Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-16
2004-03-16
Solola, Taofiq A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S284700
Reexamination Certificate
active
06706882
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of (pyridinylidene)-phthalides and, more particularly, relates to a process for preparing (pyridinylidene)-phthalides starting from 3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids and pyridinecarbaldehydes. The (pyridinylidene)-phthalides are known compounds, described in the literature.
In the International patent applications WO 98/35958 in the name of Novartis and WO 00/05218 in the name of the same applicant various (pyridinylidene)-phthalides are used as useful intermediates for preparing phthalazines endowed with inhibitory activity of angiogenesis and PDE4 enzyme respectively.
BACKGROUND OF INVENTION
Several methods for synthesizing arylidenephthalides are known and some of them, particularly, have been employed for preparing (pyridinylidene)-phthalides.
For instance J. Ploquin et al. In
J. Het. Chem
. (1980), 17, 961 report the preparation of (pyridinylidene)-phthalides by hot condensation between phthalic anhydride and methyl-pyridines. This reaction, however, has a poor applicative interest because, besides presenting poor yields, it is limited to obtain unsubstituted or symmetrically substituted on the phthalic ring derivatives. In fact an asymmetrical substitution would inevitably lead to the formation of regioisomers difficult to separate.
A different process for preparing, inter alia, (pyridinylidene)-phthalides also asymmetrically substituted, reported in the already cited patent application WO 00/05218, is based on the Wittig condensation between a phosphonium salt XI and an aldehyde XII as here depicted:
wherein A also represents pyridine and Z′ can be absent.
Nevertheless this process, although it has a pratically quantitative yield, presents a series of disadvantages that make it of poor industrial interest.
In fact the preparation of the phosphonium salt XI, that occurs according to the following schema:
shows some critical points. Particularly the radicalic bromuration reaction of XI is strongly esothermic, the resultant bromurated product X is unstable and therefore it must be quickly used in the reaction with triphenylphosphine to give the phosphonium salt XI.
Lastly during this last step the molecular weight of the substrate increases considerably involving an undesired increase of the reaction mass. Besides, in the subsequent Wittig reaction the formation of equimolar quantities of phosphineoxide occurs that ulteriorly complicates the synthetic feasibility.
All these problems make the above mentioned process hardly practicable at industrial level. Among the known alternative methods for preparing arylidenephthalides it is of particular interest the one described by R. H. Pager et al. in
Tetrahedron
, (1984), 40, 1517 that uses differently substituted benzaldehydes (4) and 3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid (1) as starting products.
In all the examined cases the reaction, performed directly by heating the mixture of the reagents, leads to the formation of mixtures of 3-arylidene-phthalides (3) and 3-(arylhydroxymethyl)-phthalides (2) in variable ratios, with overall yields from 47 to 90%.
The authors study the course of the above reported decarboxylation-condensation reaction by varying some experimental parameters, such as the type and the quantity of aldehyde, the solvent absence or presence, the reaction time and temperature.
Regarding the influence exerted by the substituents of the aldehyde (4) upon the course of the reaction the authors declare that “only in the case of electrondonor groups merely the dehydration product (3) is obtained “ (see lines 24, 1
st
column, page 1519).
Besides, it seems that the reaction is advantageous only if it is performed without a solvent while it results clearly disadvantageous if it is performed in its presence. In particular in apolar solvents a 140° C. it doesn't occur, while in the case of polar solvents, such as e.g. dimethylsulfoxide, it exclusively leads to obtain the alcohol (2) with poor fields and only with relevant excesses (2-6 equivalents) of aldehyde (see from line 19 forward, 1
st
column, pag. 1519). Moreover the dehydation of (2) to (3) doesn't occur appreciably in this solvent. Therefore from the work presented by Rolf H. Prager et al. it may be concluded that in order to obtain directly the compounds of formula (3) with significant yields the above mentioned reaction should be performed starting from electron-rich aldehydes (4) by heating in the absence of a solvent.
On the contrary we have surprisingly found that also using electron-poor aldehydes such as the pyridinecarbaldehydes, even in almost stechiometric ratio it is possible to obtain directly the corresponding arylidenephthalides with high yields if the reaction is performed in the presence of anhydrides.
With reference to this it has been hypothesized that the anhydride, besides probably acting as a dehydrator, is directly involved in the initial activation of the carboxylic function of the 3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids.
BRIEF SUMMARY
Therefore object of the present invention is a process for preparing pyridinylidene-phthalides of formula
wherein
Py represents a 2, 3 or 4-pyridinyl group optionally substituted by one or more substituents selected from halogen, nitro, cyano, oxo and carboxy groups;
R and R
1
, which may be the same or different, represent hydrogen, C
1
-C
6
alkyl or a group OR
2
wherein R
2
represents a linear or branched C
1
-C
6
alkyl, a C
4
-C
7
cycloalkyl or a C
1
-C
6
polyfluoroalkyl;
The bond
indicates both the isomers E and Z;
by reaction of a compound of formula
wherein R and R
1
have the above reported meanings;
with an aldehyde of formula
Py-CHO (III)
wherein Py has the above reported meaning;
by heating the mixture of the compounds having formula II and III in the presence of an anhydride and optionally in admixture with a suitable solvent.
DETAILED DESCRIPTION OF THE INVENTION
The process object of the present invention can be easily performed and it allows to obtain pyridinylidene-phthalides of formula I with good yields without using the aforesaid phosphonium salt XI.
The process object of the present invention provides for the reaction between a compound of formula II and a compound of formula III.
The compounds of formula II are known and easily obtainable for instance according to the synthetic route described in
J. Chem. Soc
. (1929), 200.
In the compounds of formula II the groups R and R
1
have the above reported meanings.
Particularly preferred compounds of formula II are those wherein at least one between R and R
1
represents OR
2
, even more preferred those wherein one or both between R and R
1
are OCH
3
.
Also the starting compounds of formula III are generally known, commercially available or obtainable according to processes reported in the literature.
Particularly preferred compounds of formula III are those wherein Py represents a 4-pyridinyl group, even more preferred if Py represents a dihalosubstituted 4-pyridinyl residue. In the process object of the present invention the compounds of formula III are generally used with respect to the compounds of formula II in a molar ratio from 0.5 to 4. Preferably they are used in a ratio from 0.8 to 1.5, even more preferably from 0.9 to 1.1.
The present process is performed in the presence of an anhydride.
The term “anhydride” means a reagent selected in the group of the organic or inorganic anhydrides, respectively derived from organic or inorganic acids, or mixed, including in this class also the acyl, alkyl and arylsulfonyl halides.
Examples of anhydrides utilizable in the present process are, in the case of the organic anhydrides, acetic, trifluoroacetic, or trifluoromethansulfonic anhydride, in the case of inorganic anhydrides, phosphoric or sulphuric anhydride or thionylchloride, while among the mixed anhydrides, acetyl, tosyl or mesyl chloride, these acyl chlorides being consider herewith as anhydrides of an organic acid and hydrogen chloride.
This, for example, acetyl chlori
Solola Taofiq A.
Zambon Group S.p.A.
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