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
1999-10-08
2002-04-23
Saucier, Sandra E. (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...
C435S148000
Reexamination Certificate
active
06376230
ABSTRACT:
BACKGROUND OF THE INVENTION
Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases. Such clinical experience has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells.
Cryptophycin compounds can now be prepared using a total synthetic process; see for example, Barrow, R. A. et al.,
J. Am. Chem. Soc.
117, 2479 (1995).
The processes claimed herein provide important elements needed for an efficient total synthetic route for preparing useful cryptophycin compounds and intermediates.
4-Hydroxy-5,6-dihydropyran-2-one and derivatives thereof are important intermediates for a number of natural products; D.Seebach et al.,
Angew. Chem. Int. Ed.
13, 77 (1974); R. M. Carlson et al.,
J. Org. Chem.
40, 1610 (1975). Additionally, this series of compounds has been used for the synthesis of pharmaceuticals, for example, the drug tetrahydrolipstatin (“THL”); J. J. Landi, Jr. et al.,
Tetrahedron Lett.,
34, 277 (1993). Current art teaches that in order to form a carbon-carbon bond at the terminal (4-) position of an acylacetate, two equivalents of strong base, for example sodium hydride and n-butyl lithium, in an aprotic solvent must be used to deprotonate both the 2- and 4-positions, proceeding through selective alkylation of a dianion with one equivalent of electrophiles; S. M. Huckin et al.,
Can. J. Chem.
52, 2157 (1974); S. M. Huckin et al.,
J. Am. Chem. Soc.
96, 1082 (1974); N. Petragnani et al.,
Synthesis,
521, 78 (1982); J. R. Peterson et al.,
Syn. Commun.
18, 949 (1988); D. Seebach et al.,
Angew. Chem.
86, 40 (1974); H. Kashihara et al.,
Chem. Pharm. Bull.
34, 4527 (1986).
However, even under such harsh conditions, paraformaldehyde or formaldehyde have been poor electrophiles and product yield has been low. In fact, a toxic reagent, PhCH
2
OCH
2
Cl has been used instead of paraformaldehyde for this purpose in a multistep synthesis; E. C. Taylor et al.,
J. Org. Chem.
50, 5223 (1985).
The present invention provides a process for making intermediates of cryptophycin compounds, including Fragment A analogs of cryptophycin, as well as a process for making cryptophycin compounds using selected intermediates.
The present invention further provides novel intermediates useful in the preparation of cryptophycin compounds.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of a compound of the formula:
wherein
G is C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, or Ar;
Ar is an aromatic or heteroaromatic group or a substituted aromatic or heteroaromatic group;
R
3
is C
1
-C
6
alkyl;
R
2a
is trityl or a suitable silyl protecting group; and
R
a
is hydrogen, allyl or C
1
-C
6
alkyl; or a pharmaceutically acceptable salt thereof;
said process comprising the steps of:
(a) contacting a compound of the formula:
wherein R
b
is a suitable carboxy protecting group; and R
3
is as defined above; with a cyclizing agent to form a compound of the formula:
wherein R
3
is as defined above and M is hydrogen or a cation;
(b) stereoselectively reducing the compound of formula (3) with a stereoselective reducing agent to yield a compound of the formula:
wherein R
3
is defined as above;
(c) reacting a compound of formula (4) with a hydroxy protecting agent to yield a compound of the formula:
wherein R
2a
is trityl or a suitable silyl protecting group, and R
3
is as defined above;
(d) reacting the compound of formula (5) with a reducing agent followed by an olefinating reagent to form a compound of the formula:
wherein G, R
3
and R
2a
are as defined above;
(e) reacting the compound of formula (6) with an oxidizing agent to provide a compound of the formula:
wherein G, R
3
and R
2a
are as defined above; and
(f) reacting the compound of formula (7) with an alkyl ester forming agent, optionally with a hydrolyzing agent to provide a compound of formula (I) and optionally forming a pharmaceutically acceptable salt thereof.
This invention further comprises a process for preparing a cryptophycin compound using a compound of formula (I).
This invention further comprises the novel compounds of formulae (3), (4) and (5).
DETAILED DESCRIPTION OF THE INVENTION
As used in the application:
(a) the designation
refers to a bond that protrudes forward out of the plane of the page;
(b) the designation
refers to a bond that protrudes backward out of the plane of the page; and
(c) the designation
refers to a bond for which the stereochemistry is not designated.
As used herein, the term “pharmaceutically acceptable salt” refers to either acid addition salts or base addition salts.
The expression “pharmaceutically acceptable acid addition salt” is intended to apply to any non-toxic organic or inorganic acid addition salt of the compounds of formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricaboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxy-benzoic, and sulfonic acids such as p-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either hydrated or substantially anhydrous form.
The expression “pharmaceutically acceptable basic addition salts” is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds of formula I or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia and aliphatic, cyclic or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, isopropyldiethylamine, pyridine and picoline.
As used herein, the term “C
1
-C
12
alkyl” refers to a saturated straight or branched chain hydrocarbon group of from one to twelve carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Included within the term is the term “C
1
-C
6
alkyl” which refers to a saturated, unsaturated, straight or branched chain hydrocarbon radical of from one to six carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, 2-methylbutyl, 3-methylbutyl, hexyl and the like. Included within the terms “C
1
-C
12
alkyl” and “C
1
-C
6
alkyl” is the terms “C
1
-C
3
alkyl” which refers to a saturated, unsaturated, straight or branched chain hydrocarbon radical of from one to three carbon atoms. Included within the scope of this term are methyl, ethyl, isopropyl, and the like.
“Substituted (C
1
-C
6
)alkyl” refers to a C
1
-C
6
alkyl group that may include up to three (3) substituents containing one or more heteroatoms. Examples of such substituents are OH, NH
2
, CONH
2
, CO
2
H, PO
3
H
2
and SO
2
R
21
wherein R
21
is hydrogen, C
1
-C
3
alkyl or aryl.
The term “(C
3
-C
8
)cycloalkyl” refers to a saturated C
3
-C
8
cycloalkyl group. Included within this group are cyclopropyl, cyclobutyl, cyclohexyl, cyclooctyl, and the like. A “substituted (C
3
-C
8
)cycloalkyl group” refers to a (C
3
-C
8
)cycloalkyl group having up to three C
1
-C
3
alkyl, halo, or OR
21
su
Aikins James Abraham
Briggs Barbara Shreve
Zhang Tony Yantao
Zmijewski, Jr. Milton Joseph
Eli Lilly and Company
Saucier Sandra E.
Titus Robert D.
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