Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-17
2001-08-07
Higel, Floyd D. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06271393
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a process for producing high-quality N2- (1(S) -carboxy-3-phenylpropyl) -L-lysyl-L- proline of the formula (2) (hereinafter also referred to as lisinopril (2)) in high yields and in an economically advantageous manner on a commercial scale. N2-(1(S)- carboxy-3phenylpropyl)-L-lysyl-L-proline (2) (lisinopril) is a compound very useful as an antihyertensive agent.
BACKGROUND ART
Lisinopril (2) can readily be synthesized by hydrolyzing an N2- (1 (S)-alkoxycarbonyl-3-phenylpropyl)-N6; trifluoroacetyl-L-lysyl-L-proline of the general formula (1)
wherein R represents an alkyl group, using a base in the presence of water and then neutralizing all the basic components in the hydrolysis mixture using an acid. On that occasion, however, it is necessary, for isolating lisinopril (2), to separate lisinopril (2) from salts (salt of trifluoroacetic acid resulting from hydrolysis and salt formed from the base and acid used) which coexist in large amounts.
In that regard, the process disclosed in EP 168769 or
J. Org. Chem.,
53, 836 -844 (1988), for example, comprises hydrolyzing N2- (1 (S)-ethoxycarbonyl-3-phenylpropyl)-N6- trifluoroacetyl L-lysyl-L-proline with sodium hydroxide, acidifying the hydrolysis mixture with hydrochloric acid, removing all the resulting coexisting substances such as sodium chloride, trifluoroacetic acid and/or the sodium salt thereof by treatment on an ion exchange column, concentrating the organic base-containing eluate (eluent being aqueous ammonia or pyridine-water), adjusting the concentrate to the isoelectric point with hydrochloric acid and recovering lisinopril (2) by causing the same to crystallize out from the final water-ethanol mixture solution containing the amine salt formed upon the above adjustment to isoelectric point.
The above process, however, is not only complicated in operation but also poor in productivity since it is necessary to remove a large amount of salts by ion exchange treatment and the eluate is dilute, so that large-scale equipment is required and a long period and a large quantity of heat energy are wasted for the concentration of the eluate. Furthermore, the quantity of waste water to be treated, inclusive of the portion resulting from regeneration treatment of the ion exchange column, is enormous. In addition, the ion exchange column potentially poses a serious problem, namely it may readily allow various microorganisms to grow therein. In view of these and other drawbacks, the above process can hardly be said to be an advantageous one from the industrial production viewpoint.
In an another example, as disclosed in Japanese Kokai Publication
Hei-
08-253497, for instance, N2-(1(S)-ethoxycarbonyl 3-phenylpropyl) -N6-trifluoroacetyl-L-lysyl- L-proline is hydrolyzed with tetrabutylammonium hydroxide, which is an organic base, the hydrolysis mixture is then neutralized with trifluoroacetic acid, which is an organic acid, so that an organic salt, namely tetrabutylammonium trifluoroacetate, alone may be formed as the salt component, and lisinopril (2) is recovered by causing the same to crystallize out at the isoelectric point thereof from a mixed solvent system composed of water and ethanol in the presence of the whole amount of the organic salt.
However, the process just mentioned above, too, can hardly be said to be advantageous from the viewpoint of economy, safety and industrial practice because of the use of special reagents such as tetrabutylammonium hydroxide and trifluoroacetic acid.
Thus, in the prior art, no process is known for separating N2- (1 (S) -carboxy-3-phenylpropyl)-L-lysyl-L-proline (2) from the salt(s) mentioned above in a simple and efficient and industrially advantageous manner.
The present invention has for its object to provide a simple, efficient and industrially advantageous process for separating the salt and lisinopril (2) formed by alkali hydrolysis of N2- (1(S)-alkoxycarbonyl-3-phenylpropyl)-N6- trifluoroacetyl L-lysyl-L-proline and subsequent neutralization from the reaction mixture.
SUMMARY OF THE INVENTION
First, the present inventors investigated the feasibility of the process comprising hydrolyzing N2-(1(S)-alkoxycarbonyl 3-phenylpropyl) -N6-trifluoroacetyl-L-lysyl- L-proline with the inorganic base sodium hydroxide and neutralizing the reaction mixture with the inorganic acid hydrochloric acid or organic acid trifluoroacetic acid, under formation of the inorganic salt sodium chloride or organic acid salt sodium trifluoroacetate, and recovering N2-(1(S)-carboxy 3-phenylpropyl) -L-lysyl-L-proline by causing the same to crystallize out from a solvent system such as water or ethanol while retaining a large amount of such salts dissolved therein. As a result, it was revealed that the yield in recovering crystals of lisinopril (2) and the extent of removal of salts are both unsatisfactory. It was also found that the presence of such salts in large amounts retards the nucleation and crystal growth of lisinopril (2) and causes deterioration in crystal property by which the filterability is reduced. It was thus found that this approach has its limits.
When, however, the salt concentration was reduced for crystallization of lisinopril (2), a tendency was shown toward improvements in the above aspects. It was supposed that reducing salt concentration in advance is necessary and helpful for recovering lisinopril (2) by crystallization. As a result of further intensive investigations made from that point of view, the inventors came to believe that, from the viewpoint of eliminating two different kinds of salts, namely the organic acid salt formed by the trifluoroacetic acid resulting from hydrolysis and the inorganic base used for hydrolysis and the inorganic salt formed upon neutralization from the inorganic base and the inorganic acid used, optimum separating method shouldbe established for each salt according to such properties as solubility in solvent and interaction with lisinopril (2).
Thus, the present invention provides a process for producing N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline of the formula (2):
from an N2- (1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl L-lysyl-L-proline of the general formula (1):
wherein R represents an alkyl group, which comprises:
the first step: subjecting the N2-(1(S)- alkoxycarbonyl 3-phenylpropyl)-N6-trifluoroacetyl-L-lysyl- L-proline (1) to alkali hydrolysis in a solvent system being selected from among mixed solution composed of water and a hydrophilic organic solvent, and water using an inorganic base in an amount of n molar equivalents (n ≧ 3) per mole of the above compound (1),
the second step: neutralizing the hydrolysis product using an inorganic acid in an amount of (n − 1) to n molar equivalents (n ≧ 3) and
separating and removing the inorganic salt formed from the above inorganic base and inorganic acid in the reaction mixture by causing the same to precipitate out from a solvent system suited for decreasing the solubility of the inorganic salt,
said solvent system being selected from a hydrophilic organic solvent, a mixed solvent composed of water and a hydrophilic organic solvent, and water, and
the third step: causing the lisinopril (2) existing in the mixture after removal of the inorganic salt to crystallize out from a solvent system at the isoelectric point thereof,
said solvent system being selected from a hydrophilic organic solvent, a mixed solvent composed of water and a hydrophilic organic solvent, and water, and
thereby recovering the lisinopril (2) in the form of crystals while retaining the salts mainly comprising the trifluoroacetic acid-derived organic acid salt in a state dissolved in the mother liquor.
The process of the present invention makes it possible to separate and recover lisinopril (2) with a reduced salt content from a lisinopril (2)- and salt-containing mixture in a simple and efficient manner.
DETAILED DESCRIPTION OF THE INVENTION
In the first step, each mole of an N2-(1 (S) alkoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysyl L-proline (1) is hydr
Fuse Yoshihide
Moroshima Tadashi
Ueda Yasuyoshi
Yanagida Yoshifumi
D'Souza Andrea M
Higel Floyd D.
Kaneka Corporation
Sughrue Mion Zinn Macpeak & Seas, PLLC
LandOfFree
Process for producing... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for producing..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2517753