Processes and intermediates useful to make antifolates

Details Processes and intermediates useful to make antifolates Processes and intermediates useful to make antifolates

2000-08-02

2002-07-30

Coleman, Brenda (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06426417

ABSTRACT:

This invention relates to synthetic organic chemistry. Specifically, the invention relates to a process for preparing intermediates useful in the syntheses of valuable antifolate compounds.
Compounds known to have antifolate activity are well recognized as chemotherapeutic agents for the treatment of cancer. A series of N-(6-amino-(pyrrolo(2,3-d)pyrimidin-3-ylacyl)-glutamic acid derivatives of formula V:
where
Y is CH═CH, O, or S;
R
3
is hydrogen, chloro, or fluoro;
R
4
is hydroxy, a carboxy protecting group, or NHCH*(C(D)R
5
)CH
2
CH
2
C(O)R
5
;
R
5
is hydrogen or a carboxy protecting group;
R
6
is hydrogen or an amino protecting group;
R
7
is hydroxy or amino; and the configuration about the carbon atom designated * is S; and the pharmaceutical salts thereof were disclosed as antifolates or intermediates to antifolates in U.S. Pat. Nos. 4,684,653 and 4,882,334.
A key step in the synthesis of the compounds of formula V, disclosed in U.S. '334 and '653, is the hydrogenation of compounds of formula VI:
where Z
1
and Z
2
are both hydrogen or taken together form a bond; R
4
′ is a carboxy protecting group or NHC*H(C(O)R
5
′)CH
2
CH
2
C(O)R
5
′;
R
5
′ is a carboxy protecting group; and
R
6
′ is an amino protecting group;
providing the isomeric mixture of compounds of formula V(a):
The resulting compound of formula V(a) can optionally have its protecting groups removed to give an isomeric mixture of the compounds of formula V. U.S. '334 and '653 further taught that the individual diastereomers of formula V could be separated mechanically by chromatography or preferably the individual diastereomers could be separated by forming diastereomeric salts with chiral acids, such as camphorsulfonic acid, followed by selective crystallization of one of the diastereomers.
U.S. '334 and '653 taught that compounds of formula VI can be obtained by first coupling a compound of formula VII with a compound of formula VIII:
where X is bromo or iodo; in the presence of a palladium/trisubstituted phosphine catalyst of the type described by Sakamoto in
Synthesis
, 1983, 312 et. seq.
The synthesis outlined above suffers in many respects. On an industrial scale, use of a noble metal catalyst is expensive, leads to purification and environmental issues, and can be erratic due to varying amounts of the precious metal that is in the correct oxidation state/complex form for catalysis. Furthermore, if the preferred crystallization separation procedure taught above is followed, after isolating a diastereomer by filtration, the filtrate will contain mixtures of the two diastereomers. This filtrate is often not amenable to further separation by crystallization, and thus separation efficiency suffers without resorting to an undesired chromatographic separation. In certain cases, e.g., where Y is S, R
3
is hydrogen, R
4
is NHC*H(C(O)R
5
)CH
2
CH
2
C(O)R
5
, and R
7
is hydroxy, as much as 80% of the desired isomer (the one with greater antifolate activity) could be found in the filtrate/fractions.
An improvement over the prior art would not rely on precious metal catalysis to produce the compounds of formula VI and would increase the absolute yields of the desired diastereomer of formula VI from mixtures containing both diastereomers by crystallization.
The present invention relates to a compound of formula III:
where:
Y is CH═CH, O, or S;
R is C
1
-C
6
alkyl;
R
1
and R
2
are independently C
1
-C
6
alkyl or taken together with the nitrogen to which they are attached form a heterocycle;
R
3
is hydrogen, chloro, or fluoro;
R
4
is hydroxy, a carboxy protecting group, or NHC*H(C(O)R
5
)CH
2
CH
2
C(O)R
5
where the configuration about the carbon atom designated * is S; and
R
5
is hydrogen or a carboxy protecting group; or a salt or solvate thereof.
The present invention also relates to a compound of formula IV:
where:
R
6
is hydrogen or an amino protecting group; and
R
7
is hydroxy or amino; or a salt or solvate thereof.
Moreover, the present invention relates to a process for preparing compounds of formula IV:
which includes reacting a compound of formula III(a):
where:
R
4
′ is a carboxy protecting group or NHC*H(C(O)R
5
′)CH
2
CH
2
C(O)R
5
′ where the configuration about the carbon atom designated * is S; and
R
5
′ is a carboxy protecting group;
with 2,4-diamino-6-hydroxypyrimidine in the presence of a suitable acid and solvent.
Furthermore, the present invention also relates to a process for preparing a compound of formula IV, or a salt or solvate thereof, which includes reacting a compound of formula V(b):
or a salt or solvate thereof, with an oxidizing reagent in the presence of a suitable solvent.
The Compounds
In the general formulae of the present document, the general chemical terms have their usual meanings. For example, the term “C
1
-C
4
alkyl” refers to methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, s-butyl, t-butyl, and cyclobutyl. The term “C
1
-C
6
alkyl” encompasses those listed for C
1
-C
4
alkyl in addition to aliphatic, straight, branched, or cyclic, monovalent moieties having five or six carbon atoms and includes, but is not limited to, pentyl, cyclopentyl, hexyl, cyclohexyl, 2-methylpentyl, and the like. The term “C
1
-C
4
alkoxy” refers to a C
1
-C
4
alkyl group attached through an oxygen atom.
The term “halo” or “halide” refers to chloro, bromo, or iodo.
The term “heterocycle” refers to a 5 or 6 membered saturated, partially unsaturated, or aromatic heterocyclic ring which contains a nitrogen atom and may optionally contain an additional heteroatom selected from N, S, or O.
The term “carboxy protecting group” refers to a substituent of a carbonyl that is commonly employed to block or protect the carboxy functionality while reactions are carried out on other functional groups on the compound.
This substituent, when taken with the carbonyl to which it is attached, may form an ester, e.g., C
1
-C
6
alkyl, substituted C
1
-C
6
alkyl, C
2
-C
6
alkenyl, substituted C
2
-C
6
alkenyl, benzyl, substituted benzyl, benzhydryl, substituted benzhydryl, trityl, substituted trityl, and trialkylsilyl ester. The exact species of carboxy protecting group is not critical so long as the derivatized carboxy group is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. When R
4
contains a carboxy protecting group, the protecting group is preferably C
1
-C
4
alkoxy or benzyloxy. The most preferred protecting groups are methoxy, ethoxy, and benzyloxy. A carboxy protecting group “removable by catalytic hydrogenation” includes, for example, benzyl protecting groups. Other examples of these groups are described in T. W. Greene, “Protective Groups in Organic Synthesis,” John Wiley and Sons, New York, N.Y., (2nd ed., 1991), (hereafter referred to as Greene) chapter 5.
The term “C
2
-C
6
alkenyl” refers to a mono-unsaturated, monovalent, hydrocarbon moiety containing from 2 to 6 carbon atoms which may be in a branched or straight chain configuration. The term is exemplified by moieties such as, but not limited to, ethylenyl, propylenyl, allyl, butylenyl, and pentylenyl.
The terms “substituted C
1
-C
6
alkyl” and “substituted C
2
-C
6
alkenyl” refer to a C
1
-C
6
alkyl and C
2
-C
6
alkenyl group respectively substituted from 1 to 3 times independently with a halo, phenyl, tri(C
1
-C
4
alkyl)silyl, or a substituted phenylsulfonyl group.
The terms “substituted benzyl”, “substituted benzhydryl”, and “substituted trityl” refers to a benzyl, benzhydryl, and trityl group, respectively, substituted from 1 to 5 times independently with a nitro, C
1
-C
4
alkoxy, C
1
-C
6
alkyl, or a hydroxy(C
1
-C
6
alkyl) group. These substitutions will only occur in a sterically feasible manner such that the moiety is chemically stable.
The term “trialkylsilyl” refers to a monovalent silyl group substituted 3 times independently with a C
1
-C
6
alkyl group.
The term “substituted phenylsulfonyl” refers to a h

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