Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-03
2002-08-13
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06433162
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to porphyrin compounds, pyrrole compounds useful in making the porphyrin compounds and methods for synthesizing porphyrin compounds.
Porphyrin compounds as well as methods for synthesizing the same are well recognized in the art. However, porphyrin compounds are very expensive. For example, porphine is offered at costs as high as $15,000/g. The current best-known porphine synthesis entails the tetramerzation of hydroxymethylpyrrole, an unsubstituted pyrrole monomer. The lack of substituents requires high dilution (e.g., 0.005M porphine) to obtain optimal yields (i.e., 15%). Purification by alumina chromatography is both necessary and tedious due to the very low solubility of porphine.
Attention is directed towards the following patents and scientific publications related to porphyrins and their synthesis which are herein incorporated by reference in their entirety. U.S. Pat. No. 3,579,533 to Yalman; U.S. Pat. No. 5,241,062 to Wijesekera, et al.; U.S. Pat. No. 5,659,029 to Ellis Jr. et al.; U.S. Pat. No. 5,674,467 to Maier et al.; U.S. Pat. No. 5,703,230 to Boyle et al.; U.S. Pat. No. 5,284,831 to Kahl et al; JP 1238585 A, assigned to Maruyamaka; JP 63238078 A, assigned to Central Glass Co. Ltd.; JP 63238057 A., assigned to Central Glass Co. Ltd.; and SU 1553060 A, assigned to Ivan Mother Child;
Synthesis
, Anderson et al, (1985) 353;
Synthetic Communications
, Mueller-Westerhoff et al, 24(10), 1389-1393 (1994);
Tetrahedron Letters
, Kuroda et al., 30(18), 2411-2412 (1989);
J. Heterocyclic Chem
., Longo et al., 12,1305-1309 (1975);
Bull. Chem. Soc. Jpn
., Ono et al., 62, 3386-3388 (1989);
Chem. Lett
., Ono et al., 1237-1240 (1989);
Bull. Chem. Soc. Jpn
., Kinoshita et al., 65, 2660-2667 (1992);
J. Amer. Chem. Soc
., Whitlock et al., 96(12) 3959-3965 (1974); and
J Porphyrins Phthalocyanines
, Ellis et al., Vol. 1, 305-307 (1997).
Longo et al. disclose a slow and low-yield synthesis of unsubstituted porphyrin (porphin) by condensation of 2-hydroxymethyl-pyrrole in dilute solutions, at near neutral pH. As a result, porphin is unpatentable.
U.S. Pat. No. 3,579,533 to Yalman discloses a method for synthesizing porphyrins and metal chelates of porphyrins, comprising condensation of 2-hydroxylalkyl-pyrroles having primary of secondary carbinols in the pyrrole 2-position. The condensation occurs in the presence of acids and/or optional metal salts.
Ellis et al. (in the Journal of Porphyrins and Phthalocyanines) disclose synthesis of porphin, from 2-hydroxymethyl-pyrrole, in yields up to 15.3%, by use of a two-phase reaction solvent system, comprising an aqueous solution of an acid, and a water-immiscible organic solvent. U.S. Pat. No. 5,659,029 to Ellis et al. teaches the optional presence of organic substituent groups on the 3 and 4 positions of the pyrroles, and the beta positions of the porphyrin.
Kuroda et al. disclose a method for the synthesis of 2-hydroxyalkyl-pyrroles with various alkyl and aryl substituted hydroxyalkyl groups, via acylation of pyrroles, and reduction.
Ono et al., (Bull. Chem. Soc. Jpn. 62,3386 (1989), disclose a method of preparing substituted hydroxymethyl-pyrroles by reacting organic nitro and isocyanide compounds, obtaining hydroxymethyl pyrroles with two different substituents in the pyrrole 3 and 4 positions.
Japanese patent applications JP 63238057 and JP 63238078 to Central Glass Co. Ltd. relate to methods of preparing unsymmetrically di-substituted 3,4-hydroxymethyl-pyrroles, with at least one perfluoroalkyl substituent, and condensations of the pyrroles to Type I porphyrins. Japanese patent application 1238585 to Muruyama discusses a different method of preparation of unsymmetrical 3,4-hydroxymethyl-pyrroles with a variety of alkyl substituents, and their condensation to porphyrins.
U.S. Pat. No. 5,241,062 to Wijesekera et al disclose methods of making and using “leaving group” substituents bonded to the oxygen of 2-hydroxyalkyl-pyrroles. The leaving groups included various benzoates and sulfonates. Various electron withdrawing substituents were present on the pyrroles and porphyrins.
Kinoshita et al. disclose several methods for the synthesis of 3,4-unsymmetrically disubstituted, 2-hydroxymethyl-pyrroles, in which the hydroxyl group can be replaced by a variety of “leaving groups”.
U.S. Pat. No. 5,674,467 to Maier et al., and U.S. Pat. No. 5,284,647 to Niedballa et al., disclose the production of porphyrins having 5-butyl substituted phenyl groups in the porphyrin meso positions, by a well-known method of condensing 4 moles of pyrrole with 4 moles of 5-butyl- substituted benzaldehydes.
U.S. Pat. No. 5,703,230 to Boyle et al. disclose a method of iodinating one meso position of various substituted porphyrins, to yield mono-iodinated porphyrins.
Despite the knowledge possessed by those skilled in the art, the need still exists for an improved technique for synthesizing porphyrin compounds.
SUMMARY OF THE INVENTION
The present invention relates to a method of producing porphyrin compounds which is capable of providing a significantly improved porphyrin yield at a reduced cost.
To this end, one aspect of the present invention relates to a method for synthesizing porphyrin compound which includes the step of removing one or more substituent groups from a substituted porphyrin compound. Preferably, the removal step involves acid cleavage and the substituent group is an acid cleavable substituent such as a t-butyl group.
Another aspect of the present invention relates to a method which produces porphyrin compounds from substituted pyrrole compounds, where the substituent on the pyrrole compound selected so as to aid in the porphyrin ring formation, which substituent can be subsequently removed. In this regard, the method comprises (i) reacting the substituted pyrrole compound so as to provide a substituted porphyrin compound containing the substituent(s) followed by (ii) removal of the substituents from the substituted porphyrin compound.
Other aspects of the invention include porphyrin compounds and, in particular, porphyrins of formula (II),
where both R
1
and R
2
are not hydrogen, and porphyrins of formula (V),
where R
c
is a removable substituent, e.g., an acid cleavable hydrocarbyl group such as an alkyl or aryl.
Yet additional aspects of the invention include pyrrole intermediates compounds, and, in particular, the pyrroles of formula (I), (VI) and (VII)
where L is a leaving group such as a hydroxy group.
Other aspects of the presents invention include methods for synthesizing the foregoing compounds.
REFERENCES:
patent: 3579533 (1971-05-01), Yalman et al.
patent: 5241062 (1993-08-01), Wijesekera et al.
patent: 5284647 (1994-02-01), Niedballa et al.
patent: 5284831 (1994-02-01), Kahl et al.
patent: 5659029 (1997-08-01), Ellis, Jr. et al.
patent: 5672717 (1997-09-01), Verkade et al.
patent: 5674467 (1997-10-01), Maier et al.
patent: 5703230 (1997-12-01), Boyle et al.
patent: 63238078 (1988-04-01), None
patent: 63238057 (1988-10-01), None
patent: 1238585 (1989-09-01), None
patent: 1553060 (1990-03-01), None
patent: WO 00/56706 (2000-09-01), None
Fujii et al., Chemical Abstracts, vol. 126:263974, 1997.*
Triebs et al., Chemical Abstracts, vol. 76:3820, 1972.*
Rodd's Chemistry of Carbon Compounds, 2ndEd., vol. IV, Part B, “Heterocyclic Compounds”, pp. 262-267, Elsevier, 1977.
Houben-Weyl, “Methods of Organic Chemistry”, 4thEd., vol. E 9d, “Hetarenes IV”, pp. 596-597; George Thieme Verlag 1998.
Barton, et al. “Comprehensive Organic Chemistry. The Synthesis and Reactions of Organic Compounds” vol. 4, pp. 333-339, Pergamon Press 1979.
Kadish et al. Inorg. Chem. 24 (1985) 4512.*
Ogose et al,. Chemical Abstracts 111:39183 (abstract for JP63238057) 1989.*
Buchler in The Porphyrins, vol. 1 Structure and Synthesis, Part A, ed. D. Dolphin, Academic Press, New York, 1978, pp. 389-482.*
Anderson, et al.,The Synthesis of 3-Substituted Pyrroles from Pyrrole;Synthesis 353-364 (1985).
Mueller-Westerhoff, et al.,Azines and Imines of 4- and 5-t-Bu-Pyrrole-2-Aldehyde, A Useful Synthesis of the
Liebeskind Lanny S.
Nickel Eric G.
Emory University
Needle & Rosenberg P.C.
Raymond Richard L.
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