JPH03123765A - Production of 4-amino-3-hydroxypentanoic acid derivative - Google Patents

Abstract

PURPOSE:To highly stereoselectively and efficiently obtain the subject compound which is an intermediate for producing medicines utilizing only one carbon source of a raw material by reacting a 2-aminopropanal derivative used as a starting raw material with a ketene silyl acetal in the presence of a Lewis acid. CONSTITUTION:A 2-aminopropanal derivative expressed by formula I (R<1> is 1-4C linear or branched alkyl or 5-8C substituted or unsubstituted cycloalkyl; R<2> is protecting group of amino group) is used as a raw material and reacted with a ketene silyl acetal expressed by formula II (R<2> to R<4> each are independently 1-4C linear or branched alkyl or substituted or unsubstituted aryl) in an amount of preferably 2-3 equiv. in the presence of a Lewis acid catalyst in a solvent, such as dichloromethane, at -100 to +50 deg.C to afford the compound expressed by formula III. The Lewis acid catalyst is used in an amount of preferably 0.005-2.0 equiv., preferably 0.05-1.5 equiv. based on the compound expressed by formula I which is the raw material.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a ketene silyl acetal represented by the general formula 4 (representing a linear or branched alkyl group or a substituted or unsubstituted aryl group) in the presence of a Lewis acid. The general formula (wherein R1 represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, a substituted or unsubstituted cycloalkyl group having 5 to 8 carbon atoms, and R A 2-aminopropanal derivative represented by the general formula (wherein R3, R4, R1, Rh each independently has a carbon number of 1 to (in the formula, According to the present invention, (S)-
From a 2-aminopropanal derivative represented by the general formula (1) having the configuration, to a 4-amino-3-hydroxypentanoic acid derivative represented by the general formula (f[[) having the (33,4S)-configuration can be produced with high stereoselectivity,
For example, from a (S)-2-aminopropanal derivative represented by the general formula (1) having an isopropyl group or a cyclohexyl group as R1, to a (S)-2-aminopropanal derivative represented by the general formula (II[) having an isopropyl group or a cyclohexyl group as Ill, (33.43)-4-amino-3-hydroxypentanoic acid derivatives can be produced with high stereoselectivity.

The 4-amino-3-hydroxypentanoic acid derivative represented by the general formula (l[[) produced by the present invention has uses as a raw material for the synthesis of pharmaceuticals.

For example, in the general formula (III), a compound in which R1 is an isopropyl group, the asymmetric carbon at the 3-position is an (S)-configuration, and the asymmetric carbon at the 4-position is an (S)-configuration is a therapeutic agent for hypertension due to its human renin inhibitory action. Intermediates for the production of peptidomimetic compounds useful as (J, Bogsr+et al, +^nnJe
p,in Med,Ches,+Academlc
Press, 1985+Vo1.20. pp257-
226. J., Boger, et al., J.M.
ed,Chew,.

2dan+1779 (1985), R,Matiued
a, eL al,, Ches+, Lstt,.

1985.1041. M.G.Bock et al.
,,J,Med,Chem,, 31.1918 (198
8), ni, l1zuka, at al, +Ches,
Pharm, Bull. 1st.

2278 (1988), JP-A-61-236770. JP-A-64-26596° JP-A-1-143898. JP-A-1-143899). In addition, in the general formula (1), a compound in which R1 is a cyclohexyl group, the asymmetric carbon at the 3-position is an (S)-configuration, and the asymmetric carbon at the 4-position is an (S)-configuration, has a stronger human renin inhibitory effect on hypertension. Intermediates for the production of peptide-like compounds useful as therapeutic agents for diseases (J, Boger, at al., J. Med, Ch.
em, 28.1779 (1985), Morisawa et al., 109th Annual Meeting of the Pharmaceutical Society of Japan, Nagoya, 1989, Collection of Lecture Abstracts I
Lp6. Jiwada, et al, +Hypert
enslon.

■, 70B (198B), JP-A-62-33141.
It can be used as JP-A-64-26596).

[Conventional technology]

4-Amino-3-hydroxypentanoic acid derivatives, which are intermediates in the production of useful pharmaceuticals, are conventionally synthesized from (1) (S)-α-amino acids to (S)-α-aminopropanal derivatives from ethyl acetate. Method for reacting prepared metal enolates (J, Bogere et al., J. Med.
, Chea, 28.1779 (1985), D.
H, Rlch.

et al., J. Org. Chea., 43.36
24 (1978), Wlu et al.

J. Org. Chem., 43,754 (197B
), M.T., Reetz, et al.

Angew, Chea, Int, Ed, Engl., 2
5.1) 41 (1987), ).

((S)-α- synthesized from 21(S)-α-amino acids
A method of reacting an aminopropanal derivative with a lithium enolate prepared from an ester of acetic acid and an optically active alcohol (R, M, Devant, et al, +Tet
rahedron Lett,, 29.2307 (19
8B),) (31) Optically active 3-aminopropanal derivative synthesized from (S)-α-amino acid
A method of reacting (methylthioacetyl)-2-oxazolidone derivatives and further carrying out a desulfurization reaction (J, 5avrda
, 5ynth, Commun.

17, 1901 (19B?) , ) , +41 (S
) -α-Aminopropanal derivative synthesized from α-amino acid is reacted with an optically active diol to obtain an optically active acetal derivative, which is then ring-opened with allylsilane (W, S, Johnson, et al. ,
, Tetrahedron Lett1 Fallen, 6535
(1987), ), (51 (S)-α-aminopropanal derivative synthesized from (S)-α-amino acid and 1.
Method by Dels-Alder reaction with 3-dimethoxy-1-trimethylsilyl-1,3-butadiene (M
,M,Midland,et al., ,J,A-,Ch.
em, Sac,, Dan L436B (1989), ).

(S)-4- synthesized from +61(S)-α-amino acid
Method for reducing the 3-position carbonyl group of amino-3-oxopentane #I derivative (R, Noyor14etrahe
droneLett, 29.6327 (1988), J
jouin, et al, +J, org.

Chea, 54, 627 (1989), D.H.RI.
ch,et al,,J,Org,Chem,.

53.869 (198B), Gate, M, 5chaldt,
et al, +Tetrahedron.

44.3489 (1988), P, F, 5chuda,
at al,, Eur, Pat, Appl.

0306143 A1. ), (71(S) -cx
(S)-4-amino-2(Z) synthesized from -7 amino acid
)-by epoxidation of penten-1-ol derivatives (H, Kogen.

at al, + J, Chea, Soc, Ches
, Commun, , 1987+3 ratio).

(81(S)-Optically active 2- synthesized from α-amino acid
Method by ring-closing reaction of amide alcohol derivative to 2-oxazolidone derivative <S, Kano+et al, +
Tetrahedron Lett, +28.6331
(1987), ), +91 (S) Method by reduction of optically active pyrrol-2(5H)-one derivatives synthesized from -α-amino acids (P, Jouln+et al.
,J.,Ches,Soc.,Perkin L 19
8ヱ, 1) 7? ,).

Method for producing αl from optically active 2-oxo-3-oxapurine derivatives (T, Kumeda, et al, +J,
org, chess, +53.3381 (1988),)
, Qll (R) -2,3-isopropylidene glyceraldehyde, a method for producing from w derivatives such as 1,2,5,6-di-0-isopropylidene-D-glucose (MJinoshlta at al.

Bull, Chew, Soc, Jpn,, 48,57
0 (1975), J. Mulzer, atal, Li.
ebigs Ann, Chem, 1988+445.
and H, Yanagisawa+et al, +ch.
em, Lett, +1989+687. ) etc. were synthesized. However, among these production methods, the stereoselectivity or reaction yield in the production of the 3-position hydroxyl group is low, and the separation and purification of the reaction product is a major obstacle. (The fourth method is (S
In addition to the chiral center derived from )-α-amino acid, another chiral source is used, so it is difficult to implement it industrially in terms of economy and removal and recovery of the chiral source. Although the method (5)-〇〇 has high stereoselectivity in the production of the 3-position hydroxyl group, it is a production method that requires multiple steps, and it is very difficult to implement it industrially.

[Problem to be solved by the invention]

The present inventors have discovered the above formula (I), which is an intermediate for pharmaceutical production.
The 4-amino-3-hydroxypentanoic acid derivative represented by ll) is synthesized from the 2-aminopropanal derivative represented by the general formula (1) using the only asymmetric source of (1). A method for stereoselectively and efficiently producing (3S,4S)-4-amino-3-hydroxypentanoic acid derivatives from 2-aminopropanal derivatives having the (S)-configuration represented by the general formula As a result of searching for a method to efficiently produce with high stereoselectivity, the production method of the present invention was discovered and the present invention was completed.

[Means to solve the problem]

The 2-aminopropanal derivative represented by the general formula (1) used in the present invention can be easily produced according to the following reaction formula.

(In the formula, "and R represent the same meanings as above, Rt represents a straight chain or branched lower alkyl group having 1 to 4 carbon atoms,
) [First step] In this step, a 7-mino protecting group is introduced into the 2-aminopropionic acid ester derivative represented by the general formula (IV), and then the ester group is reduced, and if necessary, the 3-position phenyl 2-amino- represented by general formula (V) by reducing groups such as
This is to produce propatool derivatives (see reference side).

As the 2-aminopropionic acid ester derivative, 2-
Examples include methyl aminopropionate derivatives, ethyl 2-aminopropionate derivatives, and isopropyl 2-aminopropionate derivatives, which can be produced by known methods.
hes+, Phar cod, Bu1). +13+995
(1965), and S.R.
d W, Karo+”Functional Grou
p Preparations”, Academic
Press+New York, 1968. pP245
~265. reference).

Preservation of amino groups introduced into 2-aminopropionic acid ester derivatives! ! Any group can be used as long as it can be removed by hydrolysis under acidic conditions, but groups with 1 to 1 carbon atoms such as formyl group, acetyl group, propionyl group, butyryl group, and isobutyryl group are preferable.
4 straight chain or branched alkanoyl group, benzoyl group,
Unsubstituted or substituted aroyl groups such as p-chlorobenzoyl group and p-methoxybenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, isopropoxy carbonyl group, and t-butyloxycarbonyl group having 1 to 1 carbon atoms
Unsubstituted or substituted aralkoxycarbonyl groups such as straight-chain or branched alkoxycarbonyl groups, benzyloxycarbonyl groups, p-/)lolobenzyloxycarbonyl groups, and p-)toxybenzyloxycarbonyl groups are used. . These protecting groups can be introduced by known methods (T., W. Greene, “Protective
e [;roups in OrganicSynth
esig”, John-Wllley & 5ons, N
ew York, 1980゜pp218-287)
.

Reduction of the ester group of the 2-aminopropionic acid ester derivative in which the amino group is protected is carried out using sodium borohydride in the presence of a suitable reducing agent, such as lithium chloride or lithium bromide (see reference side).

In addition, the compound in which a cyclohexyl group is present at the 3-position of the 2-aminopropanol derivative represented by the general formula (V),
It can also be obtained by hydrogenating the 3-position phenyl group of the corresponding 2-amino-3-phenylpropatur derivative in the presence of a suitable catalyst, for example 5% rhodium-alumina.

In this step, the general formula (TV) having the (S)-configuration
When using the 2-aminopropionic acid ester derivative represented by, the 2-aminopropanol derivative represented by the general formula (V) having the (S)-configuration can be obtained without racemization. .

In this step, when (S)-leucine methyl ester and (S)-phenylalanine methyl ester are used as the 2-aminopropionic acid ester derivatives represented by general formula (IV), Monkey (S)
-Leucinol derivatives and (S)-cyclohexylalaninol derivatives can be obtained without racemization (see reference side).

[Second Step] In this step, the 2-aminopropanal derivative represented by the general formula (V) is oxidized to produce the 2-aminopropanal derivative represented by the general formula (+). An example of a suitable oxidation method is a method using sulfur dioxide-pyridine complex-triethylamine in dimethyl sulfoxide (see reference side).

In this step, when using a 2-aminopropanol derivative represented by the general formula (V) having the (S)-configuration, 2-aminopropanol derivatives represented by the general formula (1) having the (S)-configuration −
Aminopropanal derivatives can be obtained without racemization.

In this step, when (S)-leucinol derivatives and (S)-cyclohexylalaninol derivatives are used as the 2-aminopropanol derivatives represented by the -i formula (V), the general formula (+) The represented (S)-leucinal derivatives and (S)-cyclohexylalaninal derivatives can be obtained without racemization (see reference side).

4-Amino-3-hydroxypentane represented by general formula (Ill) is produced by the following production method of the present invention from the 2-aminopropanal derivative represented by general formula (1) produced by the above synthetic process. Acid derivatives can be efficiently produced with high stereoselectivity.

H (In the formula, 171% R1, R1, R4 Rゝ and R- are the same as above. (represents the same meaning).

[Third step] -a As the ketene acetal represented by formula (II),
0-methyl-〇-trimethylsilylketene acetal,
0-ethyl-〇-)limethylsilylketene acetal,
0-Methyl-〇-1-butyldimethylsilylketene acecool, 0-ethyl-〇-[-butyldimethylsilylketene acetal, 0-methyl-〇-1-butyldiphenylsilylketene acetal, 0-1-butyl-0 -1-
Examples include butyldimethylsilylketene acecool, 0-phenyl-0-trimethylsilylketene acetal, and preferably 0-methyl-o-trimethylsilylketene acetal.

The silyl ketene acetal used is synthesized from methyl acetate according to a conventional method and can be used as it is in the reaction without purification.
Rathke et al, +5ynth, Commu
n, 3+67 (1973), ), this reaction requires the presence of a Lewis acid, and the Lewis acids used include titanium tetrachloride, boron trifluoride/ether complex,
tin tetrachloride, zinc chloride, zinc iodide, magnesium bromide, tris[2,2-bis(trideuteromethyl)-1),
1-) deuterium-6,6,7,7,8,8゜8-hebutafluorooctanedionate-(3゜5)]-europium (I[[) (Eu(fad)s) etc. Illustrated. Lewis acid is 2
I can stay.

This reaction is carried out in a solvent, and the solvents used include halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, hydrocarbon solvents such as toluene and xylene, ether, and tetrahydrofuran. , ether solvents such as dioxane, acetonitrile, dimethylformamide, etc., but dichloromethane is preferably used.

The reaction is carried out at -100°C to 50°C, but for weak Lewis acids such as titanium tetrachloride, temperatures of -100°C to -40°C are suitable, and for weak Lewis acids such as zinc iodide, the temperature is 0°C.
C to 50 C gives the most favorable results.

When a 2-aminopropanal derivative having an (S)-configuration is used in this reaction, a 4-amino-3-hydroxypentanoic acid derivative having a (33,43)-configuration is
It is produced with high stereoselectivity towards derivatives having the (3R,4R)-configuration.

In this reaction, (S)-leucinal derivative and (
S)-cyclohexylalaninal m1 is represented by the general formula (1
) When used as a 2-aminopropanal derivative represented by (3S.

4S)-4-amino-3-hydroxy-6-methylhebutanoic acid derivative and (3S,4S)-4amino-5-cyclohexyl-3-hydroxypentanoic acid derivative are (3
R,43)-configuration with high stereoselectivity (I & O 94:6 and 95:5), respectively.

The 4-amino-3-hydroxypentanoic acid derivative represented by the general formula (+) obtained by the above synthesis process is subjected to a hydrolysis reaction under acidic conditions to form an amino group at the 4-position and a carboxylic acid at the 1-position. The groups were simultaneously deprotected, and 4-amino-3-hydroxypentanoic acid, which is useful as a pharmaceutical synthesis intermediate represented by the general formula (wherein R1 represents the same meaning as above), was obtained. The decomposition reaction (3S, 4S
)-4-amino-3-hydroxy-6-methylhebutanoic acid derivative and (3S.

When carried out on 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid derivatives, optical Activity (3
3,43)-4-amino-3-hydroxy-6-methylhebutanoic acid ((35,43)-statin) and (3S
.

4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid [(33,4S)-cyclohexylstatin] is obtained, respectively.

Hereinafter, the content of the present invention will be explained in detail using Examples and Reference Examples, but the present invention is not limited by these in any way.

Reference example 1 (S)-leucine methyl ester 239■ (1,65m
mol) in 5 ml of anhydrous methylene chloride, and after adding 228 ml (1,65 mmol) of water-cooled potassium carbonate, 0.23 ml (1,98 mol) of isopropyl chlorocarbonate was added.
mmol) was slowly added dropwise. After stirring for 1 hour under water cooling, saturated *'e water was added and extracted with ether. The extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1) to obtain N-(isopropoxycarbonyl)-(S)-leucine methyl ester. 333 (87%) of the compound was obtained as a colorless oily compound.

(α)i, 0 4JQ°(c 1.53.CHC
l3)'H-NMR (CDCI 3) δ: 4.90
(2H, m and 5ept, J=6.2Hz).

4.40 (IH, s+), 3.73 (38, s), 1.
3 to 1.8 (31), m).

1.23(6)1. d, J-6,1Hz), 0.95(
6H, m).

IR(CllCl3): 3460.2970.1
730.1710.1510.1)10C1)-'MS
(m/z): 231 (M, 172.8G, 43
゜Reference Example 2 333 mmol (0,144 mmol) of N-(isopropoxycarbonyl)-(S)-leucine methyl ester was dissolved in 4 ml of anhydrous tetrahydrofuran, and 18 ml of lithium chloride was dissolved.
31g (4,32mmol), sodium borohydride 163g (4,32mmol) absolute ethanol 6
ml of IMa! Acid was added (pH 2-3) and extracted with ethyl acetate. After drying the extract over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate 2:1) to obtain 292 N-(isopropoxycarbonyl)(S)-leucinol (quantitative yield). .

(α) i'-30,9" (C1,05,Cll
Cl,)'If-+iMR(CDCIs) δ;4.
90 (IH, 5ept, J・6.2Hz), 4.70 (
1) 1, m), 3.65 (31), m), 2.45 (1
B, brs), 1.3-2.0 (3H, m), 1.23
(68, d, J=6.2Hz), 0.93 (6H, d.

JJ, 4Hz).

IR(CICI=) :3460,2970.1700
, 1510.1) 10cm-'MS (m/z): 2
04(M'+1), 172. 130. 86.
43 Reference Example 3 N-(isopropoxycarbonyl'I-(S)leucinol 281g (1,38mmo 1), toluene 1ml, dimethyl sulfoxide 1.8ml (25,4
mmol) and triethylamine 1.16 ml
(1), 30 mmol) of sulfur dioxide
1.321X (3.30 mmol) of pyridine complex salt was added and stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After drying the extract, the solvent was distilled off under reduced pressure. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate-8=1),
219 ftM (79%) of N-(isopropoxycarbonyl)-(S)-leucinal was discharged as a colorless oil.

(ff) 3” +34.4° (CO, 964, Cll
Cl'H-NMR (CDCIs) δ: 9.59
(1B, s), 4.92 (2H, m andsI!p
t, J-6,2Hz), 4.25(ill, w
), 1.3~! ,9. (31), @).

1.24 (6H, d, J-6, 2Hz), O', 97
(61), a).

IR (CHCIs): 3460, 29B0.2720
．． 1720. , 1710.15001380.1)1
0cm-' MS (m/z): 172.130.86.43° Reference Example 4 (S)-Phenylalanine methyl ester hydrochloride 3.9
0 g (1i3 mmo 1) was suspended in 20 ml of anhydrous tetrahydrofuran, and 5.5 ml of triethylamine was added under water cooling.
1 (39 mmol +) and 2.3 ml (20 mmol) of isopropyl carbonate were added and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. It was washed successively with a sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous magnesium sulfate, it was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 10:l) to obtain a white solid N-(isopropoxycarbonyl"I").
-(S)-Phenylalanine methyl ester 4.35g
(91%).

136-37℃.

lINMR(CDCI*) δ:1.21([i)I
, d, J-6Hz, CIIMer).

3.1) (21), d, J-6Hz, r'l+c1)g
), 3.72 (31), S, OMe) 4.50-5.2
0 (2JI, m, CtII and NH), 4.92
(LH.

Quir! tet, J-6Hz, CHMst)+7
-04 to 7.48 (5H1a+Ph).

TR(KBr):1740.1685cn-'MS(m
/z): 266 (CM"++1'), 20
6,162.131,120゜Reference Example 5 N-(isopropoxycarbonyl)-(S)phenylalanine methyl ester 2.52g (9.5mmol)
was dissolved in anhydrous tetrahydrofuran, and lithium chloride 1.
22g (29mmol), sodium borohydride 1
．． 09 g (',! 9 mmol) and 25 ml of absolute ethanol were sequentially added and stirred at room temperature for 16.5 hours.
The reaction solution was concentrated under reduced pressure, and 1M hydrochloric acid was added to the residue to give p +
+2~3! 1! After adjusting, the mixture was extracted with ethyl acetate.

The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexane-ethyl acetate 5
; 1-3: 1) to obtain 2.21 g (98%) of white solid 9N-(isopropoxycarbonyl)-(S)-phenylalaninol.

sap　78-81℃.

NMR (CDC1z): δ1.21 (6H, d,
J=6Hz, C)1Met), 1.96-2.30(I
H, m, OR), 2.88 (2H, d, J-7Hz, p
hCHg), 3.44-4. IG(3)1. m, Ct-
Hand CHxOH), 4.65-5.13(1)1
．． s, NH), 4.92(1)1. quintet J
-61)z,CHMex)+7.05~7.47(5H
, a+, Ph).

+R (KBr): 1690 cm-' MS (m/z): 237 (M'), 206.146
．． 120° elemental analysis value: Total as C+sH+vNOs: C65,80X; H8,07! ;N
5.90! .

Analysis values: C65,99χ, H8,03χ; ! 15
．． 81χ.

Reference Example 6 2.05 g (8.6 mmol) of N-(isopropoxycarbonyl)-(S)phenylalaninol was dissolved in 6 ml of methanol, and 40 g of rhodiuno-alumina catalyst was dissolved.
3) Add 0.6 ml of acetic acid and under hydrogen atmosphere (4 atm)
and stirred at room temperature for 5 hours. After removing the catalyst, the solvent was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane-ethyl acetate 5:l) to give N(isopropoxycarbonyl)-(S)-cyclo as a colorless oil. Xylalaninol 2.09 g (100%)
I got it.

NMR (CDCIs): δ1.23 (61),
d, J=6)1z, CIIMez), 0.71-2.
13(131), s, cycloba*yri, 3.3
6-4.02 (3H.

m, C1-Hand CHtOH), 4.51-5.1
5 (IH, m, N old 4.93 (IH, quntet)
J=6Hz, CHMez).

1R (neat): 1690 am-'MS (m/z)
:244(CM+1)' 212,170.12
6 element analysis value i C+! HtsNO!・0. IHI
Calculated value as O: C63,69χ, H10,36X
: N 5.71! .

Analysis+! ! ; C63,56χi H10,39χ,
N 5.75χ.

Reference Example 7 N-(isopropoxycarbonyl)-(S)cyclohexylalaninol 138 ml (0.57 mmol), anhydrous toluene 0.33 ml, anhydrous dimethyl sulfoxide 0.
Sulfur trioxide-pyridine complex salt 491nr (3.1mmol) was added to a mixture of 67ml (9.4mmol) and triethylamine 0.43ml (3.1mmol).
1) was added and stirred at room temperature for 20 minutes.

Ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, hexane-acetic ether 10:
1-5:1) to obtain N-(isopropoxycarbonyl)-(S)-cyclohexylalaninal 107 ? (78?()) in the form of a colorless oil.

(α)4' +26.6° (C=0.939.Cl
lCl,).

NMR (CDCI, ): δ0.60-2.06
(131), vcycloheyyl).

1.23 (6tl, d, J=7Hz, cHMet>, 4
．． 03-4.43 (IH.

m, Cx-H), 4.93 (IH, q, J-6Hz, C
) IMez), 5.20 to 5.52 (LH, m, NH)
, 9.56 (LH,s, CHO).

IR(neat): 1730.1690 cm-'MS
(m/z): 242 (M+1)', 212, 17
0,126° Example 1 H N-(-(sobroboxycarbonyl)-(S)leucinal 28.9w (0,144mmo 1) and molecular sieve 4A (5w) under argon flow, 0-methyl-
〇-) Limethylsilylketene acetal 63,0 Akebono (0
, 2 ml of the methylene chloride solution of 101) was added to the opening of 431n, and after cooling to -78°C, 17 ml of boron trifluoride/ether complex (IM menalene chloride solution) O was slowly added dropwise.The reaction solution was stirred for 1 hour. After adding saturated sodium bicarbonate solution and extracting with ethyl acetate, washing with 1M hydrochloric acid and drying, the solvent was distilled off under slight pressure. This crude material is a silica gel column [
171-Graphy (hexane:ethyl acetate-4,1)
(3S,4S)-3-hydroxy-6-methyl-4-((N-isopropoxycarbonyl)amine]
Methyl hebutanoate: 19.4 kg, its (3R,43) monomer, 6.54 kg, and a mixture of both: 2.6 kg (total yield 72%)
I got it. The production ratio of (33,43)-isomer and (3R,43)-isomer is determined by gas chromatography (5XSi1ar
The ratio was determined to be 80:20 from 1OC, 190°C).

(3S, 4S) - Tree [α) 3' - 43,2° (C1,0?, Cl1C13)
'It-NMR (CDCh) δ: 4.98 (Hl,
st+pt, J=6.21)z).

4.82(ill,brd,J=9.71)z)
, 4.03 (1B, brs).

3.72 (3H, s), 3.67 (IH, m), 3.3
0 (III, brs) 2.53 (2H, m), 1.66
(III, Peng), 1.54 (IH, w).

1.35 (ltl, m), 1.23 (6) 1. d, J=
6.2Hz), 0.93 (6H, m).

:R(CtlCIx) :3470.2980.1?1
0.1505.1)10 C1)-'MS(IS/z)
:276.216.1721308643゜(3R,
4S) Integral [α] b0-29.8°CC, 0,650, C) IC1
,)l1p63~65℃(fro@EtxO-hexa
ne).

'H-NM[1(CDCIs) δ: 4.8
9 (IH, 5ept, J-6, 1Hz).

4.62(1)1. brd, J-7,8)1z)
, 4.02 (Ill, brs).

3.71 (4H, s and s), 3.35 (L
H, brs), 2.50 (2H, m), 1.68 (1)
(, 糟), 1.34 (2H, m), 1.23 (6N.

d, J=6.1Hz), 0.94 (6H,d,
J=6.5Hz).

IR(CHCI,) :3460.2970.1?1
0.1505.1) 10 Value - 1MS (m/z):
316, 256, 212, 170, 126, 71, 43
゜Example 2 0i (N-(isopropoxycarbonyl)-(S) leucinal 8.7N (0,0433 mmo I) and molecular sieve 4A 4■ under an argon atmosphere, O methyl-〇-
Trimethylsilylketene acecool 19mg (0,1
Add 0.5 ml of 3 mmol I) menalene chloride solution,
After cooling to -78°C, 0.065 ml of titanium tetrachloride (1M methylene chloride solution) was slowly added dropwise to the reaction mixture, which was stirred for 1 hour. A small amount of saturated aqueous sodium bicarbonate was added and filtered through Celite. The solvent of the Ill solution was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane:
Purified by ethyl acetate = 4:l) to give (3S, 43)
10.6 μm (89%) of a mixture of methyl-3hydroxy-6-methyl-4-((N-isopropoxycarbonyl)amine)heptanoate and its (3R,4S) were obtained.(3S,4S) The production ratio of monolithic and (3R24S) monolithic is determined by gas chromatography (5χ5ilarlOC, 1
90°C) to 95:5.

Examples 3 to 7 Examples 3 to 5 are set in the same manner as in Example 2, and Examples 6 to 7 are set in the same manner as in Example 1.
1 result was obtained. However, the Lewis acid, solvent, and reaction temperature used the conditions indicated.

Example 8 0H N-(isopropoxycarbonyl)-(S)-cyclohexylalaninal 61.0■ (0,253 mmol)
and Molecular Sheep 4A (30g) under Ambon air flow,
0-Methyl-〇-)limethylsilylketene acecool 1
) 0 w (0,759 mm o 1) in methylene chloride solution was added, and after cooling to -78°C, 0.25 rnl of titanium tetrachloride (1M methylene chloride solution) was slowly added dropwise. The reaction solution was stirred for 1 hour. After that, a small amount of saturated sodium bicarbonate solution was added, and the mixture was filtered through Celite. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate-4:l) to obtain 16.7μ of the raw material (
27%), (33,43)-5-cyclohexyl-3-
Hydroxy-4-((N-isopropoxycarbonyl)
50.0 µm (63%) of methyl amino]pentanoate, 6.0 µm (7.5%) of its (3R,43) body, and 2.8 µm of a mixture of both were obtained.

The production ratio of (33,4S) and (3R,43) was determined by gas chromatography (5χ5ilar l0C19
0°C) to 96:4.

(3S, 4S) integral (α)p −36,6° (C1,1), cHcI3)H
-NMR (CDC1z) δ: 4.88 (1) 1,5
ept, J-6, 2Hz) 4.77 (LH, brd, J
=9.8Hz), 4.02(IH,brd,J-6,7
Hz), 3.71(3)1. s), 3.69 (IH, m
), 3.24 (IH.

brs), 2.52 (2H, m), 1.82 (IH, b
rs), 1.66 (4H.

s), 1.3-1.6 (2H, m), 1.23 (6H,
d, J=6.2Hz).

1.1-1.3 (2H, 1) 1), 0.8-1.1 (2
)1. m).

IR (CHCIs): 3470.2940, 2870
．． 1?10.1505.1440゜1) 10cm-' MS (s/z): 316,256,212,170,1
26,100.43゜(3R,43) integral [α] 2. -30,8” (CO,510,CHC
l5)mp 73-74℃Cfrom hexane)
.

'H-NMR (CDCIs) δ: 4.89 (IH,
5ept, J-6,01lz).

4.60 (IH,brd,J-7,7Hz), 4.02
(IH, W), 3.77(1)1. m), 3.71 (3
H, s), 3.38 (1M, brs), 2.48 (2H
, m) +1.83 (IH,brd,J-13,0Hz)
, 1.53-1.76 (4H, ■), 1.1-1.5 (
5H, m), 1.23 (6H, d.

J-6,0Hz), 0.7-1.1 (2H, m).

rR(CHCI,) :3690.3460,293
0.2860.1710.1500゜1430.1)1
0 cm-' MS (II/Z): 276.216, 172, 13
0,86,43゜Reference Example 8 H H (33,43)-3-hydroxy-6-methyl was added and the 0 reaction solution was heated at 100°C for 13 hours, and the solvent was distilled off under reduced pressure, and the residue was ion-converted. Column chromatograph 4-
(Dowex AG50W-X2.pH51) 31 liquid (
1M pyridine-acetic acid)] (3S.

The pure product was recrystallized from water-ethanol to obtain 500μ.

[α]6・-20,4°(CO,501,H*0)Q
202-205°C Literature value (M, Klnoshita et al, Bu
ll, Chem, Soc.

Jpn,, Dan, 570 (1975)).

[α) Da -20 Responsibility C0,64+watsr) MP 2
01-203°C (decomp).

'H-NMR(D*Q) δ: 4.10(1
) (, theory), 3.30 (lit, import) 2.53 (III
, dd, J-5, 1 and 15Hz), 2.48 (1
8゜dd, J-7,0and 15Hz), 0.94(
6H, d, J-5, 7) 1z).

1.2-1.9 (3H)).

IR(KBr) :3440.3220.2970.2
890.1600.1550.1510°1430.1
390,1)70. T20 1MS (m/z) +1
76 (M'+1), 172, 157, 140, 1) 8,
100゜86, 40.30゜Reference Example 9 OH OH (33,43)-5-cyclohexyl-3-hydroxy-4 ((N-isoproboxylic carbonyl 6NN salt 1 was added and heated at 100°C for 8 hours. After distilling off the 0 reaction solution under reduced pressure, the residue was ion-exchanged.
rl? Togelafie (Dowex AG501)-
X2. Purification was performed using a pHSll equilibrium solution (1M pyridine-acetic acid), and a pure product was obtained by dissolving in 1M hydrochloric acid, adjusting the pH to 5 to 6 with LM NaOH aqueous solution t8, and filtering and drying the precipitated crystals.

[α] et al. -25,3 Responsibility C0,435,1M IIC
I) Meal p 213-216°C Literature value ()1. Yanaglsawa et al., c.
hem, Lett, 687 (1989).

@p 230~231℃(dec,)(&)3 -2
6.2° (C1,0, It-1HC,1) 處H-N?
IR ([1 to 0) δ: 4.00 (III, ■), 3
35 (IH, m).

225 (2H)), 0.8 to 2.0 (13H, spear).

IR (KBr): 3430, 3220, 2950.28
B0,1610.1550,1510°1440.13
85,1335.1) 15,1070,1035.98
0°885cm-'

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a straight chain or branched alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted cycloalkyl group having 5 to 8 carbon atoms. 2-aminopropanal derivatives represented by the general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^3, R^4, R^5, R^6 each independently represent a straight chain or branched alkyl group having 1 to 4 carbon atoms or a substituted or unsubstituted aryl group) and a Lewis acid present. There are general formulas ▲mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, R^1, R^2 and R^3 represent the same meanings as above), which are characterized by the following reaction. A method for producing an amino-3-hydroxypentanoic acid derivative. (2) The asymmetric carbon at the 3rd position is (S)-configured, and the asymmetric carbon at the 4th position is (
4-amino-3- according to claim (1), which has the S)-configuration.
A method for producing a hydroxypentanoic acid derivative. (3) The method for producing a 4-amino-3-hydroxypentanoic acid derivative according to claim (2), wherein R^1 is an isopropyl group or a cyclohexyl group.