JPH044308B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to N ² -(1-carboxy-3-phenylpropyl)-L-lysine derivatives, particularly the following optically active N ² -(1-(S)-carboxy-3 −
(phenylpropyl)-L-lysine derivative (), [In the formula, R ¹ represents an alkyl group, and R ² represents an acyl-type protecting group. The asterisk (*) represents the (S) configuration for the asymmetric carbon. ] ^N2- (1-(S)-ethoxycarbonyl-) is expected to be used as an antihypertensive agent due to its excellent angiotensin-converting enzyme (ACE) inhibitory activity.
3-phenylpropyl)-L-lysyl-L-proline () [In the formula, the asterisk (*) represents an asymmetric carbon (S)
extremely useful as an intermediate for the production of
The object of the ^present invention is to industrially advantageously produce N2-(1-(S)-carboxy-3-phenylpropyl)-L-lysine derivatives. (Prior art) As a method for producing N ² -(1-carboxy-3-phenylpropyl)-L-lysine derivative, as shown in the following formula, β-benzoylacrylate ethyl () and L-lysine ester are used. The derivative (N ⁶ -benzyloxycarbonyl-L-lysine benzyl ester ()) was subjected to a so-called Michael addition reaction in the presence of a catalytic amount of triethylamine to form a diastereomer mixture N ² -(1-
Ethoxycarbonyl-3-oxo-3-phenylpropyl) ^-N6 -benzyloxycarbonyl-L
- After converting into lysine benzyl ester (), ^N2 having the desired configuration is subjected to a crystallization operation.
-(1-(S)-Ethoxycarbonyl-3-oxo-3-phenylpropyl)-N ⁶ -benzyloxycarbonyl-L-lysine benzyl ester (-
a) was obtained, which was further subjected to catalytic reduction using palladium carbon as a catalyst to give ^N2- (1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysine (), and then lysine The side chain amino group was protected by reaction with benzyl chloroformate, and the product was purified by silica gel chromatography to give N ² -(1-(S)-ethoxycarbonyl-3-phenylpropyl)-N A method for obtaining ⁶ -benzyloxycarbonyl-L-lysine () is known (Japanese Unexamined Patent Publication No. 103364/1983). (Problem to be Solved by the Invention) However, in the method using this L-lysine ester derivative, in addition to the esterification operation of the L-lysine derivative, N ⁶ -benzyl which has formed a salt with the acid used during esterification is Oxycarbonyl-L-
It is necessary to perform an operation to liberate the α-amino group of lysine benzyl ester, and furthermore, this ester can be selectively removed while keeping the ethyl ester moiety derived from β-benzoyl ethyl acrylate stable. Because it must be based on
Naturally, it is limited to esters that are relatively difficult to prepare, such as benzyl esters and tert-butyl esters. In addition, since lysine is a basic amino acid with an amino group in its side chain, in order to react only with the amino group at the α position, the amino group at the ε position must be protected with a protecting group that is normally used in peptide synthesis. However, when a benzyloxycarbonyl group is used as a protecting group, it is hydrogenolyzed and eliminated during the reduction reaction from (-a) to (). In order to subject () to further reaction, it is preferable to protect the ε-amino group of the lysine residue, so benzyloxycarbonyl group was introduced using benzyl chloroformate again. ) has reactivity not only in the ε-amino group but also in the α-amino group of the lysine residue, so the generation of by-products is unavoidable. Therefore, the molar yield of () obtained by purification with a silica gel column relative to () is low at 42%, and the overall yield from N ⁶ -benzyloxycarbonyl-L-lysine benzyl ester is 15.8%, indicating a high degree of processing. The yield is low despite using high-quality raw materials, and there are various methods for producing N ² -(1-carboxy-3-phenylpropyl)-L-lysine derivatives in terms of operability and economy. It has its drawbacks. (Means and Effects for Solving the Problem) The present inventors have previously discovered that N-(1-(S)-ethoxy carbonyl-3-oxo-3-phenylpropyl)-L
-A method for economically and efficiently producing alanine and N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine
178954), N-(1-(S)-
ethoxycarbonyl-3-phenylpropyl)-
L-alanyl chloride inorganic acid salt and its efficient production method (JP-A-62-48655), and N-(1-
Using (S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine, N-(1-(S)-ethoxycarbonyl-3-phenylpropyl), which is one of the ACEIs and is expected to have excellent effects. enylpropyl)-L
- Method for economically and efficiently producing alanyl-L-proline (enalapril) (JP-A-62-
No. 48696) was applied for a patent. Based on these technologies, the present inventors have discovered that ^N2-
(1-(S)-carboxy-3-phenylpropyl)
^-N2- (1-(S)-) which is extremely useful as a synthetic intermediate for -L-lysyl-L-proline (lisinopril)
Carboxy-3-oxo-3-phenylpropyl)-L-lysine derivative () and N2-( ^1- (S)-carboxy-3-phenylpropyl)-L-lysine derivative obtained by reducing it ( ) As a result of repeated studies to establish a simple, economical, and efficient industrial manufacturing method, the general formula () was developed. A β-benzoyl acrylic acid derivative represented by [wherein R ¹ represents an alkyl group] and the general formula () By reacting the L-lysine derivative represented by the formula [wherein R ² represents an acyl-type protecting group] with an equivalent amount of base, N ² -(1 -Carboxy-3-oxo-3-phenylpropyl)-L-lysine derivative () is obtained, and the configuration of the asymmetric carbon newly generated by carrying out the reaction under specific controlled reaction conditions. found that the desired (S) configuration can be produced with high priority over the unwanted (R) configuration, and the product N ² -(1-carboxy-3-oxo-3- It was revealed that N ² -(1-carboxy-3-phenylpropyl)-L-lysine derivative ( ) can be easily produced by catalytic hydrogenolysis of L-lysine derivative (phenylpropyl)-L-lysine, and the present invention was achieved by It was completed. The present invention can be expressed by the following formula. [R ¹ and R ² represent the same groups as above] The present invention will be explained in detail below. The β-benzoyl acrylic acid derivative, which is one of the starting materials of the present invention, exists in trans and cis forms. It can be easily obtained by esterifying trans-β-benzoyl acrylic acid obtained by a known method such as dehydration condensation. Moreover, the cis form can be prepared by isomerizing the trans form by light irradiation. Both the trans isomer and the cis isomer can be used in the addition reaction of the present invention, but the trans isomer, which is less processed, is preferred from the standpoint of industrial use. R ¹ is an alkyl group stable to catalytic hydrogenolysis,
Since the 3-oxo group is not eliminated during catalytic hydrogenolysis, it is particularly advantageous when compound () is further subjected to a reaction. These groups include methyl group,
Ethyl group, n-propyl group, iso-propyl group,
_C1 to _C4 alkyl groups such as n-butyl group and tert-butyl group can be used. Benzyl, nitrobenzyl, and methoxybenzyl groups are eliminated by catalytic hydrogenolysis, so they are not suitable for this purpose. Another raw material, L-lysine derivative, is L-
Lysine has two amino groups at the α-position and the ε-position, so if it is used in the addition reaction without protecting the amino group, the reaction will proceed, but the amino group at the α-position will be added to the target product at the ε-position. A large amount of by-products are produced by the reaction of the amino groups of the target compound, and the proportion of the target compound is about 50%. Therefore, in order to react only the amino group at the α-position, it is preferable to protect the amino group at the ε-position with a protecting group commonly used in peptide synthesis. As N-protecting groups, acyl-type protecting groups such as trifluoroacetyl, formyl, and phthaloyl groups are stable against catalytic hydrogenolysis and do not leave off during catalytic hydrogenolysis; ) is advantageously subjected to further reaction. Lysine with a protected ε-amino group exists as a zwitterion like other neutral amino acids, and since the α-amino group is protonated, it does not have nucleophilic properties, and as it is, it cannot be converted into β-benzoyl acrylic acid. shows no reactivity against It is known that the ionization state of neutral amino acids, which generally exist as zwitterions, changes depending on the pH of the solution as shown below. H ₃ N ⁺ −CH(R)−COOH−H ⁺ (pK′a ₁ ) ―――――――――→ ←―――――――――― +H ⁺ H ₃ N ⁺ −CH(R )−COO ^- −H ⁺ (pK′a ₂ ) ―――――――――→ H ₂ N−CH(R)−COO ^- [R represents the side chain of the amino acid] ε-Protects the amino group The resulting lysine is anionized by adding a base and comes to function as an amine component. That is, it is thought that what can substantially react in this case is a salt of lysine with a protected ε-amino group and a base. The amount of base to be used is preferably stoichiometrically equivalent to lysine with a protected ε-amino group. Examples of the base used in the reaction include alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, quaternary ammonium hydroxides, amines, and ammonia. Quaternary ammonium hydroxides include tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, tetraamylammonium, tetrahexylammonium, tetraoctylammonium, benzyltrimethylammonium, benzyltriethylammonium,
Cetyltrimethylammonium, decyltrimethylammonium, ethyltrimethylammonium, octyltrimethylammonium, phenyltrimethylammonium, trimethylstearylammonium, β-hydroxyethyltrimethylammonium, trioctylmethylammonium, tetradecyldimethylbenzylammonium, etc., and examples of amines include methylamine , ethylamine, propylamine, butylamine, amylamine, hexylamine, cyclohexylamine,
Primary amines such as heptylamine, octylamine, allylamine, α-phenylethylamine, β-phenylethylamine; dimethylamine,
Secondary amines such as diethylamine, dipropylamine, dibutylamine, diamylamine, dihexylamine, dicyclohexylamine, diallylamine, morpholine, piperidine, hexamethyleneimine; trimethylamine, triethylamine, tripropylamine, tributylamine, triamylamine, trihexylamine , triallylamine, triethanolamine, N-methylmorpholine, N,N-dimethyl-cyclohexylamine, N,N,N',N'-tetramethylethylenediamine, and 4-dimethylaminopyridine. If the protecting group for the ε-amino group of lysine is stable against these bases,
It is possible to convert lysine with a protected amino group into a salt by a simple operation such as stirring in water or an alcohol as a solvent at room temperature or with heating, and then react it with a benzoyl acrylic acid derivative. In addition, a stoichiometric amount of these bases is added to a mixture of a benzoyl acrylic acid derivative and a lysine with a protected ε-amino group, and in the reaction system,
It is also possible to carry out a mild reaction while forming a salt in situ. The reaction solvent for the Michael addition reaction, in which a β-benzoyl acrylic acid derivative and lysine with a protected ε-amino group are reacted using a base, is water, alcohols such as methanol, ethanol, propanol, butanol, dioxane, and tetrahydrofuran. In addition to ethers such as n-hexane, acetonitrile, etc., or a mixed solvent thereof can be used, but it is usually appropriate to use an alcohol-water solvent. The reaction proceeds very quickly when an alcohol-water solvent is used, and is usually completed within several minutes to one hour at room temperature. In the Michael addition reaction between a β-benzoyl acrylic acid derivative and an L-lysine derivative, N ² -(1-(S)-carboxy-3-phenylpropyl)-L-lysine with the desired (S,S) configuration is Preferred conditions for selectively increasing the production rate of derivatives vary depending on the combination of reaction reagents, but factors that have a major influence include reaction temperature, pH, and the type and use of the protective group for the ε-amino group of the L-lysine derivative. Examples include the types of bases that can be used. The reaction temperature is not particularly limited and can be carried out over a wide range, but the ^N2- (1-carboxy-3-oxo-3-phenylpropyl)-
When an L-lysine derivative is left under alkaline conditions such as in a reaction system, a decrease in the amount of the product over time or a change in the composition ratio between diastereomers may be observed. Changes in the composition ratio between diastereomers can easily occur during the reaction, so in order to maintain the production rate of () with the (S,S) configuration, the reaction temperature is usually kept below 25°C, especially below 15°C. It is preferable to do so. However, after the reaction is complete, the alkali used
When the system is acidified by adding an equivalent amount or more of an acid, especially a mineral acid such as hydrochloric acid or sulfuric acid, to the quaternary ammonium or weak base, no change in the product is observed and it becomes stable, making subsequent operations easier. The N ² -(1-carboxy-3-oxo-3-phenylpropyl)-L-lysine derivative is isolated by neutralizing the alkali with an acid and then distilling the solvent off under reduced pressure in the usual manner. Although this can be easily done, if necessary, it is also possible to isolate by neutralizing, distilling off the solvent under reduced pressure, and extracting with a solvent. It is also possible to isolate it as its hydrochloride or sulfate. Without further isolation, the N ²
-(1-carboxy-3-phenylpropyl)-L
-It is also possible to isolate it as a lysine derivative. As a specific example, trans-β-ethyl benzoylacrylate and ε-trifluoroacetyl-L
- When reacting lysine in an ethanol-water system,
Alkali metal hydroxides and alkaline earth metal hydroxides include lithium hydroxide, sodium hydroxide,
Potassium hydroxide is suitable, and especially when lithium hydroxide is used, the target N- (1-(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl)-N ⁶ -
Trifluoroacetyl-L-lysine can be obtained. Further, when the reaction temperature is set to 10°C or less, almost no change in the composition ratio between diastereomers is observed. After the addition reaction, an acid such as hydrochloric acid or sulfuric acid is immediately added to the reaction system to form an alkali salt of N ² -(1-ethoxycarbonyl-3-phenylpropyl)-N ⁶ -trifluoroacetyl-L-lysine. N ² −
It can be converted into (1-ethoxycarbonyl-3-phenylpropyl)-N ⁶ -trifluoroacetyl-L-lysine or its hydrochloride or sulfate and stably isolated by a conventional method. In addition, an equivalent amount or more of hydrochloric acid or sulfuric acid is added to the alkali used in the reaction solution, and N ² -(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-N ⁶ -trifluoroacetyl-L-lysine is added. The following reduction operation can also be carried out continuously without isolating the product. N ² -(1 ^- carboxy-3-oxo-3-phenylpropyl)-L-lysine derivative
Catalytic hydrogenolysis to carboxy-3-phenylpropyl)-L-lysine derivatives is carried out in the presence of an appropriate amount of acid (sulfuric acid, hydrochloric acid, formic acid, etc.), e.g., water, alcohols, polar protons such as acetic acid, etc. The process proceeds slowly and with good yield in a neutral solvent. Suitable catalysts include palladium, Raney nickel, and the like. N ² -(1-ethoxycarbonyl-3-oxo-3-phenyl)-N ⁶ -trifluoroacetyl-
In the case of L-lysine, use alcohol such as ethanol as a solvent, add an appropriate amount of palladium carbon as a catalyst in the presence of an acid, and heat at 0°C to 60°C, preferably 5°C.
By hydrogenating at ℃ to 40℃ and reacting for several hours to 24 hours, it is almost quantitatively converted to N ² -(1-carboxy-3-phenylpropyl)-N ⁶ -trifluoroacetyl-L-lysine. be able to. After the reduction reaction is completed, it is possible to easily isolate the catalyst by separating the catalyst, neutralizing the acid with an alkali, removing the solvent, and performing operations such as extraction.If necessary, the desired product can be isolated by recrystallization. It is also possible to obtain compounds with the (S,S) configuration. ^N2- (1-carboxy-3-phenylpropyl)-L-lysine derivatives obtained as above, especially ^N2- (1-(S)-carboxy-3-phenylpropyl)-L-lysine derivatives can be easily converted into lisinopril derivatives by known methods commonly used for peptide synthesis, such as the acid chloride method, NCA method, active ester method, and mixed acid anhydride method. (Effects of the Invention) As is clear from the above explanation, the present invention provides ^N2- (1-
(S)-carboxy-3-phenylpropyl)-L
^-N2- (1-carboxy-3-oxo-3-phenylpropyl)-L-lysine derivatives, which are extremely useful as intermediates for the synthesis of lysyl-L-proline (lisinopril), especially its optically active form ^N2
-(1-(S)-carboxy-3-oxo-3-phenylpropyl)-L-lysine derivatives and compounds obtained by reducing them at low cost and in high yield, and are economical for lisinopril. Moreover, it provides an extremely advantageous method for efficient industrial production. (Example) The present invention will be described below with reference to Examples. Quantitative analysis was performed by high performance liquid chromatography (HPLC). As mentioned above, N ²
-(1-Carboxy-3-oxo-3-phenylpropyl)-L-lysine derivatives are slightly unstable in alkaline conditions, and the (S,S) form is easily converted to the (R,S) form thermodynamically. Therefore, the test solution was subjected to analysis after being sufficiently acidified to stop the composition change. In principle, the following conditions are used for analysis: (S,
The S) and (R,S) bodies were completely separated and quantified. However, depending on the polarity of the N ² -(1-carboxy-3-oxo-3-phenylpropyl)-L-lysine derivative,
The solvent ratio of the mobile phase was adjusted appropriately. Column: Finepak SIL C _18-5 (manufactured by JASCO Corporation) 4.6mm ID x 250mm Mobile phase: 60mM phosphate buffer (PH2.5)/acenitrile = 75/25 (v/v) Both speeds: 1.2ml/ min Detection: 210 nm Internal standard: 5-benzylhydantoin Example 1 40.8 mg of trans-β-benzoylacrylate ethyl acrylate (hereinafter referred to as t-EBA) was mixed with ethanol/water =
Dissolve in 2.0 ml of 3/1 solution and add N ⁶ -trifluoroacetyl-L-lysine (hereinafter L-Lys).
0.2 ml of an aqueous solution or suspension containing the alkali metal hydroxide (0.2 mmole) or alkaline earth metal hydroxide (0.1 mmole) shown in Table 1 to the suspension in which 48.4 mg (Tfa) was added; The reaction was quickly added under ice-cooling and stirred for 30 minutes, then an acid was added to stop the reaction, and ^the product was analyzed by HPLC. -3-oxo-3-phenylpropyl)-N ⁶
-Trifluoroacetyl)-L-zine was observed to be produced.

[Table] Example 2 204.0 mg of trans-β-ethyl benzoylacrylate (hereinafter referred to as t-EBA), 254.0 mg of N ⁶ -trifluoroacetyl-L-lysine, and 5.0 mg of water-EtOH
ml of various amines shown in Table 2.
Add 1.0 mmole instantly at 0°C while stirring with a magnetic stirrer, stir for 60 minutes, add acid to stop the reaction, and perform HPLC.
The product was analyzed using N ² as shown below.
-(1-ethoxycarbonyl-3-oxo-3-
Formation of (phenylpropyl)-N ⁶ -trifluoroacetyl-L-lysine was observed.

【table】

[Table] Example 3 40.8 mg of t-EBA was dissolved in 2.0 ml of a solution of ethanol/water = 3/1, and 48.4 mg of L-Lys (Tfa) was added to this.
0.2 ml of an aqueous solution containing the alkali metal hydroxide (0.2 mmole) shown in Table 3 was quickly added to the suspension under ice cooling or at 20°C, and after stirring for 30 minutes, the same procedure as in Example 1 was carried out. Analysis of the product was performed using ^N2- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl)- as shown below.
Production of N ⁶ -trifluoroacetyl-L-lysine was observed.

【table】

[Table] Example 4 2.45 g of t-EBA was dissolved in 50.0 ml of a solution of ethanol/water = 3/1, and 2.42 g of L-Lys (Tfa) was added to this.
g was added and suspended, and the mixture was heated to 30°C. 2.45 g of potassium carbonate was quickly added to this, and stirring was continued. After 20 minutes, the reaction solution became almost homogeneous, and after 60 minutes, 1.67 ml of concentrated hydrochloric acid was added to stop the reaction, and analysis by ^HPLC was performed. propyl) −N ⁶ −
Production of 3.48 g of trifluoroacetyl-L-lysine was observed. The ratio of the diastereomers produced was (S,S) form/(R,S) form = 61.0/39.0. Next, the solvent of this reaction solution was distilled off under reduced pressure, 50 ml of ethanol was added to the resulting residue, and 4.0 ml of 2.5N-NaOH was gradually added while stirring under ice cooling.
The solvent was distilled off under reduced pressure at room temperature. The residue was extracted by adding ethyl acetate, and after filtration, the ethyl acetate extract was washed with water, dried over sodium sulfate, concentrated under reduced pressure, and crystallized by adding ether- ⁿ -hexane to it.
-(1-ethoxycarbonyl-3-oxo-3-
3.08 g of (phenylpropyl) ^-N6 -trifluoroacetyl-L-lysine was obtained. [(S,S) body/
(R, S) body = 60.5/39.5]. Example 5 81.6 g of t-EBA was dissolved in a 1.0 solution of ethanol/water = 3/1, and 48.4 g of L-Lys (Tfa) was added to this.
was added and suspended, and the mixture was cooled on ice to an internal temperature of 3°C.
200.0 ml of N-LiOH aqueous solution was added dropwise to this solution over 20 minutes with stirring, and after the addition was completed, stirring was continued for an additional 40 minutes. The reaction was stopped by adding 33.3 ml of concentrated hydrochloric acid,
Analysis by HPLC was performed and ^N2- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) ^-N6 -trifluoroacetyl-L-lysine
Production of 84.9g was observed. [(S,S) body/(R,
S) Body = 78.0/22.0]. This reaction solution was treated in the same manner as in Example 4, and N ² -(1-ethoxycarbonyl-
75.8 g of 3-oxo-3-phenylpropyl)-N ⁶ -trifluoroacetyl-L-lysine was obtained as crystals. [(S,S) body/(R,S) body=79.0/
21.0〕. ^1H −NMR (90MHz, CDCl ₃ +DMSO−d ₆ ): δ
(ppm); 1.15-1.4 (t, 3H), 0.9-1.9 (m, 6H), 3.0
~3.55 (m, 5H), 3.6 ~ 3.85 (m, 1H), 3.95
~4.3 (q, 2H), 7.3~8.1 (m, 5H), 8.13~
8.53 (m, 1H) IR (cm ^-1 , KBr disk): 3375, 2950, 1710, 1630, 1600, 1550, 1210, 1185, 690 [α] ²⁵ _D = +23.7° (c = 1.0, N- HC1) Example 6 40.8g of t-EBA was dissolved in 500ml of ethanol,
48.4 g of L-Lys (Tfa) was added to this and suspended, and the internal temperature was cooled to -5°C. Add N-LiOH aqueous solution to this
200.0 ml was continuously added over 150 minutes with stirring, and after the addition was complete, stirring was continued for an additional 30 minutes. Internal temperature is during reaction-
It was kept at 5°C. The reaction was stopped by adding 33.3 ml of concentrated hydrochloric acid, and analysis by ^HPLC was performed.
(1-ethoxycarbonyl-3-oxo-3-phenylpropyl) ^-N6 -trifluoroacetyl-
Production of 81.4 g of L-lysine was observed. [(S,S) body/
(R, S) body = 82.1/17.9]. This reaction solution was treated in the same manner as in Example 4, and ^N2- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) ^-N6-
65.0 g of trifluoroacetyl-L-lysine was obtained as crystals. [(S,S) body/(R,S) body=
81.9/18.1]. Example 7 13.1 ml of concentrated hydrochloric acid was added to 500 ml of ethanol, and to this was added the N ² -(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-N ⁶ -trifluoroacetyl-L- obtained in Example 6. 35.0 g of lysine was added and dissolved, 10.5 g of 10% palladium carbon was added thereto, and hydrogenation was performed at 40° C. under normal pressure. After the reaction, the catalyst was suctioned off, the ethanol solution was adjusted to pH4.5 with sodium hydroxide, water was added,
Ethanol was distilled off by concentration under reduced pressure and replaced with water. Pass through the precipitated white crystals to obtain ^N2- (1-ethoxycarbonyl-3-phenylpropyl) ^-N6-
32.0 g of trifluoroacetyl-L-lysine was obtained. [(S,S) body/(R,S) body = 81.9/18.1].
This was recrystallized from water-ethanol to give ^N2- (1-
(S)-Ethoxycarbonyl-3-phenylpropyl) ^-N6 -trifluoroacetyl-L-lysine was obtained. ^1H -NMR (90MHz, _CDCl3 ): δ (ppm); 1.2~
1.43 (t, 3H), 1.42~2.25 (m, 8H), 2.5~2.85
(m, 2H), 3.0~3.55 (m, 4H), 4.05~4.35 (q,
2H), 6.9~7.4 (m, 5H) IR (cm ^-1 , KBr disk) 3320, 1740, 1700, 1615, 1205, 1170, 750, 700 mp 135.5~137.0℃ [α] ²⁵ _D = +7.8゜(c=2.0, EtOH) Example 8 8.16g of t-EBA was dissolved in 100ml of ethanol,
Add 9.69 g of L-Lys (Tfa) to this and suspend it, -
While maintaining the temperature at 5°C, 20.0 ml of N-LiOH aqueous solution was continuously added over 150 minutes with stirring. After addition, further
After continued stirring for 30 minutes, 10.0 ml of concentrated hydrochloric acid was added to stop the reaction. To this was added 130 ml of ethanol and 5.0 g of 10% palladium carbon, and hydrogenation was carried out at 40° C. under normal pressure. After the reaction, the catalyst was removed and treated in the same manner as in Example 7 to obtain 14.1 g of ^N2- (1-ethoxycarbonyl-3-phenylpropyl) ^-N6 -trifluoroacetyl-L-lysine. [(S,
S) body/(R,S) body = 82.0/18.0]. Reference example 4.08 g of t-EBA was dissolved in 50 ml of a solution of ethanol/water = 10/1, and 5.0 g of N ⁶ -benzyloxycarbonyl-L-lysine (L-Lys(z)) was added and suspended. At room temperature, lithium hydroxide monohydrate
0.75 g was added instantly, and stirring was continued for 1 hour. After the reaction was completed, 5.94 ml of concentrated hydrochloric acid was added, 2.0 g of 10% palladium carbon was added, and hydrogenation was carried out at 40° C. under normal pressure. After the reaction, the catalyst was removed, the pH was adjusted to 8.9 with sodium hydroxide, the solvent was distilled off under reduced pressure, ethanol was added to the residue for extraction, and insoluble materials were removed by filtration. The pH of the liquid was adjusted to 4.6 with hydrochloric acid, and the residue obtained by concentration under reduced pressure was crystallized with ether to give N ² -(1-ethoxycarbonyl-3-phenylpropyl)-L-lysine hydrochloride 4.0 I got g.

Claims (1)

[Claims] 1 General formula () [In the formula, R ¹ represents an alkyl group] A β-benzoyl acrylic acid derivative represented by the following:
General formula () [In the formula, R ² represents an acyl-type protecting group] The general formula () is characterized by reacting the L-lysine derivative represented by () with an equivalent amount of base. [In the formula, R ¹ and R ² are the same as above] N ² -(1-carboxy-3-oxo-
3-Phenyl)-L-lysine derivative manufacturing method. 2. The production method according to claim 1, in which an alkali metal hydroxide, an alkali metal carbonate, an alkaline earth metal hydroxide, a quaternary ammonium hydroxide, an amine, or ammonia is used as the base. 3. The manufacturing method according to claim 1 or 2, in which N ⁶ -trifluoroacetyl-L-lysine is used as the L-lysine derivative and ethyl trans-β-benzoylacrylate is used as the β-benzoylacrylic acid derivative. . 4 N ⁶ -trifluoroacetyl-L-lysine and ethyl trans-β-benzoylacrylate are reacted using lithium hydroxide, sodium hydroxide or potassium hydroxide, and N ² -(1-(S)-
3. The manufacturing method according to any one of claims 1 to 3, which preferentially synthesizes ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-lysine. 5. The production method according to any one of claims 1 to 4, wherein after the addition reaction, an equivalent or more amount of mineral acid is added to stabilize the product. 6 General formula () [In the formula, R ¹ represents an alkyl group] A β-benzoyl acrylic acid derivative represented by the following:
General formula () [In the formula, R ² represents an acyl-type protecting group] is reacted with the L-lysine derivative represented by () using an equivalent amount of base, resulting in the general formula () [In the formula, R ¹ and R ² are the same as above] N ² -(1-carboxy-3-oxo-
After catalytic hydrogenolysis of the 3-phenyl)-L-lysine derivative, the general formula () [In the formula, R ¹ and R ² are the same as above] A method for producing an N ² -(1-carboxy-3-phenylpropyl)-L-lysine derivative. 7 ^N2- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) ^-N6 -trifluoroacetyl-L-lysine is catalytically hydrogenolyzed to produce ^N2
7. The production method according to claim 6, wherein -(1-ethoxycarbonyl-3-phenylpropyl) ^-N6 -trifluoroacetyl-L-lysine is converted. 8 General formula [In the formula, R ¹ is an alkyl group, R ² is an acyl protecting group, and X and Y are each a hydrogen atom or together represent an oxygen atom] N ² -(1-carboxy-3-phenylpropyl )-L-lysine derivative. 9 N ² -(1-carboxy ^- 3
-phenylpropyl)-L-lysine derivative.