Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-10-17
1993-08-03
Page, Thurman K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D48722
Patent
active
052330346
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention concerns a new process for the purification of hemin, a novel hemin derivative usable in the process, as well as a process for its preparation.
Hemin is used in medicine i.e., as a water soluble complex compound with basic amino acids, for example L-arginine, for the preparation of pharmaceutical preparations, especially injection preparations, which may be used for the treatment of various types of anemia and especially for the treatment of porphyrism, (see FI-patent 68970).
Hemin may be prepared by splitting hemoglobin from blood using different methods. Thus as the starting material, for example, whole blood or red cell concentrates may be used. According to a modification of a method described by Labbe et al. in the publication Biochem., Biophys. Acta 1957, 26, 437, hemin may be isolated from human blood (red cell concentrate) with a mixture of acetone and acetic acid. In this treatment the cell material and the proteins are separated as a solid substance, which is removed by centrifugation. The centrifuged solution contains the hemin. By evaporating the major part of the solvents the hemin is made to crystallize at room temperature.
A problem has, however, been the preparation of hemin in a form sufficiently pure for medicinal use. According to literature (Fischer, Hans: Organic Synthesis, Collective, Vol. 442-443 (1955) hemin may be crystallized from chloroform pyridine glacial acetic acid. Crystallization from chloroform pyridine-glacial acetic acid does not purify hemin very effectively. In the DE-publication 36 08 091 Al is disclosed a process for the separation and purification of hemin by crystallizing the same from an acid aqueous solution in the presence of tensides. A disadvantage of this purification process is the insufficient degree of purity of the hemin obtained, which is approximately 98% by weight.
SUMMARY OF THE INVENTION
Now it has, according to the invention, been discovered that hemin may be prepared in a form sufficiently pure for its medical use. Thus the invention concerns a novel process for the purification of hemin which makes it possible to prepare hemin with a good yield and in a very pure form, typically with a degree f purity of 99 to 100%. The invention concerns also a novel hemin derivative formed in the process, as well as a process for its preparation.
DETAILED DESCRIPTION
Thus the invention concerns a novel process according to which raw hemin prepared for example as described above, is dissolved while heating in 1,3-dimethyl-2-imidazolidinone (DMI), the mixture is allowed to cool in order to crystallize the hemin as a 1:3 adduct of hemin and DMI, whereafter the adduct obtained is split by treating the same in warm water, a lower alcohol, or in a mixture thereof, or by heating in a vacuum, and the liberated hemin is recovered.
The invention concerns also as a novel compound the adduct of hemin and DMI which may be illustrated with the following formula ##STR1##
In the formula, n=3 when the adduct is washed and dried in a vacuum at a temperature not higher than 50.degree. C. By drying in a vacuum at higher temperatures, DMI is split off from the adduct, whereby n will vary between 0 and 3. The composition of the adduct may be determined with HPLC. The adduct is a crystalline product which is completely resolved at 105.degree. C.
The process according to the invention is preferably carried out by using DMI in an amount by weight which is approximately 5 to 10 times, especially approximately 6 to 8 times in excess with respect to the weight of hemin. Hemin dissolves very well in hot DMI. This the dissolution of hemin preferably takes place at a temperature of approximately 60.degree. to 80.degree. C. The adduct formed after dissolving while hot crystallizes when the solution is cooled to a temperature below room temperature but above approximately 8.degree. C. (the melting point of DMI is 8.degree. C.), preferably it is cooled to about 10.degree. C., whereby the hemin-DMI adduct is crystallized with a small crystallizati
REFERENCES:
patent: 4761472 (1988-08-01), Schultze
Labbe et al., "A New Method of Hemin Isolation," Biochem., Biophys. Acta 1957, 26, 437.
Merck Index, 4534 Hemin, p. 4537.
"Organic Syntheses", Coll. vol. 3, pp. 442-443 (1955) by John Wiley and Sons, Inc.
"Modern Experimental Organic Chemistry" by Fishel and Fort, pp. 23-35 (1971), by the Macmillan Company.
Huhtamaki Oy
Page Thurman K.
Venkat Jyothsna
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