Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-17
2001-03-20
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06204393
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for economically advantageously crystallizing a maleate salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (hereinafter also referred to as “enalapril”) of the formula (I):
on a commercial scale in a high quality and a high yield to thereby purify the maleate salt. The N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt (enalapril maleate) is a compound very useful as an antihypertensive agent.
BACKGROUND ART
A process for crystallizing a pharmacologically acceptable salt of enalapril (I), particularly enalapril maleate that the pharmacologically acceptable salt is maleate salt, is disclosed, for example, in U.S. Pat. No. 4,442,030, U.S. Pat. No. 4,374,829 and U.S. Pat. No. 5,359,086 wherein the process is conducted by recrystallization from an organic solvent such as acetonitrile. However, it is assumed that a trace amount of the organic solvent is unavoidably introduced into the final product, thus imparting undesirable characteristics to enalapril maleate which is taken in by a human being. Accordingly, the use of organic solvents should be avoided. From such a point of view, the use of an aqueous liquid would produce favorable results.
As to a process for taking enalapril maleate out of an aqueous liquid in the form of crystals, for example, Journal of Organic Chemistry, Vol. 53, 836-844(1988) discloses a process wherein enalapril maleate having a small content of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate which is an optical isomer that the configuration of carbon atom to which ethoxycarbonyl group bonds is different from enalapril, is obtained by recrystallizing enalapril maleate from water. However, no detail of procedure, yield, purification effect and so on is disclosed therein.
Also, U.S. Pat. No. 4,374,829 discloses a process for obtaining an enalapril salt by converting enalapril to its pharmacologically acceptable salt in water followed by an operation such as evaporation of water or freeze drying. However, the process requires a long time in its operation and accordingly have problems such as waste of time, lowering of productivity, waste of vast energy and complication of operation, so the process has many problems to be solved in production on a commercial scale.
Thus, it has been desired to provide a process for economically advantageously crystallizing enalapril maleate having a high quality directly from an aqueous liquid in a high yield.
The maleate salt of the enalapril (I) can be obtained in general by mixing enalapril and maleic acid in a suitable solvent, preferably an aqueous liquid, to produce the enalapril maleate and obtaining it in the form of crystals after forming a slurry with a high concentration by concentration, freeze drying or the like. However, in case of obtaining the crystals directly from the above aqueous liquid without applying any special procedure, it is difficult, from the point of solubility, to achieve a large amount of crystallization. In particular, in case of purification by a recrystallization method wherein enalapril maleate is once dissolved in an aqueous liquid and then recrystallized, it is particularly difficult to raise the amount of crystallization owing to solubility characteristics of enalapril maleate. For increasing the amount of crystals deposited in this recrystallization method, it is required to make the difference in the amount of dissolution large between at the time of forming the solution and at the time of crystallization. For example, in case of the cooling crystallization, a large amount of crystallization is not achieved since the change in solubility of enalapril maleate based on the difference in temperature is relatively small. Thus, it is necessary to combine it with a concentrating crystallization so as to decrease the amount of mother liquor to thereby increase the amount of crystals deposited. However, such an operation requires a long time and, therefore, it is not an advantageous process from the viewpoints of waste of time, lowering of productivity, waste of vast energy and complicated operation. Further, since the solubility of enalapril maleate is generally low even at high temperatures, the amount of the solution becomes large relatively and this brings about disadvantages such as enlargement of dissolution equipment, lowering of productivity and increase of waste water. Therefore, the application of the process to a commercial scale production requires a further improvement. Also, increase in thermal hysteresis through dissolution and concentration operations is unfavorable because it leads to a serious problem such as increase in production of impurities. However, no effective means for solving these problems has been known.
Also, in case of forming enalapril maleate in a solvent from enalapril and maleic acid and then crystallizing the maleate, there arise problems that a diketopiperazine derivative is by-produced and a carboxy derivative contaminates.
Accordingly, it is an object of the present invention to provide a simple and economically advantageous process suitable for industrial production wherein enalapril maleate having a high quality is obtained in a high yield by dissolving enalapril maleate in an aqueous liquid in a high concentration and crystallizing the maleate directly from the resulting solution.
A further object of the present invention is to provide a process for obtaining enalapril maleate having a high quality in a high yield and a high efficiency from enalapril and maleic acid.
DISCLOSURE OF INVENTION
The present inventors have found that:
(i) as a manner for obtaining a solution of enalapril maleate dissolved in an aqueous liquid in a high concentration it is effective to dissolve the maleate under a condition of a pH of not less than 4 by using a base,
(ii) a large difference in solubility of enalapril maleate is obtained by mixing the aqueous liquid of pH 4 or higher obtained in (i), in which enalapril maleate is dissolved in a high concentration, with an acid to lower the pH, preferably to lower the pH to a pH 2 to 3,
(iii) as a consequence, enalapril maleate having a high quality can be economically advantageously crystallized in a simple manner in a high yield merely by lowering the pH of the aqueous liquid obtained in (i) without applying any additional procedure, and at that time a salting out effect based on a neutral salt (particularly inorganic salt) produced by the acid contributes to increase in the amount of crystals deposited, and
(iv) by using the process mentioned above, enalapril maleate having a low content of impurities such as N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline (hereinafter also referred to as “carboxy derivative (III)”) of the formula (III):
is obtained, while suppressing by-production of a diketopiperazine derivative of the formula (II):
Thus, the present invention provides a process for crystallizing a maleate salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline of the formula (I):
which comprises mixing an aqueous liquid having a pH of not less than 4 and containing N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I), maleic acid and a base with a sufficient amount of an acid to convert substantially all of said base into a neutral salt.
The base changes into a neutral salt by mixing of the aqueous liquid with an acid, whereby the solubility is lowered to crystallize the compound (I) as its maleate salt out of the aqueous liquid. Further, the produced neutral salt contributes to crystallization of the maleate salt by salting out effect. According to the process of the present invention, a maleate salt of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline (I) having a low content of N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline of the formula (III):
can be obtained, while restraining by-production of a diketopiperazine derivative of the formula (II):
BEST MODE FOR CARRYING OUT THE INVENTION
An aqueous liquid having a pH of at least 4 and containing enalapril, maleic acid
Fuse Yoshihide
Kinoshita Koichi
Moroshima Tadashi
Ueda Yasuyoshi
Yanagida Yoshifumi
Armstrong Westerman Hattori McLeland & Naughton LLP
Kaneka Corporation
Stockton Laura L.
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