Processes for large scale production of tetrapyrroles

Details Processes for large scale production of tetrapyrroles Processes for large scale production of tetrapyrroles

2001-01-23

2002-10-08

Raymond, Richard L. (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C534S010000, C534S011000, C534S012000, C534S013000, C534S014000, C534S015000, C534S016000

Reexamination Certificate

active

06462192

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to processes especially suitable for the large scale production of tetrapyrrolic compounds, such as meso-formyl porphyrins, meso-acrylate porphyrins, purpurins and benzochlorins. In particular, tin ethyl etiopurpurin (SnET2), sometimes called rostaporfin, and the intermediates necessary for its production without chromatography are disclosed. In addition, much of the chemistry disclosed is applicable to the large scale manufacturing of benzochlorins. Purpurins, benzochlorins and several of the intermediates in the synthesis may be useful as photosensitizers in photodynamic therapy, or as porphyrin building blocks in the synthesis of other porphyrinic materials.
BACKGROUND OF THE INVENTION
Photodynamic therapy is a procedure that uses photoactive (light-activated) drugs to target and destroy diseased cells. Photoactive drugs transform light energy into chemical energy in a manner similar to the action of chlorophyll in green plants. The photoactive drugs are inactive until irradiated by light of a specific wavelength, thereby enabling physicians to target specific groups of cells and control the timing and selectivity of treatment. The result of this process is that diseased or unwanted cells are destroyed with less damage to surrounding normal tissues. For a more detailed description of photodynamic therapy, see U.S. Pat. Nos. 5,225,433, 5,198,460, 5,171,749, 4,649,151, 5,399,583, 5,459,159, and 5,489,590, the disclosures of which are incorporated herein by reference.
A large number of naturally occurring and synthetic dyes are currently being evaluated as potential photoselective compounds in the field of photodynamic therapy. Perhaps the most widely studied class of photoselective dyes in this field are the tetrapyrrolic macrocyclic compounds generally called tetrapyrroles, some of which are shown below.
In particular, and relevant to this invention, are the chlorin ring systems called purpurins and benzochlorins. Purpurins are a class of chlorin in which an annelated five membered cyclopentenyl ring is directly attached to the reduced pyrrole ring. A notable example of a metallo-purpurin that is showing great promise in the field of photodynamic therapy is tin dichloride ethyl etiopurpurin I (7) (currently prepared by Scheme 1). An older method for synthesis of (7) was outlined in U.S. Pat. No. 5,051,415, the disclosure of which is incorporated herein by reference.
Benzochlorins on the other hand have an annelated benzene ring directly attached to the reduced pyrrole ring. A notable example of a benzochlorin is octaethylbenzochlorin (13) (prepared by Scheme 2) which serves as a starting chlorin for many promising photosensitizers (see U.S. Pat. Nos. 5,552,134; 5,438,051; 5,250,668; 5,109,129; 4,988,808; 5,514,669; 6,008,211; 5,856,515; 5,744,598; 5,512,559; and 5,424,305, the disclosures of which are incorporated herein by reference). To date, very inefficient routes to the synthesis of purpurins and benzochlorin ring systems have been reported and there exists no reported satisfactory method of manufacturing these materials on a large scale.
As a result, a method that enables the synthesis of compounds having these two ring systems, the purpurins and the benzochlorins and their intermediates, on a large scale is of immense value. The present invention provides processes for the large scale preparation of meso-formyl porphyrins, meso-acrylate porphyrins, metal free meso-acrylate porphyrins, metallo-porphyrins, purpurins, metallated purpurins and benzochlorin compounds, the purification steps of which are achieved simply by fractional crystallizations.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present invention as claimed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to processes for synthesizing meso-formyl porphyrins, &bgr;-formyl porphyrins, metallo meso-acrylate porphyrins, metal free meso-acrylate porphyrins, purpurins, metallo-purpurins, metal lo-porphyrins and benzochlorins and isolating these compounds simply by fractional crystallization techniques that are amenable to large scale syntheses of such compounds. Processes for the isolation of such compounds will be set forth in the following detailed descriptions of each of the steps of schemes 1 and 2. These processes require no chromatographic separations or additional chemical reactions and are therefore suitable for use on a large scale. The present invention is also particularly relevant to the formylation of metallo-tetrapyrrolic molecules, the reaction of formyl tetrapyrrolic compounds with Wittig reagents, the demetallation of metallo-tetrapyrrolic compounds, the cyclization of meso-acrylate tetrapyrroles to purpurin compounds, the reduction of meso-acrylate tetrapyrrolic compounds, the cyclization of meso-(3-hydroxypropenyl) tetrapyrrolic compounds to benzochlorins and the tin metallation of tetrapyrrolic molecules, all on large scale.
As used herein, the term “tetrapyrrole” or “tetrapyrrolic compound” is intended to encompass a large number of compounds with at least three joined pyrrolic rings having widely differing functionality as described in the literature (for example, see “Porphyrins and Metalloporphyrins” Ed. K. Smith, Elsevier, 1975, N.Y.; “The Porphyrins”, Ed. D. Dolphin, Vol. I-V, Academic Press, 1978; and “The Porphyrin Handbook”, Ed. K. Kadish, K. M. Smith, R. Guilard, Academic Press, 1999). These compounds contain various and ranging substituents on the &bgr;-pyrrole positions or meso-positions of the tetrapyrrolic rings, either symmetrically or asymmetrically substituted on the tetrapyrrolic macrocycle. Simple tetrapyrrolic ring systems include porphyrins, chlorins, iso-bacteriochlorins and bacteriochlorins. Additionally, molecules resembling porphyrins such as corroles, porphodimethenes, phthalocyanines, naphthalocyanines, azoporphyrins, phlorins, texaphyrins, porphyrin “isomers” (such as porphycenes, porphacyanine, homoporphyrins, corrphycenes, vinylogous corroles, vinylogous porphyrins, sapphyrins, pyrhporphyrins, smaragdyrins, isosmaragdyrins, ozaphyrins, pentaphyrins, heteropentaphyrins, orangarins, dehydropentaphyrins, rubyrins, bronzaphyrins, octaphyrins, and the like ) have been developed with a wide range of functionality both at the peripheral positions and at the internal heterocyclic “core” of these molecules. All of these compounds are considered to be within the scope of the term “tetrapyrrole” or “tetrapyrrolic compound” as used herein.
In many of these macrocycles the inner heteroatoms have been replaced by O, S, Se, Te forming new macrocycles with interesting properties. Many of these materials are capable of coordinating metals and will undoubtedly find commercial uses in the fields of medicine and industry and thus are applicable to the inventions set forth in the specification, particularly with regard to formylation, Wittig reactions, demetallation and metallation with tin. Accordingly, there will be a need for highly pure material, especially in pharmaceuticals, which can be made on a large scale.
Examples of the various substituents that can be present on the &bgr;-pyrrole or meso-positions of the tetrapyrrolic compounds of the invention include functional groups having a molecular weight less than about 100,000 daltons and can be a biologically active group or organic. Examples are, but are not limited to: (1) hydrogen; (2) halogen, such as fluoro, chloro, iodo and bromo (3) lower alkyl, such as methyl, ethyl, n-propyl, butyl, hexyl, heptyl, octyl, isopropyl, t-butyl, n-pentyl and the like groups; (4) lower alkoxy, such as methoxy, ethoxy, isopropoxy, n-butoxy, t-pentoxy and the like; (5) hydroxy; (6) carboxylic acid or acid salts, such as —CH
2
COOH, —CH
2
COONa, —CH
2
CH
2
COOH, —CH
2
CH
2
COONa, —CH
2
CH
2
CH(Br)COOH, —CH
2
CH
2
CH(CH
3
)COOH, —CH
2
CH(Br)COOH, —CH
2
CH(CH
3
)COOH, —CH(CI)CH
2
CH(CH
3
)COOH, —CH
2
CH
2
C(CH
3
)
2
COOH, —CH
2
CH
2
C(C

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