Processes and intermediates useful to make antifolates

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

2000-02-15

2001-07-17

Aulakh, Charanjit S. (Department: 1625)

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

Organic compounds

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

Reexamination Certificate

active

06262262

ABSTRACT:

FIELD OF THE INVENTION
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.
BACKGROUND OF THE INVENTION
Compounds known to have antifolate activity are well recognized as chemotherapeutic agents for the treatment of cancer. Recently, a series of 5-substituted pyrrolo[2,3-d]pyrimidine compounds of formula XVI:
where R is NHC*H(CO
2
R
1
)CH
2
CH
2
CO
2
R
1
or OR
1
, the configuration about the carbon atom designated * is L, each R
1
is hydrogen or the same or different carboxy protecting group, m is 2 or 3, and A is an aryl group; and their pharmaceutically acceptable salts were disclosed as antifolates or intermediates to antifolates. U.S. Pat. No. 5,416,211.
A key intermediate to compounds of formula XVI is the &agr;-halo aldehyde of formula XV:
Among the possible routes to compounds of formula XV disclosed in U.S. Pat. No. 5,416,211, alpha halogenation of aldehydes of formula XIV:
is most direct.
A synthesis published by Taylor and Harrington teaches the route to compounds of formula XIV shown below:
Taylor, E. C., Harrington, P. M.,
J.Org.Chem
., 55, 3222, (1990).
Another synthesis published by Larock, et. al., may be used to form the requisite aldehydes of formula XIV by a similar palladium[0] catalyzed coupling shown below:
Larock, R. C., Leung, W., Stolz-Dunn, S.,
Tet.Let
., 30, 6629, (1989).
If the procedure of Larock is followed, a mixture of desired and undesired products results, the components of which are very difficult to separate and purify to afford compounds of formula XIV. In addition, regardless of how they are formed, aldehydes of formula XIV are typically not isolated, due to their inherent instability, and are instead alpha halogenated in situ to provide the alpha halo aldehydes of formula XIX, as disclosed in U.S. Pat. No. 5,416,211.
An improvement over the prior art would provide a facile method for selectively producing a compound of formula XIV and would provide an aldehyde analogue amenable to isolation, bulk manufacturing, and storage easily convertible to it's aldehyde form.
SUMMARY OF THE INVENTION
The present invention relates to compounds of formula IV:
where
M is a metal cation;
n is 1 or 2;
R
2
is NHCH(CO
2
R
3
)CH
2
CH
2
CO
2
R
3
or OR
3
;
R
3
is independently at each occurrence a carboxy protecting group; and
X is a bond or C
1
-C
4
alk-diyl, which are useful intermediates to some of the antifolate 5-substituted pyrrolo[2,3-d]pyrimidines disclosed in U.S. 211 which correspond to the substitution parameters of the compounds of formula IV.
The present invention further relates to a process for preparing compounds of formula III:
where
R
2
is NHCH(CO
2
R
3
)CH
2
CH
2
CO
2
R
3
or OR
3
; and
R
3
is independently at each occurrence a carboxy protecting group;
which comprises reacting a compound of formula IV with a trialkylsilyl halide in a solvent.
The invention also relates to a process for preparing a compound of formula IV which comprises reacting a compound of formula III with a compound of the formula M(HSO
3
−
)
n
in a solvent.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of formula IV where R
2
is OR
3
are enantiomeric and the compounds of formula IV where R
2
is NHCH(CO
2
R
3
)CH
2
CH
2
CO
2
R
3
are diastereomeric. Single enantiomers, single diastereomers, and mixtures thereof are encompassed within the scope of this invention. It is preferred that the chiral center in the glutamic acid residue (R
2
is NHCH(CO
2
R
3
)CH
2
CH
2
CO
2
R
3
), when present, be of the “L” configuration.
In the present document, all expressions of concentration, percent, ratio and the like will be expressed in weight units unless otherwise stated, except for mixtures of solvents which will be expressed in volume units. All temperatures not otherwise stated will be expressed in degrees Celsius. Compounds or compound mixtures in brackets, except those brackets used to denote salt forms, signify intermediates which are preferably not isolated before their use in subsequent reactions.
In the general formulae of the present document, the general chemical terms have their usual meanings. For example, the term “alkyl” refers to a fully saturated, straight or branched chain, monovalent hydrocarbonyl moiety having the stated number of carbon atoms and includes, but is not limited to, a methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, and t-butyl groups, and also includes higher homologs and isomers thereof where appropriate.
The term “C
1
-C
4
alk-diyl” refers to a fully saturated straight chain divalent hydrocarbon moiety having from 1 to 4 carbon atoms wherein each carbon atom in the chain may be independently substituted once with a C
1
-C
4
alkyl group. For example, 1,2-dimethylprop-1,3-diyl is encompassed within the definition of C
1
-C
4
alk-diyl but 1,1-dimethylprop-1,3-diyl is not. The term is further exemplified by moieties such as, but not limited to, —CH
2
—, —CH
2
CH
2
—, —CH
2
(CH
2
)CH
2
—, methyleth-1,2-diyl, —CH
2
(CH
2
)
2
CH
2
—, and but-1,3-diyl. Preferred C
1
-C
4
alk-diyl groups are those that are unsubstituted and most preferred are —CH
2
— and —CH
2
CH
2
—.
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 term “C
1
-C
4
alkoxy” refers to a methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, and a t-butoxy group.
The term “halo” and “halide” refers to chloride, bromide, or iodide.
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 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 phenyl” and “substituted phenylsulfonyl” refer to a phenyl and phenylsulfonyl group respectively where the phenyl moiety of either is para substituted with a C
1
-C
6
alkyl, nitro, or a halo group.
The term “leaving group” refers to a monovalent substituent of a molecule which is prone to nucleophilic displacement. Typical leaving groups include, but are not limited to, sulfonates such as phenyl, substituted phenyl, C
1
-C
6
alkyl, and C
1
-C
6
perfluoro alkylsulfonates; halides; and diazonium salts such as diazonium halides.
The term “carboxy protecting group” as used in this specification denotes groups which generally are not found in the final therapeutic compounds but are intentionally introduced during a portion of the synthetic process to protect a group which otherwise might react in the course of chemical manipulations, and is later removed. Examples of such carboxylic acid protecting groups include 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, trialkylsilyl, aroyl groups such as phenacyl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivitized carboxylic acid is stable to the conditions of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Carboxy protecting groups similar to those used in the cephalosporin, penicillin, and peptide arts can also be used to protect a carboxy group substituent of the compounds provided here

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