring side chain to baccatin III. This allows for the synthesis of taxol, taxol analogs and their intermediates with variable A-ring side chain structures. This invention further concerns the rapid and efficient esterification of O-protected isoserine and 3-phenylisoserine acids having N-benzyloxycarbonyl groups to the C-13 hydroxl of 7-O-protected baccatin III.
Isoserine Analogs
Previously we reported partial syntheses of taxol analogs with deleted A-ring side chain substituents through a variant of the Greene, Gueritte-Voegelein protocol. Swindell et al,
J. Med. Chem
, 1991, 34, 1176. The Greene, Gueritte-Voegelein protocol may be summarized:
Our findings, according to the generalized reaction:
wherein:
P
1
is a hydroxy-protecting group, e.g., (trichloro)ethoxymethyl, methoxymethyl, 1-ethyoxymethyl, benzyloxymethyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl and allyloxymethyl, and wherein P
1
can particularly be CH
2
OCH
2
CCl
3
; and
P
2
is a hydroxy-protecting group, e.g., 3,3,3-(trichloro)ethyoxycarbonyl, trialkylsilyl, allyloxycarbonyl and benzyloxycarbonyl), and wherein P
2
can particularly be CO
2
CH
2
CCl
3
.
can be summarized in the following Table 1:
TABLE 1
(Lactate, Phenyllactate and Isoserine
Side Chain Esterifications)
Equivalents
Coupling
Yield
R
Acid
Reagent
Time
Product
(%)
H (8)
a
6
DPC
24 h
12
53
a
Ph (9)
a
6
DPC
48 h
13
37
b
PhCONH (10)
a
6
DPC
6 h
14
87
PhCH
2
OCONH
6
DCC
15 m
15
97
(11)
c
2.2
DCC
30 m
100
a
See, Swindell et al, J. Med. Chem., 1991, 34, 1176.
b
Yield includes subsequent deprotection of 2′ and 7-hydroxyl groups.
c
This work.
One of our goals in carrying out that work was the discovery of biologically active taxol analogs with structurally simpler side chains that might be attached to baccatin III through conventional esterification chemistry more efficiently than can the taxol side chain. We detected for the lactate and phenyllactate analogs (12 and 13) a straightforward relationship between side chain complexity and side chain attachment rate and efficiency. However, we were surprised to find that N-(benzoyl)isoserine side chain acid 10, arguably as sterically demanding as phenyllactic acid 9, was esterified to 7-O-protected baccatin III 7, Magri et at,
J. Org. Chem
., 1986, 51, 3239, with a remarkably high rate and efficiency. We proposed the intervention of a dihydrooxazine of the formula:
formed from the preliminary intramolecular acylation of the benzamide carbonyl oxygen. We suggested: (i) that cyclic acylating agent 16, because of its limited steric requirement, would be particularly reactive toward the baccatin III C-13 hydroxyl; and (ii) that more complex dihydrooxazine analogs to 16 might offer a general solution to the taxol side chain attachment problem.
Owing to the cent
Krauss Nancy
Swindell Charles S.
Henson Michael R.
Martin Timothy J.
NaPro BioTherapeutics, Inc.
Trinh Ba K.
Weygandt Mark H.
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