Process to prepare taxol

Details Process to prepare taxol Process to prepare taxol

1999-05-04

2001-01-23

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S110000, C548S136000, C548S159000

Reexamination Certificate

active

06177573

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a chemical process to prepare taxol and taxol analogs by use of an arylsulfonyloxazolidine.
2. Description of the Related Art
Taxol and taxotere are known to be useful for treating cancer. Numerous documents disclose various processes to prepare taxol, taxotere and taxol analogs, see for example, “Taxol, Science and Applications”, CRC Press, 1995, Ed. M.
Suffless and Drug Fut.,
21, 95 (1966).
International publication WO95/20582 discloses &Dgr;
6,12
-taxol where the benzyl moiety on the side chain nitrogen has been replaced with (CH
3
)
3
C—NH—CO—, see EXAMPLE 32. In addition, various silyl protecting groups at C-7 were disclosed. These taxol derivatives were made by coupling an oxazolidine and an appropriately protected baccatin III moiety. The oxazolidine that was coupled was not a arylsulfonyloxazolidine.
International Publication WO93/06079 disclose a process to prepare compounds similar to the substituted amino-3-phenyl (2R,3S) isoserinates (II) by use of a &bgr;-lactam and not from a compound similar to the alkyl (2R,3S)-phenylisoserinates (I). There is no disclosure of any of the “X
3
—” substituents of the present invention.
Japanese publication 06319588 discloses compounds similar to the nitrites (CCIII) of the present invention where X
3
of the present invention is hydrogen. In the present invention X
3
can not be hydrogen.
International Publication WO94/29284 discloses 2,2-dimethyl-4-(4-iodophenyl)oxazolidines which have traditional carbon/oxygen/hydrogen substituents attached to the 3-nitrogen. The oxazolidines of the present invention do not have any halogen on the 4-phenyl group and has sulfur containing substituents on the oxazolidine nitrogen.
U.S. Pat. No. 4,814,470 discloses taxol derivatives in which the isoserine side chain is different than that of the final products of the present invention. In addition, the process used to make these compounds is different than that of the present invention.
U.S. Pat. No. 4,857,653 discloses a process to produce taxol and 10-desacetyltaxol. The prior art process requires zinc and acid or fluoride to remove the C
7
protecting group. The C
7
silyl protecting groups of the present invention do not need zinc and acid to be removed. In addition, the isoserine side chain is produced by removal of a protecting group (BOC) whereas in the present invention the opening of an oxazolidine ring produces the isoserine side chain.
U.S. Pat. No. 4,924,011 discloses a process for coupling a hydroxy protected (2R,3S) 3-phenylisoserine derivative with a baccatin III or 10-deacetylbaccatin III to produce a taxol like compound. The present invention couples an oxazolidine, not a hydroxy protected (2R,3S)-3-phenylisoserine derivative to form a taxol precursor.
U.S. Pat. No. 4,924,012 discloses a process to prepare derivatives of baccatin III and of 10-desacetyl baccatin III which comprises coupling an isoserine-acid with a baccatin III-derivative. The present invention does not utilize an uncyclized isoserine-acid but rather an oxazolidine-acid.
U.S. Pat. No. 4,942,184 discloses water soluble taxol derivatives which do not contain a free hydroxyl group on the isoserine side chain. The compounds of the present invention have a free hydroxyl group on the isoserine side chain.
U.S. Pat. No. 4,960,790 discloses taxane compounds where either the hydroxyl group on the isoserine side chain or at C
7
is protected (with an amino acid). The present invention does not use any amino acid protecting groups.
U.S. Pat. No. 5,015,744 discloses a process for producing taxol using an oxazinone which is a six member ring. The process of the present invention uses a five member oxazolidine ring which is structurally and behaves mechanistically different from the oxazinone ring.
U.S. Pat. No. 5,227,400 discloses furyl and thienyl substituted taxanes which are produced from &bgr;-lactams and not by the processes of the present invention.
U.S. Pat. No. 5,248,796 discloses 10-desacetoxy-taxanes. The taxane products of the present invention have either an acetate or hydroxy function at C
10
in the &bgr;-configuration.
J. Org. Chem.,
57, 4320-23 (1992) discloses the amminolysis of a phenyl substituted-epoxide-CO—O—C
2
H
5
with ethanolic ammonia in a Parr reactor at 100°. The ammonolysis of the epoxide (CVI) uses aqueous ammonia and can be performed at room temperature.
International Publication WO95/20582 discloses a method for the preparation of taxol-like compounds which comprises coupling a oxazolidine and a baccatin III-type moiety. The oxazolidine which is coupled dose not contain a sulfonamide substituent.
Chem. Int. Ed. Engl.,
35, 451-3 (1966) and
Chemical
&
Engineering News,
6 (Feb. 19, 1996) discloses an osmium catalytized process to add amino and hydroxyl groups to carbon-carbon double bonds so that only one of two possible enantiomers is formed. This process can be used to produce &bgr;-hydroxyamino groups with specific chiralities. With regard to taxol, this document discloses the reaction sequence of methyl cinnamate being reacted according to the disclosed chemistry to produce a hydroxysulfonamide of phenylisoserine which is &phgr;—CH(NHR)—CH(OH)—CO—OCH
3
where R is CH
3
—SO
2
—. The toluenesulfonamide group is then removed to produce enantiomerically pure (2R,3S)phenylisoserine which is then reacted with &phgr;—CO—Cl to produce the side chain required for taxol with >99% enantiomeric purity. The claimed invention does not use the sulfonamide as an intermediate for producing the taxol side chain but rather in producing an oxazolidine (not produced by the prior art) which is attached to the baccatin III portion of taxol prior to the opening of the oxazolidine.
Japanese publication JP06319588 discloses a 3(S)- and 3(R)-3(substituted)amino-2-hydroxynitriles, R(RNH)CH—CH(OH)—CN, where the substitution on the amino group does not include sulfur (—SO
2
—) as in the present invention.
PCT patent application PCT/US95?00551 (International Publication WO95/20582) discloses a &Dgr;
12
-taxol where the 3′-amino group is substituted with a 4-methylphenyl-SO
2
— group. Unlike the 4-methylphenylsulfonamide group which is part of the active end product, the sulfonamide groups of the present invention are protecting groups and are lost prior to the formation of the final taxol (X) compound.
Oxazolidines are well known to those skilled in the art and are final end products with regard to some utilities and intermediates with regard to others. However, N-sulfonyl oxazolidines are not known.
SUMMARY OF INVENTION
Disclosed is a substituted amino-3-phenyl (2R,3S) isoserinate of formula (II)
&phgr;—CH(NHX
3
)—CH(OH)—CO—O—X
1
  (II)
where X
1
is:
(1) C
1
-C
8
alkyl,
(2) C
5
-C
7
cycloalkyl,
(3) —CH
2
—&phgr; where the —&phgr; is optionally substituted with 1 or 2
(a) —O—X
1−1
where X
1−1
is C
1
-C
3
alkyl,
(b) —F, —Cl, —Br, —I;
where X
3
is —SO
2
—X
3−1
where X
3−1
is:
(1) 4-nitrophenyl,
(2) 2,4-dinitrophenyl.
Also disclosed is a substituted amino-3-phenyl (2R,3S) isoserinate of formula (II)
&phgr;—CH(NHX
3
)—CH(OH)—CO—O—X
1
  (II)
where X
1
is:
(1) C
1
-C
8
alkyl,
(2) C
5
-C
7
cycloalkyl,
(3) —CH
2
—&phgr; where the —&phgr; is optionally substituted with 1 or 2
(a) —O—X
1−1
where X
1−1
is C
1
-C
3
alkyl,
(b) —F, —Cl, —Br, —I;
where X
3
is —SO
2
—X
3−1
where X
3−1
is:
(1) 2-benzothiazol,
(2) 9-anthracenyl,
(3) 5-methyl-1,3,4-thiadiazolyl.
Further disclosed is an oxazolidine ester of formula (III) where X
3
is —SO
2
—X
3−1
where X
3−1
is:
(1) 4-nitrophenyl,
(2) 2,4-dinitrophenyl,
(3) 2-benzothiazol,
(4) 9-anthracenyl,
(5) 5-methyl-1,3,4-thiadiazolyl and where X
1
is as defined above.
Additionally disclosed is an oxazolidine acid of formula (IV) where X
3
is —SO
2
—X
3−1
where X
3−1
is:
(1) 4-nitrophenyl,
(2) 2,4-dinitrophenyl,
(3) 2-benzothiazol,
(4) 9-anthracenyl,
(5) 5-methyl-1,3,4-thiadiazolyl and where X
2
is as defined above and salts thereof.
Discl

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