JPS58185565A - Production of optically active tetrahydroisoquinoline - Google Patents

Abstract

PURPOSE:An optically active 3-aminopropionic acid derivative obtained through a novel diasteromer is used for reaction with phosgen and the product is made to react with an optically active tetrahydroisoquinoline derivative to give the titled compound used as a hypotensor. CONSTITUTION:Racemic 3-aminopropionic acid derivative of formula I (R<1> is lower alkyl substituted with phenyl; R<4> is lower alkyl) and an optically active N-benzyloxyphenylaminopropionic acid derivative are used to give a novel salt and an optically active 3-aminopropionic acid derivative is obtained therefrom. The product is made to react with phosgen to prepare a compound of formula II. The compound is made to react with an optically active tetrahydroisoquinoline derivative of formula III (R<5> is lower alkyl, aralkyl) to a compound of formula IV, when necessary, followed by hydrolysis to remove R<4> and R<5>, by catalytic hydrogenation to remove R<5>, when R<5> is aralkyl, or by combination of hydrolysis and catalytic hydrogenation to remove R<4> and R<5> to give the objective compound of formula V (R<2> is H, lower alkyl; R<3> is R<2>, aralkyl).

Description

[Detailed Description of the Invention] The present invention is based on the general formula (wherein R1 is lower alkyl M substituted with a phenyl group, R
2 is a hydrogen atom or lower alkyl M, and R is a hydrogen atom.

Represents a lower alkyl group or an aralkyl group. ) relates to a new method for producing an optically active tetrahydroisoquinoline derivative.

Compound CI) has an excellent angiotensin-converting enzyme inhibitory effect and is a useful pharmaceutical compound as a hypotensive agent.For example, the representative compound (3S)-2-(N
-((2R)-2-ethoxycarbonyl-4-phenyl-n-butyl)-N-ethylcarbamoyl 1-1.2,
3.4-tetrahydroisoki/phosphorus-3-carvone Shun・
When calcium salts were orally administered to spontaneously hypertensive rats, a dose of 50%'/19 lowered the rat blood pressure by 33 am.
Hy- can be lowered and the effect lasts for more than 6 hours.

According to the present invention, the target compound CI') is composed of an optically active 3-aminopropionic acid derivative represented by the general formula 0 (where R1 is a phenyl-substituted lower alkyl group and R4 is a lower alkyl group) and phosgene. The reaction is carried out to obtain a compound represented by the general formula (wherein Rt and R4 represent the same taste as above), which is then combined with the general formula (however, R8
represents a lower alkyl group or an arafrekyl group) to produce an optically active tetrahydro ink/response represented by the general formula (wherein R1, R4 or RS represent the same meanings as above). The compound can then be prepared by further removal of R4 and Rs if necessary.

Alternatively, the target compound [I] can be prepared by reacting an optically active trahydroisoquinoline derivative represented by the general formula (wherein R6 represents a lower alkyl group or an aralkyl group) with phosgene to form a compound of the general formula (wherein R3 has the same meaning as above). This is then combined with an optically active 3-aminopropionic acid derivative represented by the general formula 0 (where R1 is a phenyl-substituted lower alkyl group and R4 is a lower alkyl group). The general formula for the reaction (however, R4 or R5 has the same meaning as above)
An optically active tetrahydroisoquinoline derivative represented by
4 can also be produced by removing R1 or by removing R4i and R1.

In the method of the present invention, the 3-aminopropionic acid derivative represented by the general formula CID is, for example, a compound in which R1 is a lower alkyl group substituted with a phenyl group such as a 7enethyl group, and R4 is a lower alkyl group such as methyl kabo or ethyl kabo. As a trihydro ink/phosphorus-3-carboxylic derivative represented by general formula CIV)
T f! Examples include compounds in which Rs is a methyl group, an ethyl group, a lower alkyl group, a benzyl group, or an aralkyl group such as a 4P-methoxybenzyl group, a dimethylphenyl group, or a trimethylphenyl group. .

The present invention will be described in detail below.

General formula for producing optically active 3-aminopropionic acid derivatives [
The optically active form of the 3-aminopropionic acid derivative represented by 10 has the general formula IC! I(INH-CH*-CH-C0OR'(II,
I 1 (wherein R1 is a lower alkyl group substituted with a phenyl group and R4 is a lower alkyl group) A racemic body of 3-γ minopropion #-conductor represented by I 1 (R1 represents a lower alkyl group substituted with a phenyl group) and an optically active element penzyloxyphenylalanine are reacted to form a corresponding salt. Then, one of the lIIm diastereomers, an optically active 3-aminopropionic acid derivative and an optically active N-benzyloxycarbonylphenylalanine salt, was separated by utilizing the solubility difference between the two diastereomers produced, and then the chain ring was separated. It can be produced by disassembling it. N-benzyloxycarbonyl- as a resolving agent
〇-7 When enylalanine is used, (R)-3-tinominopropionic acid derivative/N-benzyloxycarbonyl-D-phenylalanine salt is used as a sparingly soluble salt, and N-
When benzyloxycarbonyl-L-7-modalalanine is used, (i9) -3-aminopropionic acid derivative/N-benzyloxycarbonyl-L-phenylalanine salt is crystallized as an ms salt.

The optically active H-benzyloxycarbonylphenylalanine used as the resolving agent is preferably free.

In addition, the 37i nopropionic acid derivative, which is the agent to be resolved, is not only a synthetically obtained wing-shaped and S-shaped isochiya compound (racemate), but also a so-called low-purity optically active compound containing one optically active substance in the spike. Even the body can be used.

When carrying out optical resolution, an optically active agent is used as a resolving agent.
It is appropriate to use 0.5 mol to 1.0 mol of the pendyloxylponylphenyl ester based on the 3-aminopropionic acid derivative as the agent to be resolved.

The solvent used in the salt-forming reaction is preferably a mixed solvent of ethyl acetate and isopropyl ether. Salt crystallization becomes easier. The appropriate amount of isopropyl ether to be added is about 1/2 to 2 times the amount of ethyl acetate used.

The salt-forming reaction can be carried out, for example, by stirring both compounds in the above-mentioned solvent at room temperature or under heating.

The crystallization operation of the poorly soluble salt produced is performed by cooling the reaction solution or
This can be easily carried out by condensation or by adding an organic solvent, and the ring chain can be precipitated as highly pure crystals.

The precipitated poorly soluble salt can be removed using conventional solid-liquid separation methods such as filtration,
It can be separated and obtained by methods such as centrifugation.

The poorly soluble diastereomer obtained in the above manner can be further subjected to treatments such as washing and recrystallization, if necessary.

9. All of the various diastereomers obtained in the present invention are optically pure 3-amino/propionic acid M conductors (II).
] mole and 1 mole of N-benzyloxycarbonylphenylalanif, and is a new compound. Its main physical properties are shown in Table 1 below.

111 Table Note 1 - In the table, I-L-D-Phs or N-Z-L-ph
・It represents N pendylcarbonyl 〇 or L-7 enylalanine.

Note 2; [α]t'' was measured with (C-1, ethanol).

The thus obtained (R)-3-aminopropion # derivative/N-benzyloxycarbonyl-D-phenylalanine salt or (8)-3-aminopropion etss
-N-benzyloxycarbonyl-L-phenylalanine salt can be easily converted to (R) by treatment with an alkali.
Alternatively, it can be a (S)-3-aminopropion derivative. Examples of alkalis include potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate.

Alkali metal hydroxide salts such as potassium hydrogen carbonate, alkali metal carbonates, alkali metal hydrogen carbonate salts, etc. can be used. Furthermore, since optically active N-benzyloxycarbonylphenyl γ-lanine and an alkali metal salt are dissolved in water, it can be recovered and reused.

Process for producing an optically active tetrahydroquinoline derivative The reaction between the optically active form of compound (II') or compound [■] thus obtained and phosgene is carried out by reacting the optically active form of compound (IF) or CIV) with phosgene in an appropriate solvent. This can be carried out by reacting with phosgene in the presence or absence of a deoxidizing agent.

Examples of deoxidizers include organic triethylamine such as triethylamine, tripropylamine, N-methylmorpholine, and pyridine.
Class bases are preferred. As an example of a solvent, -(- is 0, for example, methylene chloride, chloroform, tetrahydro7rane, dioxane, etc.). IV) and the deoxidizing agent dissolved therein are added dropwise at 0 to -30°C, particularly at about -20°C Δ. After the reaction proceeds smoothly, excess phosgene is removed under reduced pressure. Compound (13) or [2] can be obtained in good yield by using the method. Note that it is preferable that both compounds [2] and [2] are used immediately in the next step without being isolated.

The following condensation reaction between compound (1) and [group 6 0 is compound [■] and ([) can be carried out in an appropriate solvent in the presence or absence of an acid deoxidizing agent. . In addition to those exemplified in the first step, cymicylformamide can also be suitably used as the dehydration agent and reaction agent. The reaction can generally be carried out under conditions of 0 to 80°C. For example, the reaction proceeds smoothly even at room temperature (about 25°C), but by slightly heating (35 to 40°C), Furthermore, the reaction can be accelerated and the compound [■] can be obtained in good yield.

By hydrolyzing the thus obtained compound [■], the groups R4 and R5 are removed, and it is possible to produce the target compound of the general formula CI] in which R2 and R3 are hydrogen atoms. The hydrolysis reaction can be easily carried out by treatment with an alkali in a suitable phase medium. Water and ethanol are used as solvents.

Lower alkalis such as ethanol or mixtures thereof may be mentioned, and suitable alkalis include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide, and alkali metal carbonates such as potassium carbonate and sodium carbonate. used. The reaction is carried out at about U to 50°C, especially about 20 to 3
The process is preferably carried out at 0°C.

In addition, from the catalytic reduction of the compound [■] in which - is a T-ralkyl atom, the target compound [I
) can be manufactured. This can be carried out by carrying out the catalytic reduction reaction. As the catalyst described in 1, 4F
For example, metal catalysts such as palladium black, nickel (carbon) platinum oxide, etc. can be used. Examples of solvents include: eg methanol, ethanol.

Lower alkanols such as propyl alcohol are suitable. It is generally preferred to carry out the reaction under conditions of about 20 DEG to 40 DEG C. and 1 to 5 atmospheres. For example, the reaction is carried out in a room 1 parti (about 25°C) I
II! It moves smoothly under 1,000 yen (approximately 3 atm).

Furthermore, a compound in which R3 and R4 of target compound CI) are both hydrogen atoms is a compound Fnol in which R5 is an aralkyl group.
CV') can also be produced by subjecting it to a catalytic reduction reaction and a hydrolysis reaction. The reduction reaction and the hydrolysis reaction can be carried out under the conditions as described above.

The object compound of the present invention C1, which was cleaved as in the above reaction.]
can be made into a pharmacologically acceptable salt through six salt-forming reactions.

The following is a more detailed explanation of the embodiments.

Example 1 (1) N-benzyloxy-D-phenylalanine 6,
5'! Racemic form 2-(2
-Phenylethyl)-3-ethylamide/propionic acid methyl ester (5.17 g) was added, then isopropyl ether lQa/ was added and left to stand at room temperature for 1 g. The precipitated product was collected by filtration and extracted with isopropyl ether [.

Wash and dry. Obtained crystals! J, 159 to ethyl acetate 25. , by recrystallizing from I/ (2R)
-2-(2-phenylethyl)-3-amiZl robionic acid methyl ester/H-benzyloxycarbonyl-D
- Phenylalanine salt 4.59 is obtained as colorless crystals.

Yield -3S, S< m, p, 169-111°C and Q! Pa -6,9° (C=1.metal) +21
Crystals 3.07 obtained at +11 were dissolved in an aqueous potassium carbonate solution and extracted with ether. Neeko Le Extraction Pl! Wash with salt water and dry. By adding hydrogen chloride-methanol rsWl to the ether solution and collecting the precipitated crystals by filtration (2R)
-2-(2-phenylethyl)-3-ethylamitube 0
1.45P of pinenoic acid methyl ester hydrochloride is obtained as colorless linbene nuclei crystals.

Yield: 95.1 s, p, 142-144°C [α]'5 + 23.2° (C-1, methanol) + 31
(2R)-2-(2-phenylethyl)-3-ethylaminopropionic acid methyl ester 4.7F obtained by treating the hydrochloride obtained in the same manner as in 21 with sodium hydrogen carbonate and triethylamine 3°OII. Dissolve in 20°C of methylene chloride, and gradually drop the solution into a 30°C methylene chloride solution containing 2.52°C of phosgene under water cooling. After stirring at the same temperature for about 30 minutes, one reaction is completed. The liquid is concentrated to dryness under reduced pressure. Dimethylformamide 20- is added to the resulting residue, and (3!3)-1,
2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl ester 3.82 and triethylamine a, op
Add dimethylformamide lol's liquid dropwise and let it cool at room temperature.
Stir at night. Add water to the reaction solution and extract with ether. The extract was sequentially washed with dilute hydrochloric acid and water and transferred. Then, by distilling off the solvent, (3s)-2-[N-(
(2R)-2-methoxycarbonyl-4-phenyl-n
-N-ethylcarbamoyl] -1,2,3
, 4-tetrahydroisoquinoline-3-carboxylic acid methyl ester 7.29 is obtained as a colorless syrup.

Yield: 80.1 IRν1; 1735, 1650IRν1
．． 1 Mass m/e; 452 (M+)+41 (
4.0 g of the compound obtained in step 31, methanol 60
- Add 3.09 g of potassium hydroxide to the solution.

Stir overnight at room temperature. Methanol is distilled off under reduced pressure,
After acidifying with hydrochloric acid, the mixture is extracted with ethyl acetate.

After washing the extract with brine and drying, the solvent was distilled off to give (3S)-2-CM-((2R)-2-carboxy-4-phenyl-n-butyl)-N-ethyl. 3.29 g of [carbamoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are obtained as bell-colored crystals.

Yield 85.3% Peng, p, 114-115°C (decomposition) ['ll]
': + 24.4° (C=1.ethanol) I wing ν
""1Cm';t'yao, 1725.1590
.

ax 580 Example 2 tl) N-benzyloxycarbonyl-phenylalanine 6.5f, racemic 2-(2-phenylethyl)-3-γminoethylpropion methyl ester 5
．． 19 and ethyl acetate 20- were treated in the same manner as in Example 1-(1) to obtain (2S)-2-(2-71nylethyl)-3-aminopropione methyl ester.
N-Benzyloxycarbonyl L-phenylalanine salt 4.2 lltt Obtained as a colored product.

Yield: 35.9, p, 109-11°C [α) + 6.5° (c-1, methanol) t2+
1.5 fI of the crystal obtained in Example 1-W(2)
By processing the same a + ko, we get (2S)-2-(2
-Phenylethyl)-3-ami/propionic acid methyl ester hydrochloride 0.72 is obtained as thin flakes.

Yield '11.8 < m, p, 142-143°C [1 piece -23,0° (C=1.methanol) Example 3 fil N-benzyloxycarbonyl-D-phenylalanine 12. Racemic 2-(2-phenylethyl)-3-ethylaminopropionic acid ethyl ester 10. Add OF8, then add isopropyl ether 60aZwoU11j and add i(
zLeave it alone. The precipitated crystals are collected by filtration, washed with 15 d of a mixed solution of ethyl acetate and isopropyl ether (1:1), and then dried.

The obtained crystals were dissolved in ethyl acetate 17-I, isopropyl ether 17-I was added, and the mixture was left at room temperature F overnight. Then, the precipitated crystals were collected by filtration to obtain (2R)-2-(2-phenylethyl)-3-ethylaminopropionic acid ethyl ester/N-benzyloxycarbonyl-D-phenylalanine salt 7.49 as colorless crystals.

Yield: 33.6 m, P, 93-95°C [α]"j -16,9@(C=1, ethanol) +21 +1) The crystals obtained in 6.02 were made alkaline by adding a heavy soybean aqueous solution. After washing the ether extract with brine and drying, hydrogen chloride-ethanol solution was added and the precipitated crystals were collected by filtration to obtain (2R)-2-(2-phenylethyl). )-3-Aminopropionate ethyl ester is recrystallized from ethanol-ether to obtain colorless phosphorus crystals from 1-1.

m, p,, 114-116℃ [α]υ+18.6' (C=1.ethanol)+3
(2R)-2-(2-1-noenylethyl)-3-ethylamine/flopionic acid ester 7.1 f, ) ethylamine (2R)-2-(2-1-noenylethyl)-3-ethylamine obtained by treating the hydrochloride obtained in the same manner as 1 +21 with sodium hydrogen carbonate 4,8F4
．． 2) g, methylene chloride 20-, phosgene 3, fi
9 (3!: ) -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester 7.6
f and dimethylformamide 40- in Example 1-(3
)-2-4N by performing the same coma treatment as
-((2rM effect toxic power rubo = 4-) ・niru n-
butyl)-N-ethylcarbamoyl]-1,2,3,4
-Tetrahydroiso-F-11-3-J rubonic acid be/dyl ester 12.79% is obtained as a colorless viscous candy.

Yield 82.3<TRIf','a'xm(t-as: 1730
+1650Mass la/v: 5 4 2
(M+) f4+ candy obtained at +31 6.0
Dissolve 6 Qr/I of ethanol and add 10 (7 ml) of ethanol.
Add 0.29 e of MulA element and catalytically reduce the temperature to room temperature and pressure. Filter off the catalyst and condense the filtrate by M[F, +4 (3s) 2-CN-((2R)-2-ethoxycarbonyl-4=phenyl-n-butyl)-N-ethyl 4.89 g of (carbamoyl)-1,2,3,4-tetrahytroinquinoline-3-carboxylic acid are obtained as a colorless syrup.

Yield 96. Cyclohexylamine salt colorless needle crystals (recrystallized from acetone) m, p, 133-135°C ['M]. +20.8° (C=1.ethanol) IR
νNN13j): 1730.1630.1560 Benzylamine salt of this product (l hydrate) Colorless fine crystals (recrystallized from ethyl acetate)"-P,
107~111℃ [α] 1+21.2° (C=1.≠Tanol) IR-
Ox 1 (ci'): asso, 34so, 1730+1
650.1Fi15 Calcium salt of M (l hydrated e) Colorless powder product (recrystallized from ethanol-water) la, p, 1
47～153℃(tJ+solution)(,1!Complete+t 9.
a°CC=0.7.19/-s,)IRIIN:! :”
(z')! 1730.1640.1610+51
To a solution of 2.07 g of the candy-like substance obtained in the above (3) in 31) Ml of 90% ethanol, 1.59 ml of potassium hydrochloride was added and stirred at room temperature. 1-+
Same as 41; here t! 1! One thing to do (34) -
2-(N-((2R)-2-carboxy-4-phenyl-n-butyl)-N-ethylcarbamoyl)-1,2°3.4-tetrahydroisoquinoline-3-carboxylic 1
．． 2 is obtained as colorless crystals.

Yield: 76.7< The chemical properties of the crystals were consistent with those obtained in Example 1-+41.

Practical example 4 [1) +4-benzyloxycarbonyl-L-phenyl r-lanine 7.29. Racemic 2-(2-7dynylethyl,)-3-ethyl r minoproxyenate 6.
OF, ethyl acetate 20jtd and isopropyl ether 45- were treated in the same manner as in Example 3-1).

By recrystallization, 3.97 g of (23)-2-(2-phenylethyl)-3-ethylaminopropionic acid ethyl ester/N-benzyloxycarbonyl-L-phenylalanine salt is obtained as colorless crystals.

Yield 29.5% jl, p, 92-95°C CQ'1B+ 16.6 (C=l, ethyl)
+21ill 1 given crystal 2.5y Example 3
-+21 by treatment and recrystallization (2!
3) -2-(2-phenylethyl)-3-ethylaminopropionic acid ethyl ester hydrochloride 1.27 g was obtained as 1 as a colorless solid.

Yield -88,6 rn, p, 113-116°C [α] knee xs7° (C=1.ethyl) Actual example 5 11) (2S) -2-(2-phenylethyl J
-3-enalaminogu2]pionic acid ethyl ester 7°19, (33) 7.1,2,3.4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester 7.6
F, phosgene 3.6y-,) ethylamine 4.8y
+4°22, methylene chloride 40rJ and dimethylformamide 20- were treated in the same manner as in Example 1-+31 to obtain (3B)-2-[N-((2S)-2-ethoxycarbonyl-4-phenyl-n- j f le)−
N-ethylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester 1
2.3 fl are obtained as colorless syrup.

Yield: 79.7", 'A11'"(c; ): 1730,
1650Mass tm/a: 542 (M+)(
Example 3 6.0y of colorless syrup obtained with 21fil
-(33)-2-C by processing in the same manner as in 41
N-((23)-2-ethoxycarbonyl-4-7x
= 71/-n-butyl)-N-ethylcarbamoyl 1-1.2. &4-tetrahydroisoquinoline-3-
4.7y of carboxylic acid is obtained as a colorless syrup.

Yield 94.0 Benzylamine salt of beak quartz (monohydrate) Colorless fine crystals (recrystallized from ethyl acetate-isopropyl ether) Layer, p, 95-98°C [α]: +s, s° (C-t , ethanol) ■” ”:
! ', 1(d): 3500*3450*1735.

610 Example 6 Methylene chloride containing 1111X gene 2.62 30. dW
lfll+c, press - about 30'C"l' (3B)
-1,2; 3゜4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester 5.4 f, ) ethylamine 3. .

Add 304 ml of methylene chloride solution from step 2 dropwise. 30 at the same temperature
Stir and concentrate the reaction solution under reduced pressure. The remaining amount obtained was dissolved in methylene chloride 30-, and (2R)-2-(2-7-dylethyl)- obtained in the same manner as in Practical Example 3-121 was dissolved therein.
3-ethylaminopropionic acid ethyl ester 5.1
f,) ethylamine 2゜52 methylene chloride 30
Add 5 g of solution dropwise and stir overnight at room temperature. Hereinafter, by processing in the same manner as in Example 1-+31, (3g)-2
-(N-((2R1-2-1)4dicarbonyl-4-phenyl-n-butyl)-N-ethylcarbamoyl)-1
, 8.6 g of 4-tetrahydroisoquinoline-3-carboxylic acid benzyl ester are obtained as a colorless syrup.

Yield 78.5< (2) -Colorless syrup 3-(
(3S)-2-CN-((2R)-2-ethoxycarbonyl-4-phenyl-n-butyl)hotethyl Rubamoyl 1-1.2 .3.2.21 of 4-tetrahydroisoquinoline-3-carboxylic acid is obtained as a colorless syrup.

Yield: 87.9 The physicochemical properties of the main island were consistent with those obtained in Example 3-+41.

Claims (5)

[Claims] (1) The optically active 3-aminopropion steep derivative represented by the general formula % formula % () (where R1 represents a phenyl group-substituted lower alkyl group, and R4 represents a lower alkyl group) is reacted with phosgene to form the general formula (However, R' and R' represent the same meanings as above) is obtained, and then this is combined with an optically active tetrahydroisoquinoline derivative represented by the general formula (where U& represents a lower alkyl group or an aralkyl group). to obtain an optically active trahydroisoquinoline derivative represented by the general formula (wherein R1, R4 or R1 have the same meanings as above), and then, if necessary, further remove the compound, or
or by carrying out catalytic reduction and hydrolysis to remove the groups R4 and R". represents a group, R'
has the same meaning as above). (2) Obtain a compound represented by the general formula (wherein, R' represents a lower alkyl group or an aralkyl group) (wherein R1 represents the same meaning as above), and then combine this with the general formula (0 formula%) (however, , -R1 is a phenyl group-substituted lower alkyl group R4
(represents a lower alkyl group) is reacted with 184 optically active 3-aminopropionic acids represented by the formula % (wherein R1@R4 or R1 represents the same meaning as above) to obtain optically active tetrahydro Isoquinoline-induced 4
the compound, if necessary, by further (+0) aqueous lysis to remove R4 and R1, or if t is an aralkyl group, catalytic reduction to remove the group R1; The general formula % is characterized in that the group and R'' are removed by hydrolysis with 11
has the same meaning as ``Aki''] A method for producing an optically active tetrahytroin quinoline derivative. (3) A racemic form of a 3-aminopropionic acid derivative represented by the general formula (% formula %) (wherein R1 is a phenyl-substituted lower alkyl group and R4 is a lower alkyl group) is reacted with optically active N-benzyloxyphenylalanine. Using the solubility difference between the two resulting diastereomers, one of the dissolvable diastereomers, optically active 3-minoprobionic acid derivative (de-optically active N-pendyloxycarbonylphenylalanine salt), is prepared. By decomposing the salt, the general formula C obtained in this way
Those according to claim 1 or 2 using an optically active form of the 3-amino/propionic acid derivative represented by III, ・ko (4) A salt consisting of a 3-y minopropionic acid derivative represented by the general formula % formula % ([] (where H1 represents a phenyl-substituted lower alkyl group and H4 represents a lower alkyl group) and N-benzyloxycarbonylphenylalanine. (5) The compound according to claim 4, which is a salt consisting of an optically active 3-aminopropionic acid derivative represented by the general formula CI[] and optically active N-benzyloxycarbonylphenylalanine.