Process for producing N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline

The process for producing N.sup.2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-proline in a simple, efficient and industrially advantageous manner, including the following steps: PA1 1) subjecting N.sup.2 -(1(S)-alkoxycarbonyl-3-phenylpropyl)-N.sup.6 -trifluoroacetyl-L-lysyl-L-proline (1) to alkali hydrolysis in a mixed solution composed of water and a hydrophilic organic solvent using an inorganic base in an amount of n molar equivalents (n .gtoreq. 3) per mole of the above compound (1), PA1 2) neutralizing the hydrolysis product using an inorganic acid in an amount of (n - 1) to n molar equivalents (n .gtoreq. 3) to form a compound (2) and removing the inorganic salt formed by causing the same to precipitate out from a solvent system suited for decreasing the solubility of the inorganic salt, and PA1 3) causing the compound (2) existing in the mixture after removal of the inorganic salt to crystallize out at the isoelectric point thereof and thereby recovering the compound (2) in the form of crystals while retaining the salts including the trifluoroacetic acid-derived organic acid salt in a state dissolved in the mother liquor.

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.
 ##STR1##
 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)
 ##STR2##
 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):
 ##STR3##
 from an N2- (1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl
 L-lysyl-L-proline of the general formula (1):
 ##STR4##
 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 .gtoreq. 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 .gtoreq. 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
 hydrolyzed using n molar equivalents (n .gtoreq. 3) of an inorganic base
 in a solvent system selected from among a mixed solvent composed of water
 and a hydrophilic organic solvent, and water.
 In the general formula (1):
 ##STR5##
 (R being an alkyl group), which represents the N2- (1(S)
 -alkoxycarbonyl-3-phenylpropyl) N6-trifluoroacetyl-L-lysyl-L-proline, R is
 a group hydrolyzable under alkaline conditions, preferably an alkyl group,
 more preferably an alkyl group containing 1 to 4 carbon atoms, still more
 preferably an ethyl group.
 The N2- (1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl
 L-lysyl-L-proline (1) to be used can be prepared by the methods described,
 for example, in Japanese Kokai Publication Hei-01-254651, Japanese Kokai
 Publication Hei-05-201882, EP 168769 or J. Org. Chem., 53, 836-844 (1988).
 The inorganic base to be used for hydrolyzing the N2-(1(S)-alkoxycarbonyl
 3-phenylpropyl)-N6-trifluoroacetyl-L-lysyl-L-proline is not particularly
 restricted but includes, among others, hydroxides and carbonates of alkali
 metals or alkaline earthmetals. As specific examples of such base, there
 may be mentioned, among others, alkali metal hydroxides such as sodium
 hydroxide and potassium hydroxide; alkali metal carbonates such as sodium
 carbonate and potassium carbonate; and alkaline earth metal hydroxides
 such as magnesium hydroxide and calcium hydroxide. Other inorganic bases
 may also be used. Among them, basic sodium compounds and basic potassium
 compounds are preferred. From the operability viewpoint, these bases are
 preferably used in the form of aqueous solutions. It is generally
 advantageous to use them in the form of aqueous solutions having a
 concentration of 5 to 50% by weight, preferably 20 to 48% by weight. These
 bases may be used singly or two or more of them may be used in
 combination. For example, the first step can preferably be carried out
 using one molar equivalent of sodium hydrogencarbonate and (n - 1) molar
 equivalents (n .gtoreq. 3) of sodium hydroxide.
 The inorganic base using in an amount of n molar equivalents is required
 for the hydrolysis of the N2-(1 (S)- alkoxycarbonyl
 3-phenylpropyl)-N6-trifluoroacetyl-L-lysyl-L-proline (1). Generally, the
 base is used in an amount of not less than 3 molar equivalents (n .gtoreq.
 3) relative to the N2- (1(S) -alkoxycarbonyl 3-phenylpropyl)
 -N6-trifluoroacetyl-L-lysyl-L-proline (1). The inorganic base may be added
 all at once from the beginning, or successively or portionwise so that the
 pH may be maintained at a selected value or varied stepwise during
 hydrolysis. The final pH of the reaction mixture is preferably made 12 or
 higher.
 While the hydrolysis can generally be conducted in an aqueous system, it is
 also possible to conduct the hydrolysis in a mixed solution composed of
 water and a hydrophilic organic solvent which contains the other organic
 solvents in an amount having no adverse influence. The hydrophilic organic
 solvent to be contained is not particularly restricted. Generally, there
 may be mentioned monohydric alcohols containing 1 to 4 carbon atoms, such
 as methanol, ethanol, propanol, isopropanol and t-butanol and, in that
 case, it is preferred that R in the general formula (1) representing the
 N2-(1(S)- alkoxycarbonyl 3-phenylpropyl)-N6-trifluoroacetyl-L-lysyl-
 L-proline to be used is the same as the alkyl group of the above-mentioned
 alcohol. Ethanol can be used more preferably and, in that case, it is
 preferred that R in general formula (1) be an ethyl group. When a mixed
 solvent composed of water and a hydrophilic organic solvent, in particular
 a mixed solvent composed of water and such an alcohol as mentioned above,
 is used, the mixing ratio is generally 1:1 to 1: 99, preferably 1: 1 to
 1:9, more preferably 1:1 to 1:7, by weight.
 As regards the operation temperature in the hydrolysis step, an especially
 high temperature is not required. Practically, the reaction can be carried
 out generally at a temperature not higher than 70 .degree.C, preferably
 not higher than 60 .degree.C at which the solvent system will not be
 frozen, preferably at 0 to 50 .degree.C, more preferably at about 30
 .degree.C.
 In the second step, the reaction mixture from the first step is neutralized
 using an inorganic acid in an amount of (n - 1) to n molar equivalents (n
 .gtoreq. 3), and the inorganic salt formed in the resulting mixture from
 the above inorganic base and inorganic acid is removed by causing the same
 to precipitate out from a solvent system, which is suited for reducing the
 solubility of the inorganic salt, as selected from among a hydrophilic
 organic solvent, a mixed solvent composed of water and a hydrophilic
 organic solvent, and water.
 The amount of the inorganic acid for neutralization is basically (n - 1)
 molar equivalents relative to the amount (n molar equivalents) of the
 inorganic base used in the first step to hydrolyze the N2- (1
 (S)-alkoxycarbonyl-3-phenylpropyl)- N6trifluoroacetyl-L-lysyl-L-proline.
 This is because one mole of the inorganic base is consumed in hydrolyzing
 the trifluoroacetyl group and the resulting trifluoroacetic acid and the
 inorganic base form an organic acid salt. Therefore, when the inorganic
 acid is used in that amount, (n - 1) molar equivalents of the inorganic
 salt is formed in addition to one molar equivalent of the organic acid
 salt formed from trifluoroacetic acid and the inorganic base, and thus the
 whole of the inorganic base component used is neutralized to form the
 salts. On that occasion, the pH of the mixture is in the vicinity of the
 isoelectric point of lisinopril (2) and the pH value is generally about
 5.2 .+-. 0.4 .
 While the inorganic acid to be used is not particularly restricted, the use
 of a strong acid is preferred from the practicability viewpoint. Thus,
 hydrochloric acid and sulfuric acid are preferred among others, and
 hydrochloric acid is particularly preferred. These inorganic acids may be
 used singly or two or more of them may be used in combination. While these
 inorganic acids can be used as they are, they may be used as solutions
 prepared by dilution with an aqueous medium.
 When an inorganic acid stronger in acidity than trifluoroacetic acid,
 preferably hydrochloric acid, is used, acidification can be advantageously
 carried out to an extent exceeding the isoelectric point and the amount of
 the inorganic acid to be used, based on the inorganic base used (n molar
 equivalents), is within the range of over (n - 1) up to n molar
 equivalents, whereby the same molar equivalents of the inorganic salt as
 the inorganic acid component used can be formed. On that occasion, the
 amount of the trifluoroacetic acid component not involved in salt
 formation with the inorganic base component increases, so that the pH of
 the mixture becomes lower than the isoelectric point of lisinopril (2).
 On the contrary, when the inorganic acid is used in an amount outside the
 range of not less than (n - 1) molar equivalents to n molar equivalents or
 when an acid weaker than trifluoroacetic acid is used in an amount of more
 than (n - 1) molar equivalents but not more than n molar equivalents, the
 inorganic base component or inorganic acid component is not wholly removed
 in this step but partly remains and, in the next step of recovery of
 lisinopril (2) by crystallization, further neutralization becomes
 necessary and troubles may unfavorably arise, for example the salt formed
 on that occasion may contaminate the desired crystals or may worsen the
 crystallizability of the desired product.
 In the above procedure, the time over which the whole amount of the
 inorganic acid is to be added is not particularly restricted but generally
 is not less than a quarter of an hour, usually not less than a third of an
 hour, preferably not less than half an hour and, from the viewpoint of
 productivity or the like, it is generally not more than 20 hours, usually
 not more than 10 hours, preferably not more than 5 hours.
 As regards the solvent system suited for reducing the solubility of the
 inorganic salt and inducing the precipitation thereof formed in the
 mixture resulting from neutralization, the use of a hydrophilic organic
 solvent as a poor solvent is effective and it is also preferably
 practicable to make a mixed solvent system composed of a hydrophilic
 organic solvent and water or, further, make a replacement of the medium by
 a hydrophilic organic solvent. The organic solvent to be selected from
 such viewpoints is not particularly restricted but specifically includes,
 among others, monohydric alcohols containing 1 to 4 carbon atoms such as
 methanol, ethanol, propanol, isopropanol and tert-butanol; acetone,
 tetrahydrofuran, acetonitrile and the like. Other hydrophilic organic
 solvents may also be used. In particular, monohydric alcohols containing
 1to 4carbon atoms are preferred and, for minimizing the possible adverse
 effects on the human body in the case of a trace amount of the solvent
 being brought into the final product, ethanol is particularly
 advantageous. These may be used singly or two or more of them may be used
 combinedly. Certain inorganic salt species may be eliminated by
 precipitation from water as well.
 The amount of the hydrophilic organic solvent to be used in the above
 procedure cannot be specified since it depends on the hydrophilic organic
 solvent species employed and the inorganic salt species to be eliminated,
 among others. When an organic solvent is used as a poor solvent for the
 inorganic salt, for instance, the percent elimination of the inorganic
 salt increases when the percentage of the organic solvent is increased.
 From such a viewpoint, the weight ratio between water and the hydrophilic
 organic solvent is generally 4:1to 1:99,preferably 1:1to 1:99,more
 preferably 3:7to 1:99. Certain inorganic salt species can be precipitated
 from water as well. As specific examples of such inorganic salt, there may
 be mentioned potassium sulfate and calcium sulfate, among others. The
 inorganic salt species can be selected on the basis of solubilities in
 water and organic solvents, referring to monographs and the like in the
 relevant field of art or based on simple experiments. The inorganic salt
 species selected can be formed by selecting the combination of inorganic
 base and inorganic acid.
 While the inorganic salt formed precipitates out rapidly, lisinopril (2)
 requires a long period for nucleation and crystal growth, so that it is
 possible to cause preferential precipitation of the inorganic salt for
 separation and removal thereof. Further, selection of more suited
 conditions is preferred; for example, the temperature is preferably
 maintained at a low level, for example 0to 30.degree.C.
 In the above procedure, it is more preferred and efficient to use an
 inorganic acid stronger in acidity than trifluoroacetic acid as the
 inorganic acid for neutralization in an amount within the range of over (n
 - 1) up to n molar equivalents relative to the inorganic base (n molar
 equivalents) to thereby effect acidification to an extent exceeding the
 isoelectric point. In particular, in this range, the use of the inorganic
 acid in an increased amount enhances the effect and the use of the same
 molar equivalents (n molar equivalents) of the inorganic acid as the
 inorganic base is most preferred. By this, it is possible to cause
 preferential precipitation of the inorganic salt and the subsequent
 separation thereof by filtration, with allowing no or almost no
 precipitation of lisinopril (2), as a result of a reduction in rate of
 nucleation and crystal growth of lisinopril (2) and an improvement in
 solubility thereof.
 The inorganic salt precipitate formed from the resulting mixture in this
 step can be separated/removed in a simple and easy manner by a common
 solid-liquid separation procedure such as centrifugal separation or
 pressure filtration.
 In the third step, lisinopril (2) existing in the resultant mixture after
 elimination of the inorganic salt is allowed to crystallize out from a
 hydrophilic organic solvent, a mixed solvent composed of water and an
 organic solvent, or water, at the isoelectric point thereof, whereby
 crystals of lisinopril (2) are recovered while allowing the salts, the
 majority of which is a trifluoroacetic acid-derived organic acid salt, to
 remain dissolved in the mother liquor.
 In allowing lisinopril (2) existing in the mixture obtained after
 elimination of the inorganic salt in the second step to crystallize out
 under isoelectric point conditions, no particular treatment is generally
 required if the mixture is already at the isoelectric point in the
 neutralization stage in the preceding step as a result of the use of (n -
 1) molar equivalents of the inorganic acid. When the mixture is in an
 acidified condition exceeding the isoelectric point as a result of the use
 of the inorganic acid in an amount of more than (n - 1) molar equivalents
 to n molar equivalents, it is judicious to attain the isoelectric point
 using a base so as to increase the percentage of crystallization of
 lisinopril (2). In that procedure, the base is generally used in an amount
 of [(number of molar equivalents of the inorganic acid used) minus (n -
 1)] molar equivalents. The neutral salt formed on that occasion is mainly
 composed of a trifluoroacetic acid-derived organic acid salt, as mentioned
 above, and it is thus possible to cause effective crystallization of
 lisinopril (2), followed by efficient separation and recovery thereof,
 while retaining the above salt in a state dissolved in the crystallization
 solvent for lisinopril (2).
 The base to be used in adjusting the mixture to the isoelectric point is
 not particularly restricted but may be selected from among those inorganic
 bases to be used in the first step of hydrolyzing. In addition, alkali
 metal hydrogencarbonates such as sodium hydrogencarbonate and potassium
 hydrogencarbonate and alkaline earth metal carbonates such as magnesium
 carbonate and calcium carbonate, for instance, are also suited for use.
 Further, aqueous ammonia and organic bases, for example amines such as
 triethylamine and pyridine, may also be used. However, basic compounds of
 sodium and basic compounds of potassium are preferred. These may be used
 singly or two or more of them may be used combinedly.
 The crystallization solvent for lisinopril (2) to be used in this step is,
 for example, water, a hydrophilic organic solvent or a mixture thereof. In
 particular, the use of a mixed solvent composed of water and a hydrophilic
 organic solvent is preferred from the viewpoint of improving the
 removability of the organic acid salt derived from trifluoroacetic acid
 and the base and the crystallizability of lisinopril (2). The hydrophilic
 organic solvent to be used can be replaced with one selected from among
 those hydrophilic organic solvent to be used in the second step. However,
 the use of the same kind of solvent system as used in the second step is
 preferred, since such use is simple and economical, hence advantageous.
 Replacement of the hydrophilic organic solvent with water is also
 practicable and preferred.
 While the concentration of lisinopril (2) for crystallization thereof
 cannot be particularly specified since it depends on the operation
 temperature, the base species used and the amount thereof, the composition
 of the crystallization solvent and the concentration of the coexisting
 salt (s), it is preferred, for further improvement in crystallization
 yield in the stage of crystallization, that the solution has a
 concentration as high as possible. From the viewpoint of preventing
 crystals from being contaminated by the salt (s), however, it is also
 important that the concentration is not too high. Practically, the lower
 concentration limit is preferably set at a level not lower than 5%, more
 preferably not lower than 10%, while the upper concentration limit is
 preferably set at a level not higher than 40%, more preferably not higher
 than 30%. Usually, the crystallization can judiciously be effected at a
 concentration of about 10 to 25%.
 The concentration of the salts, coexisting in the mixture on the occasion
 of crystallization of lisinopril (2) and mainly containing the
 trifluoroacetic acid-derived organic acid salt, is also important from the
 viewpoint of promoting good crystal growth. Although it depends on the
 operation concentration, temperature and procedure as well as on the
 coexisting neutral salt species, among others, hence cannot be specified
 in general terms, the salt concentration is generally to be not higher
 than 15% by weight, preferably not higher than 10% by weight, more
 preferably not higher than 8% by weight.
 The temperature to be employed in the crystallization of lisinopril (2)
 cannot be particularly specified since it depends on the composition of
 the crystallization solvent, the procedure and other factors. Practically,
 however, the third step is carried out at a temperature which is not
 higher than the boiling point of the crystallization solvent but at which
 the solvent will not freeze. While an especially high temperature is not
 required, to raise the temperature at the time of crystallization
 favorably leads to increased rates of nucleation and crystal growth of
 lisinopril (2). From such viewpoint, the operation is preferably carried
 out at a temperature of 40 to 70 .degree.C, more preferably at about
 50.degree.C. The yield of crystals can be increased by finally cooling to
 not higher than 20.degree.C, preferably not higher than 10.degree.C.
 The resulting crystals of lisinopril (2) can be readily recovered by an
 ordinary solid-liquid separation procedure, such as centrifugal separation
 or pressure filtration, without any particular procedure. Thus,
 high-quality crystals can be obtained efficiently and in high yields.
 When, in the practice of the present invention, N2-(1(S) -ethoxycarbonyl
 3-phenylpropyl) -N6-trifluoroacetyl-L-lysyl L-proline is used as the
 reaction substrate, a basic compound of sodium as the inorganic base and
 hydrochloric acid as the inorganic acid, for instance, the mode of
 embodiment will be as follows:
 In the first step, the hydrolysis is conducted in water or a mixture of
 water and ethanol using n molar equivalents (n .gtoreq. 3) of the basic
 compound of sodium as the inorganic base;
 in the second step, the reaction mixture is neutralized using n molar
 equivalents of hydrochloric acid as the inorganic acid and the resulting
 sodium chloride is caused to efficiently precipitate from ethanol or a
 mixture of ethanol and water and removed by filtration; and
 in the third step, one molar equivalent of the basic compound of sodium is
 added to the mixture after elimination of sodium chloride and, while the
 resulting sodium trifluoroacetate is retained in a state dissolved in the
 resulting mixture of ethanol and water, lisinopril (2) is efficiently
 caused to crystallize out, followed by collection of the crystals.
 In another preferred embodiment in which a basic compound of potassium, for
 example, is used as the inorganic base and sulfuric acid as the inorganic
 acid, the process will be as follows:
 In the first step, the hydrolysis is carried out in water or a mixture of
 water and ethanol using n molar equivalents (n .gtoreq. 3) of the basic
 compound of potassium as the inorganic base;
 in the second step, the reaction mixture is neutralized using (n - 1) molar
 equivalents of sulfuric acid as the inorganic acid to thereby adjust the
 mixture to the isoelectric point of lisinopril (2), and the resulting
 potassium sulfate is caused to efficiently precipitate from water or a
 mixture of water and ethanol and removed by filtration; and
 in the third step, while the potassium trifluoroacetate is retained in a
 state dissolved in water or a mixture of water and ethanol, lisinopril (2)
 is allowed to efficiently crystallize out, followed by collection of the
 crystals.
 BEST MODES FOR CARRYING OUT THE INVENTION
 The following examples illustrate the present invention in further detail.
 They are, however, by no means limitative of the scope of the invention.
 For purity testing, HPLC was performed and the purity was calculated by the
 absolute working curve method. The water content was determined by the
 Karl Fischer method. The sodium chloride content was determined using an
 ion chromatograph. The HPLC conditions were as follows: [HPLC]
 Column: Capsule Pack UG-120 (trademark; 4.6 mm x 25 cm; product of Shiseido
 Co.)
 Solvent: 60 mM KH2PO4(pH 2.8)/CH3CN (90:10 (by volume))
 Flow rate: 1.0 ml/min
 Temperature: 50 .degree.C
 Detection: UV 210 nm

EXAMPLE 1
 N2- (1 (S) -Ethoxycarbonyl-3-phenylpropyl)-N6-
 trifluoroacetyl-L-lysyl-L-proline (1) (32.0 g) and 25.9 g of 30% by weight
 aqueous solution of NaOH were mixed up and the hydrolysis reaction was
 allowed to proceed with stirring for about 4 hours. To the reaction
 mixture was added 20.1 g of concentrated hydrochloric acid to make the pH
 2.8 .+-. 0.5. The resulting solution was two-fold diluted with ethanol and
 the diluted solution was concentrated to the original volume. By repeating
 this dilution/concentration procedure, the concentration of water was
 reduced to 4 .+-. 2% by weight. To this solution was added ethanol to make
 the concentration of lisinopril (2) 22 .+-. 2% by weight. The resulting
 mixture was stirred for 1 hour. The precipitate was filtered off and
 washed with 30 ml of ethanol. To the resulting filtrate was added 16.1 g
 of a 15% aqueous solution of NaOH (the pH becoming 5.8). This solution was
 warmed to 45 .degree.C, seed crystals were added, and the mixture was
 stirred for 3 hours, then cooled to 5 .degree.C over 2 hours and further
 stirred for 12 hours. The precipitate crystals were collected by
 filtration and washed with three 30-ml portions of 70% by weight ethanol
 cooled to 5 .degree.C. The crystals obtained were subjected to vacuum
 drying (20 to 50 .degree.C, from 30 mm Hg to 1 mm Hg), to give 22.7 to
 23.5 g (yield: 85 to 88%) of lisinopril (2) dihydrate. The purity was not
 less than 99%, the water content was 8.2% and the sodium chloride content
 was not more than 0.1% by weight.
 EXAMPLE 2
 N2- (1(S)-Ethoxycarbonyl-3-phenylpropyl)-N6- trifluoroacetyl
 L-lysyl-L-proline (1) (32.0 g) and 25.9 g of 30% by weight aqueous
 solution of NaOH were mixed up and the hydrolysis reaction was allowed to
 proceed with stirring for about 4 hours. To the reaction mixture was added
 13.9 g of concentrated hydrochloric acid to make the pH 5.2 .+-. 0.2. The
 resulting solution was two-fold diluted with ethanol and the diluted
 solution was concentrated to the original volume. By repeating this
 dilution/concentration procedure, the concentration of water was reduced
 to 4 .+-. 2% by weight. To this solution was added ethanol to make the
 concentration of lisinopril (2) 22 .+-. 2% by weight. The resulting
 mixture was stirred for 1 hour. The precipitate was filtered off and
 washed with 30 ml of ethanol. To the resulting filtrate was added 15.0g of
 water. This solution was warmed to 45 .degree.C, seed crystals were added,
 and the mixture was stirred for 3 hours, then cooled to 5 .degree.C over 2
 hours and further stirred for 12 hours. The precipitate crystals were
 collected by filtration and washed with three 30-ml portions of 70% by
 weight ethanol cooled to 5 .degree.C. The crystals obtained were subjected
 to vacuum drying (20 to 50 .degree.C, from 30 mm Hg to 1 mm Hg), to give
 22.7 to 23.5 g (yield: 85 to 88%) of lisinopril (2) dihydrate. The purity
 was not less than 99%, the water content was 8.2% and the sodium chloride
 content was not more than 0.1% by weight.
 EXAMPLE 3
 N2- (1(S)-Ethoxycarbonyl-3-phenylpropyl)-N6- trifluoroacetyl
 L-lysyl-L-proline (1) (32.0 g) and 25.9 g of 30% by weight aqueous
 solution of NaOH were mixed up and the hydrolysis reaction was allowed to
 proceed with stirring for about 4 hours. To the reaction mixture was added
 20.1 g of concentrated hydrochloric acid to make the pH 2.8 .+-. 0.5. The
 resulting solution was two-fold diluted with ethanol and the diluted
 solution was concentrated to the original volume. By repeating this
 dilution/concentration procedure, the concentration of water was reduced
 to 3 .+-. 2% by weight. To this solution was added 5.0 g of a 48% (by
 weight) aqueous solution of NaOH (the pH becoming 5.7), followed by
 further addition of ethanol to make the concentration of lisinopril (2) 22
 .+-. 2% by weight. The resulting mixture was stirred for 1 hour. The
 precipitate was filtered off and washed with 30 ml of ethanol. To the
 resulting filtrate was added 12.0 g of water. This solution was warmed to
 45 .degree.C, seed crystals were added, and the mixture was stirred for 3
 hours, then cooled to 5 .degree.C over 2 hours and further stirred for 12
 hours. The precipitate crystals were collected by filtration and washed
 with three 30-ml portions of 70% by weight ethanol cooled to 5 .degree.C.
 The crystals obtained were subjected to vacuum drying (20 to 50.degree.C,
 from 30 mm Hg to 1 mm Hg), to give 22.7 to 23.5 g (yield: 85 to 88%) of
 lisinopril (2) dihydrate. The purity was not less than 99%, the water
 content was 8.2% and the sodium chloride content was not more than 0.1% by
 weight.
 EXAMPLE 4
 N2-(1(S)-Ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl
 L-lysyl-L-proline (1) (100.0 g) was added to a mixed solution composed of
 50.4 g of 48% by weight aqueous solution of NaOH and 39.3 g of ethanol,
 and the hydrolysis reaction was allowed to proceed with stirring for about
 4 hours. To the reaction mixture was added 62.9 of concentrated
 hydrochloric acid. Ethanol was added to the resulting solution to make the
 lisinopril (2) concentration 8 .+-. 2% by weight, and stirring was further
 continued for 1 hour. The precipitate was filtered off and washed with two
 40-ml portions of ethanol. To the resulting filtrate was added 75.5 g of
 10% by weight aqueous solution of NaOH (the pH becoming 6.0). This
 solution was warmed to 45 .degree.C, seed crystals were added, and the
 mixture was stirred for 3 hours, then cooled to 5 .degree.C over 2 hours
 and further stirred for 12 hours. The precipitate crystals were collected
 by filtration and washed with three 30-ml portions of 70% by weight
 ethanol cooled to 5 .degree.C. The crystals obtained were subjected to
 vacuum drying (20 to 50 .degree.C, from 30 mm Hg to 1 mm Hg), to give 65.9
 to 70.0 g (yield: 79 to 84%) of lisinopril (2) dehydrate. The purity was
 not less than 99%, the water content was 8.2% and the sodium chloride
 content was not more than 0.1% by weight.
 EXAMPLE 5
 N2- (1(S)-Ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl
 L-lysyl-L-proline (1) (30.0 g) and 17.0 g of 38% by weight aqueous
 solution of KOH were mixed up and the hydrolysis reaction was allowed to
 proceed with stirring for about 4 hours. To the reaction mixture was added
 6.9 g of concentrated hydrochloric acid to make the pH 5.2 .+-. 0.5, and
 stirring was further continued for 1 hour. The precipitate was filtered
 off and washed with 15 ml of water. The resulting filtrate were warmed to
 45 .degree.C, seed crystals were added, and the mixture was stirred for 3
 hours, then cooled to 5 .degree.C over 2 hours and further stirred for 12
 hours. The precipitate crystals were collected by filtration and washed
 with three 15-ml portions of water cooled to 5 .degree.C. The crystals
 obtained were subjected to vacuum drying (20 to 50 .degree.C, from 30 mm
 Hg to 1 mm Hg), to give 20.0 to 21.3 g (yield: 80 to 85%) of lisinopril
 (2) dihydrate. The purity was not less than 99%, the water content was
 8.2% and the potassium sulfate content was not more than 0.1% by weight.
 INDUSTRIAL UTILIZABILITY
 The process of the present invention makes it possible to produce
 N2-(1(S)-carboxy-3-phenylpropyl) -L-lysyl-L- proline in a simple,
 efficient and industrially advantageous manner.