Process for preparing homophthalate derivatives

Details Process for preparing homophthalate derivatives Process for preparing homophthalate derivatives

2003-07-28

2004-09-28

Owens, Amelia A. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S061000, C549S232000

Reexamination Certificate

active

06797838

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates generally to the chemical preparation of isocoumarin compounds. More specifically, the invention relates to the conversion of homophthalic anhydrides to isocoumarins and the preparation of homophthalic acid intermediates. Isocoumarin derivatives are valuable compounds in the fields of angiogenesis inhibition, immuno-regulation, and cancer therapy.
BACKGROUND OF THE INVENTION
Isocoumarins have been synthesized by a number of different methods. These methodologies include, but are not limited to: oxidation of indenes, indanone and indenones; condensation via Stobbe condensation with aldehydes and ketones and Claisen condensation with formates and oxalates; cyclization of 2-carboxybenzyl ketones, 2-vinylbenzoic acids, &agr;-cyanohomophthalic acids and 2-formylbenzoates; and reduction of phthalides. For reviews of isocoumarin synthesis, see Barry, Chemical Rev. 64:229-260,1964; Napolitano, Org. Prep. Proced. Int. 29:631-664, 1997.
Homophthalic anhydrides have also been utilized in the synthesis of isocoumarin derivatives. 2-Carboxyphenylacetates can be prepared by methanolysis of homophthalic anhydrides. Lithium borohydride reduction of these half-esters yields 3,4-dihydroisocoumarins. (Bose & Chaudhury, Tetrahedron. 20:49-51, 1964). Condensation of homophthalic anhydride with hydroquinone in the presence of stanic chloride yields 2-(2,5-dihydroxyphenyl) isocoumarin (Sorrie & Thomson, J. Chem. Soc. 2244, 1955). Homophthalic anhydride adds to ferrocene to produce ferrocenylhomophthalic acid, which can be cyclized to 3-ferrocenylisocoumarin (Boichard, Compt. Rend. 253:2702, 1961). Further, Perkin condensation of homophthalic anhydrides with aromatic aldehydes in the presence of bases such as triphenylmethylsodium, yields 3-phenyl-3,4-dihydroisocoumarin-4-carboxylic acids (Jones & Pinder, J. Chem. Soc., 2612, 1958).
Methods for preparing isocoumarin-3-yl acetic acid derivatives are disclosed in WO0107429. In one process, a homophthalate monoester derivative is reacted with a malonic acid monoester salt in a suitable solvent in the presence of a condensing agent to form a &bgr;-oxocarboxylic acid derivative, which is subsequently cyclized in a suitable inert solvent, in the presence of a base. The reaction is as follows:
An alternative method of preparation of the same compound disclosed the reaction of a homophthalic acid derivative with a malonyl halide monoester in the presence of a base. One disadvantage of these methods is that the synthesis disclosed in WO0107429 for homophthalate esters has a low yield and provides an intermediate ester with free hydroxy groups that must be subsequently protected in a separate step.
The synthesis of 3-yl-isocoumarins is also disclosed by Tirodkar & Usgaonkar, J. Indian Chem Soc., 46, 1934-933, 1969; Tirodkar & Usgaonkar, Indian J. Chem, 9: 123-125, 1970; Tirodkar & Usgaonkar, J. Indian Chem Soc., 48:192-198, 1971; and Sinha et al, Indian J. Heterocyclic Chem., 1:235-240, 1992. These methods describe the formation of 4-carboxy-3-yl-isocoumarins by reaction of an anhydride with an isochroman-1,3-dione carbanion or enolate intermediate, formed from the corresponding homophthlate under basic conditions. Decarboxylation under acidic conditions or by heating resulted in the corresponding 3-yl-isocoumarin. This reaction is summarized in FIG.
1
.
Despite the preparative methods for isocoumarins known in the art, there is still a need for economically preferable, effective and efficient process for the preparation of isocoumarin derivatives. The object of the present invention is to provide such a process. Further objects are to minimize the number of process reaction steps, to enhance overall yields of desired end products and to provide a process that is readily scalable for the production of commercial-scale quantities. Other objects and advantages will become apparent to persons skilled in the art and familiar with the background references from a careful reading of this specification.
SUMMARY OF THE INVENTION
In its most general terms, the present invention provides for the preparation of isocoumarin derivatives and intermediates useful in such preparative procedures. One aspect of the invention provides a process for preparing isocoumarin derivatives comprising reacting a homophthalic anhydride derivative with a carbonyl compound, wherein the carbonyl group is substituted with an acyl activating group, in the presence of a reaction medium comprising an inert solvent and a base. The inventors discovered this novel reaction results in the formation of isocoumarin derivatives in high yield and provides an efficient method of preparation of such compounds. Another aspect of the present invention is the preparation of homophthlate esters based on the discovery that, surprisingly, the addition of a malonate anion to a benzyne intermediate formed from a 2,4-disubtituted halobenzene, results in the selective production of a 3,5-disubstituted homophthatate ester. Suchesters can be readily converted into the equivalent anhydride and are, thereby, useful in the preparation of isocoumarin derivatives according to the methods provided by the present invention
In one aspect, the present invention provides a process for the preparation of the isocoumarin derivatives of formula (1):
where R
1
and R
2
independently represent hydrogen, halogen, which may be chloro, bromo, iodo of fluoro, an aryl group, a heteroaryl group, or a C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
alkynyl, C
1
-C
6
acyl, or C
1
-C
6
alkoxy group. R
1
and R
2
further independently represent the substituted amino function —NR
4
R
5
, where either R
4
is hydrogen and R
5
is sulfonyl or C
1
-C
6
acyl or where R
4
and R
5
are independently C
1
-C
6
alkyl or C
1
-C
6
acyl. In a preferred embodiment, R
1
is hydrogen. In another preferred embodiment, R
2
is methyl.
R
3
represents an electron withdrawing group. In preferred embodiments, R
3
is an electron withdrawing group selected from aryl, hetroaryl, sulfonate, phosphonate, cyano, —CO
2
R
7
, wherein R
7
is C
1
-C
6
alkyl, or an acid halide —COR
8
, wherein R
8
is a halogen, which may be chloro, bromo, iodo of fluoro. In a more preferred embodiment, R
3
is —CO
2
C
2
H
5
. R
3
may also form a ring structure with R
2
, wherein the ring structure incorporates an electron withdrawing element, such ring structures include anhydrides, lactones, oxo-cycloalkanes and cyclic amides, including lactams and lactims.
The substituents represented by X include halo, which may be fluoro, chloro, bromo or iodo, aryl, heteroaryl, C
1
-C
6
alkyl, C
1
-C
6
alkenyl, C
1
-C
6
alkynyl, C
1
-C
6
acyl, or C
1
-C
6
alkoxyl, or —NR
4
R
5
, where R
4
and R
5
are as defined above. X further represents —SO
2
R
6
, where R
6
is C
1
-C
6
alkyl or C
1
-C
6
acyl. The subscript n is an integer from 0 to 4, with the caveat that when n is 2, 3 or 4, the X substituents may be the same or different. In a preferred embodiment, subscript n is 2 and X is the same and is —OCH
3
. In a more preferred embodiment, the isocoumarin derivative is 2-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-propionic acid ethyl ester (2)
The process comprises reacting a homophthalic anhydride of formula (3):
where R
1
, X and subscript n are as defined above, with a carbonyl compound of formula (4):
where R
2
and R
3
are as defined above, and Y is an acyl activating substituent. In preferred embodiments, Y is a halogen, pyridyl or aryloxy, and more preferably imidazoyl or chloro.
The reaction medium further comprises an inert solvent and a base. In certain embodiments, the solvent is an aprotic solvent such as a halogenated or ethereal solvent. In a preferred embodiment, the solvent is acetonitrile or N-methyl pyrrolidinone. In some embodiments of the present invention, the base can be a tertiary amine, amidine, amide or a tertiary alkoxide base. In preferred embodiments, the base is triethylamine, N,N-tetramethylguanidine or 1,8-diazabicyclo[5.4.0]-undec-7-ene.
In some embodiments of the present invention, 2-(

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