JPH0446174A - (4r,5r)-4-((s)-(1-amino-2-cyclohexyl)ethyl)-1,3-dioxola-ne derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:Compounds of formula I (R<1> is protecting group for amino group; R<2> is protecting group for hydroxyl group). EXAMPLE:(4R,5R)-4-[(S)-(1-benzylamino-2-cyclohexyl)ethyl]-5-be-n-zylox ymethyl- 2,2-dimethyl-1,3-dioxolane. USE:An intermediate for production of medical drugs. PREPARATION:A cyclohexylmethylmagnesium halide of formula II (X is Cl, Br or I) is reacted with a cerium halide anhydride of formula III (Y is Cl, Br or I) at -80 to 0 deg.C for 100min-1hr. 1,2-addition reaction is carried out by adding an imine derivative of formula IV to the resultant reaction solution, thus producing the objective compound of formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides a dioxolane derivative having the general formula (1) (wherein R1 represents an amino group-protecting group and R2 represents a hydroxyl group-protecting group). (4R,5R)-4-(
(S)-(1-amino-2-cyclohexyl)ethyl)
-1,3-Dioxolane derivative and method for producing the same. -(4R,5R)- expressed by the above-mentioned formula (1)
4-((S)-(1amino-2-cyclohexyl)ethyl)-1,3-dioxolane derivative is (4S,5R)
-oxazolidin-2-one derivative, (2R,3S)-cyclohexylnorstatin hydrochloride ((2R,3S)-3-amino-4-cyclohexyl-3-hydroxybutyric acid (2R,3S) represented by formula (II) (see reference side below)
-Cyclohexylnorstatin hydrochloride has the formula (I[[) (wherein, the carbon atom marked with (R) is in the (R)-configuration, The carbon atom marked with ) has the (S)-configuration.) It can be used as a raw material for producing the amino acid derivative represented by (
JP 62-234071, JP 1172365, JP 2-56457, J, Chem, Soc, Che
cCommun, 1989.1678. , Ch.
em, Pharm, Bull,, 37°2570 (
1989), and Heterocycles,
30.299 (1990), ).

[Conventional technology]

Conventionally, optically active (2
R,3S)-cyclohexylnorstatin hydrochloride and its derivatives can be obtained by: 1) reacting a cyanide compound with a (S)-2-amino-3cyclohequine rublobanal derivative synthesized from (S)-phenylalanine; A method of hydrolyzing (2R,3S)-3-amino-4-cyclohexyl-2-hydroquibutyronitrile derivative obtained under acidic conditions (JP-A-62-234071, JP-A No. 1-172365, JP-A No. 1-172365) 2-56457, J, Che
m,Soc, ,Chem.

Co++nun, 1989. 1678. ,and
Chess, Phar-, Bull.

Nail, 2570 (1989), ) or 2)
N-((S)l-phenylethyltwocyclohexylacetaldimine with benzyloxyketene (2+ 2
) A method of cycloaddition and separation of β-lactam derivatives obtained as a mixture of diastereomers after alcoholysis (l(eterocyclos, 30.299 (1
990), ). however,
In method 1), 3-amino-4-cyclohequinyl 2-
The diastereoselectivity during the production of hydroxybutyronitrile derivatives is at most 4:1, and in the method 2), the diastereoselectivity during the production of β-lactam derivatives is very low at approximately 1.6:1. However, it has been very difficult to industrially produce (2R3S)-cyclohexylnorstatin hydrochloride represented by formula (ff) and its derivatives by these methods.

[Problem to be solved by the invention]

The present inventors have developed a method for efficiently producing (2R,3S)-cyclohexylnorstatin hydrochloride represented by the above formula (n) with high stereoselectivity, which is a production intermediate for useful pharmaceuticals. As a result of searching, it was discovered that the compound of the present invention represented by the above formula (I) could be an excellent intermediate represented by the above formula (II), and the present invention was completed.

[Means to solve the problem]

(4R, 5R) ~ 4- (
(S)-(1-amino-2-cyclohexyl)ethyl)
-1,3-dioxolane derivatives can be produced according to the following synthetic steps.

(In the formula, R1 represents a protecting group for an amino group or an imino group, and R2 represents a protecting group for a hydroxyl group. X and Y each independently represent a chlorine, bromine, or iodine atom.) (First step) In this step, an aldehyde derivative represented by the general formula (IV) is condensed with an amine derivative represented by the general formula (V) to produce an imine derivative represented by -Funazura (VI).

The aldehyde derivative represented by the general formula (IV) is (2S,
3S)-tartaric acid by a known method (J, FIed, Cbem, 1.14 (1964)
).

Cheg+1stry Letters, 1982
+929. + and “Modern 5ynt
hetic Method,” ed, by R
,5cheffoldOtto 5alle VerI
ay, Frankfurt set Main, V
Ql, 2°1980, pp91-171. ). As the protecting group for the hydroxyl group, one is selected that exists stably not only in this step but also in the second and third steps described later, and can be removed in the fourth step without damaging other sites. Hydroxyl protecting groups that meet this requirement include substituted alkyl groups such as methyl group, methoxymethyl group, and 2-methoxyethoxymethyl group, benzyl group, p-methoxyhensyl group,
p-nitrohensyl group, Op-dimethquinbenzyl group,
Examples include substituted or unsubstituted silyl groups such as benzhydryl group, di(p-methoxyphenyl)methyl group, trityl group, t-butyldimethylsilyl group, and t-butyldiphenylsilyl group. However, a benzyl group is preferably used. These hydroxyl-protecting groups are introduced into the aldehyde derivative represented by the general formula (IV) by a known method ("Protective Groups tn Or
ganic 5ynthesisJohn Wiley
& 5ons, New York, 1981. p
plo 86L As the amine derivative used in this step, the amino group substituent exists stably not only in this step but also in the second, third, and fourth steps described later, and
Those that can be removed during the process without damaging other parts are selected. Amine derivatives that meet this requirement include:
Examples include substituted or unsubstituted arylmethylamines such as benzylamine, p-methoxybenzylamine, p-nitrobenzylamine, Op~dimethoxybenzylamine, benzhydrylamine, di(p-methoxyphenyl)methylamine, and tritylamine. However, benzylamine is preferably used.

This step is usually carried out in a solvent in the presence of a dehydrating agent.

Any dehydrating agent can be used as long as it does not participate in the reaction, but preferably anhydrous sulfates such as anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous sulfuric acid, or molecular sieves 4
A etc. are used.

As the solvent used in the reaction, any solvent can be used as long as it does not participate in the reaction, but preferably hydrocarbon solvents such as benzene, toluene, xylene, hexane, diethyl ether, tetrahydrofuran, dioxane, 1,2 -0 reactions in which ether solvents such as dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, and carbon tetrachloride are used are 120
It progresses smoothly between ℃ and 50℃.

[Second Step] This step involves adding cyclohexylmagnesium halide represented by the general formula (■) to the imine derivative represented by -Funezo (Vl) in the presence of cerium halide represented by the general formula (■). (4R,5R)-4-((S)-(1-amino-
A 2-cyclohexyl)ethyl)-1,3-dioxolane derivative is produced.

In this step, cyclohexylmethylmagnesium halide represented by -Funazura (■) is mixed with anhydrous cerium halide represented by the general formula (■) in an equivalent amount in a solvent at -80°C.
After reacting at 0°C for 10 minutes to 1 hour, an imine derivative represented by formula (VI) is added to the resulting reaction solution to carry out a 1°2-addition reaction.

The 1°2-addition reaction to the imine derivative represented by the general formula (Vl) proceeds with high stereoselectivity, and the -1,3-dioxolane derivative has a single reaction result. In this 1,2-addition reaction, the cyclohexylmethylmagnesium halide represented by the general formula (■) and the cerium halide represented by the general formula (■) are obtained as a compound of the general formula (l). They are used in an amount of 1 to 10 equivalents, more preferably 5 equivalents each, based on the imine derivative.Used in the reaction between cyclohexylmethylmagnesium halide and cerium halide and the subsequent 1,2-addition reaction. Any solvent can be used as long as it does not participate in the reaction, but ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1°2-dimethoxyethane are preferably used alone or as a mixed solvent. The 1,2-addition reaction proceeds smoothly at -80°C to 50°C.

The compound of the present invention produced by the above synthetic process is (4R15R)-4-(
(S)-(1-amino-2-cyclohexyl)ethyl)
The -1,3-dioxolane derivative is synthesized by the following synthesis process to produce the amino acid derivative of the formula (n), which is a raw material for the production of the amino acid derivative represented by the formula (I (2R, 3S) ~
It can be efficiently induced into cyclohexylnorstatin hydrochloride.

(Fourth step) ↓ (Fifth step) ↓ (In the formula, R1 and R2 have the same meanings as above, and R3
is 01~. (represents a straight-chain or branched lower alkyl group) [3rd step] This step represents a straight-chain or branched lower alkyl group of (4.R,5R)-4-( (S)-(1amino-2-
The amino group on the 4-position substituent of the cyclohexyl)ethyl-13-dioxolane derivative is alkoxycarbonylated, and then the 1,3-dioxolane ring is cleaved and an intramolecular ring-closing reaction is conducted to form a (4S,5R)-oxazolidin-2-one derivative. , Furthermore, by removing the protecting group of the hydroxyl group on the 5-position substituent of the (43,5R)-oxazolidin-2-one derivative, the (4S,5R)-5 represented by -Funazura (IX) was obtained.
-((R)-(1,2-dihydroxy)ethyl]-oxazolidin-2-one derivatives are produced.

Alkoxycarbonylation of amino groups is carried out using an alkoxycarbonyl halide in the presence of a base in a solvent. The alkoxycarbonyl halides used include methoxycarbonyl chloride (methyl chloroformate), ethoxycarbonyl chloride (ethyl chloroformate), methoxycarbonyl bromide (methyl promoformate), and benzyloxycarbonyl chloride (benzyl chloroformate). Examples include lower alkoxycarbonyl chloride and lower methoxycarbonyl halogenide, and methoxycarbonyl chloride (methyl chloroformate) is preferably used. The bases used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate;
pyridine, 4-(N,N-dimethylamino)pyridine,
l.

8-diazabicyclo(5,4,0)undec-7-ene (DBLI), 1,4-diazabicyclo[22,2]
Examples include organic bases such as octane (DABCO), but alkali metal carbonates such as sodium carbonate and potassium carbonate are preferably used. Any solvent can be used as long as it does not participate in the reaction, but ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are preferably used. The reaction takes place from -20°C to 30°C.
Proceeds smoothly at ℃.

The next cleavage of the 1,3-dioxolane ring is carried out under acidic conditions by a known method.
ups in Organic 5 synthesis,
John Wiley & 5ons, New Y
ork, L981. pp124-128. ), preferably in a 60-90% aqueous acetic acid solution at 60°C to 100°C.
It is done by heating. The (4S,5R)-oxazolidin-2-one derivative is produced by intramolecular ring-closing reaction of the obtained 1,2-diol derivative using a base in a solvent. Bases used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, pyridine, 4-(N,N-dimethylamino)pyridine, and 1.8 diazabicyclo(5,4,O). undeku
7-ene (DBU), 1,4-diazabicyclo(2,
Examples include organic bases such as 2゜2]octane (DABCO), but alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide are preferably used. Any solvent can be used as long as it does not participate in the reaction, but preferably,
Alcohol solvents such as methanol, ethanol, propatool, isoproptool, and butanol are used. The intramolecular ring closure reaction proceeds smoothly between 0°C and 50°C.

Subsequently (4S,5R)-oxazolidine-
Removal of the protective r1 group of the hydroxyl group on the 5-position substituent of the 2-one derivative is carried out by a known method depending on the type of protecting group used (@Protective Groups in Or
ganic 5ynthesisJohn Wtley
& 5ons, Neli York, 1981.
pplo 86. ).

For example, when the protecting group for the hydroxyl group is a benzyl group, the benzyl group can be removed by hydrogenolysis using palladium hydroxide supported on carbon as a catalyst. In this case, the reaction proceeds smoothly under a hydrogen atmosphere of 1 to 5 atm in an alcoholic solvent such as methanol, ethanol, propatool, isopropanol, butanol at temperatures ranging from 0°C to 50°C.

[Fourth step] In this step, (4S,5R)-5-((R)-(1,2-
The (R) to (1,2-dihydroxy)ethyl group at the 5-position of the dihydroxy)ethyl]-oxazolidin-2-one derivative is oxidized to a carbonyl group, and the obtained carboxylic acid derivative is then esterified to form a -ship. (
43,5R)-5-alkoxycarbonyl-oxapridin-2-one derivatives are produced.

Oxidation of the (R)-(1,2-dihydroxy)ethyl group to a carboxyl group is performed using a combination of chromic acid anhydride, potassium permanganate, ruthenium chloride, and sodium periodate or sodium metaperiodate. However, a combination of ruthenium chloride and sodium metaperiodate is preferably used. The reaction is carried out in a solvent, and any solvent that does not participate in the reaction can be used, but dichloromethane, dichloromethane,
The reaction using a halogenated hydrocarbon solvent such as chloroform, hydrogen, or carbon tetrachloride proceeds smoothly at a temperature of 0°C to 50°C.

The obtained carvone fI! Esterification of the derivative is carried out by a known method ('Protective Gr
upsin Organic 5 synthesis,
John Wiley & 5ons.

New York, 2. pp152 178.
), for example, when leading to methyl ester, diethyl ether, tetrahydrofuran, dioxane, 1.2
- A method of reacting diazomethane or trimethyllinyldiazomethane in an ether solvent such as -dimethoxyethane, a method of reacting hydrogen chloride or thionyl chloride in methanol, etc. are preferably used.

[Step 5] In this step, the oxazolidin-2-one ring is simultaneously cleaved and the ester group is hydrolyzed, and then the protecting group of the amino group is removed to obtain a useful pharmaceutical product represented by II (II). (2R,3S)-cyclohexylnorstatin hydrochloride, which is a production intermediate.

Cleavage of the oxazolidin-2-one ring and hydrolysis of the ester group are carried out in a solvent under basic conditions.

Suitable bases to be used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide. Any solvent can be used in the reaction as long as it does not participate in the reaction, but alcoholic solvents such as methanol, ethanol, propatool, isopropanol, and butanol are preferably used alone or in a mixture with water. 0 used as a solvent
The reaction proceeds smoothly at 30°C to 100°C.

The subsequent removal of the protecting group for the amino group is carried out by a known method depending on the type of protecting group used ('Protective Groups inO
rganic 5ynthesis, John W.
iley & 5ons, New York, 198
1. pp272-275. ). For example, when the protecting group for an amino group is a benzyl group, the reaction is to convert the free amino group into a hydrochloride and then remove the benzyl group by hydrolysis using palladium hydroxide supported on carbon as a catalyst. The process proceeds smoothly at 0°C to 50°C in a hydrogen atmosphere of 1 to 5 atmospheres in an alcoholic solvent such as methanol, ethanol, propatool, isopropanol, butanol, or a mixed solvent of these and water.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. Note that the following abbreviations are used in the Reference Examples and Examples.

Bn: Benzyl group Reference Example 1 Oxalyl chloride (1.4 ml, 16.1 mmol) was dissolved in dichloromethane (34+l) and dimethyls/L/phoxite (2.3 ml 1.32.4 mmol) was dissolved at -78°C.
A dichloromethane solution (6 ml) of 1) was added and stirred for 10 minutes. Subsequently, the method described in the literature (J, Med, Ch
em, 1.14 (1964), and Chemi.
Try Letters, 1982.929. )
4-0- synthesized from (23,3S)-tartaric acid according to
A dichloromethane solution of benzyl-2,3-0-isopropylidene-D-threitol ([α]!'-7.9° (C = 0.91.chloroform)) (1,99 g, 7.89 gmol) (7 ml) 1) was added dropwise and stirred for 1 hour, then triethylamine (4,46-1,32,0+wt
aoI) was added and further stirred for 1 hour. The temperature was gradually raised, and when it reached O'c, it was diluted with ether. The ether solution was washed successively with 1M hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was dissolved in a small amount of ether, diluted with hexane, and washed with brine. After drying again over anhydrous magnesium sulfate, it was concentrated under reduced pressure, and the residue was distilled on a Kugelrohr to give 4-O-benzyl-2,3-0-isopropylidene-D-threitol as a pale yellow oil (L, 79 g).
, 91%) obtained as NMR (C(lCh) δ
: 1.40.1.47 (6N, s X2. CR
s X2) 3.50-3.77 (2H, m, CLO),
4.07-4.39 (2H, ts, CHCH)4.
59 (21T, s, CToPh), 7.31 (5L
s, CJs), 9.72(1)1brs, CHO)
.

Reference example 2 4-0-benzyl-2,3-0-isopropylidene-D
-Threose (505mg, 2.02ggo+) was dissolved in toluene (IC1++1), and under water cooling, hensylamine (0,225ml 1.2.06-so01) and anhydrous magnesium sulfate (602mg, 5.0mmol) were added to give 1.5 Stir for hours.

After raising the temperature to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude <4R
,5R)-4-((N-benzyl)iminomethyl25
-benzyloxymethyl~2.2=dimethyl-1,3-
Dioxolane was obtained as a pale yellow oil (701 mg, quantitative yield). This product was immediately used in the next reaction step.

N? IR(CDCI,)δ: 1.44(61(,sX
2. CHsX2).

3.4L 3.73 (2M, +w, C) IzO), 4
．． 12-4.45 (2H, s, CHCH) 4.45-4
．． gl (4H, m, CHzPh X2).

7.10-7.37 (IOH, m, CJsX2>.

7.79 (IH,brd, J=5Hz, CH=N)
.

Example 1 Cerium chloride heptahydrate (4,00g, 10.7m-o
Anhydrous cerium chloride prepared by heating 1) under reduced pressure at 130 to 140°C for 5 hours was added to tetrahydrofuran (
The mixture was suspended in 20 liters of water, subjected to ultrasonic irradiation for 1 hour, and further stirred at room temperature for 2 hours. This was cooled to -30°C, and an ether solution of cyclohexylmethylmagnesium bromide (1
M solution, 10.1-1.10.1 mmol) was added and stirred for 30 minutes.

Add crude (4R,5R)-4-( to this solution at -30°C.
(N-benzyl)iminomethyl-5-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (7
A solution of 0.01 g, 2.02-l ol) in tetrahydrofuran (10 l) was added dropwise. After stirring for 2 hours, the temperature was gradually raised, and the reaction mixture was further stirred at room temperature for 12 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium bicarbonate, and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was subjected to column chromatography (silica gel, toluene-ethyl acetate 100%
:1→50:1) to give (4R,5R)-4-(
(S)-(1-hensylamino-2-cyclohexyl)
[ethyl]-5-penzylokinemethyl-22-dimethyl-1,3-dioxolane in colorless oil (660 mg,
75% (from 4-0-benzyl-2.3-0 isopropylidene to D-threose)).

[αJP+ 12.3” (C= 1.22.Chloroform) to MR (COCh) δ: 0.77-1.7
3(13)1. ■+C6L +cHz)1.40.1.
42 (6N, sx2. (jlzX2), 2.66-2
．． 74 (II (, +mBnNCH), 3.56 (IH
, dd, J=10.3.5.5Hz, one pro
tonof CHxO), 3.57 (18, dd J
=10.3.4.4Hz, oneproton of
CH2O) + 3.75 (LH, d, J-13,1H
z, 0rleproton of NC)IxPh)
, 3.85 (18,d, J=13.1Hz, one
proton of NCI (zPh), 3.88 (
IFI, dd, J=7.9.4.0HzCHCHCHHz
O), 4.24 (LH, ddd, J = 7.9, 5.5
．． 4.4Hz.

CHC C1 (tO), 4.56 (2H, S, 0CH
tPh>-7,19-7,35 (IOH Gu, C&l (S X 2).

IR(neat): 2930. 2870cm-'
MS(-/z): 438([M+11')
, 422. 340. 216° high resolution MS
: CzsHn. NO, ([Calculated value as M + 11 force: 438.3005 Measured value: 438, 2987 Reference example 3 (4R,5R)-4-C(S)-(1-benzylamino-2-cyclohexyl)methyl] -5=benzyloxymethyl-2,2-dimethyl-1゜3~dioxolane (2
62 ml, 0.598 sardine ol) was dissolved in tetrahydrofuran (6.5 ml) and water-cooled with potassium carbonate (435 ml).
■g+ 3.15ggo+) and methoxycarbonyl chloride (methyl chloroformate) (0.24ml1.3.11+sm
The reaction mixture was stirred at the same temperature for 7 hours, diluted with ethyl acetate, washed successively with dilute hydrochloric acid, water, and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel, toluene-ethyl acetate 100:1) to give (4R,5R)-4-C(S)-(1-N-benzyl-N- methoxycarbonyl)amino-2-cyclohexyl)ethyl 5-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane in a colorless oil (288
97%).

[α]! '-24,9' (C=1.05. Rioohol L) NMR (CDC1i) δ: 0.40-2.10
(13H1m, Cj(++CHt)1.38(6)1.
SX2. C) 13X2), 3.69 (3H,s, C0z
CHs).

4.61 (4H,s, CtlzPhX2), 3.46-
4.50 (5H, m, NCHCHCHCHZO), 7.
27 (5Ls, CJs), 7.33 (5H,s, CJs)
s), IR (neat): 2950 2875 1
690cm-'MS(s/z): 495(M"
), 480. 437. 274° (4R, 5R)
-4-((S)-(1-N-benzyl-N-methoxycarbonyl)amino-2cyclohexyl>ethylcy 5
-benzyloxymethyl-2,2-dimethyl-1,3-
Dioxolane (242 kiln, 0.487 m5 ol) 8
It was dissolved in 0% acetic acid aqueous solution (12 ml), heated and stirred at 80°C for 5 hours, and then concentrated under reduced pressure to obtain the crude (2R, 3R, 4
3)-4-(N-benzyl-N-methoxycarbonyl)amino-1-benzyloxy-5-cyclohexyl-2,
3bentanediol was obtained. This product was immediately used in the next reaction step.

NMR (CDC1,) δ: 0.45-1.90 (13
F+, ■, CbH++CHx).

3.73 (3Ls, C02CH3), 7.27 (5H
, S, C61 (S), 7.32 (5H.

3+CJs).

Crude (2R,3R,4S>-4-(N-benzyl-N
-methoxycarbonyl)amino-1-benzyloxy-
10 5-cyclohexyl-2,3-bentanediol
% potassium hydroxide methanol solution (3 ml),
Stirred at room temperature for 3.5 hours.

The reaction solution was neutralized with 1M hydrochloric acid and then extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by column chromatography (silica gel, toluene-ethyl acetate 10:I), (4S, 5R)
-3-hensyl-4-cyclohexylmethyl-5-((
R)-(2-benzyloxy l-hydroxy)ethyl)
-Oxazolidin-2-one in colorless oil (189■,
92% (2 steps)).

rα]! '-29,7' (C=1.25. rioo
, nirum).

NMR (CDCIs) δ: 0.67-1.70 (13
ff, m, C6H+ 1C) [2).

2.33 (lH, brs, OH), 3.53 (1) 1
．． ddj=9.6.7.3tlzone proton
of CH20), 3.58 (IH+dd, J=9
．． 6+ 5-IHz+one proton of C
HzO), 3.64-3. ”15 (2H, ta, NC
HCHCHCHZO) + 4.09 (lH, d, J=1
5.3Hz, one proton of NCHzP
h), 4.20 (LH, dd, J=5.0.2.8H
z, CHCHCHzO) 4.52 (2) 1. s, 0C
LPh), 4.79 (IH, J=15.3Hz, o
neproton of NCLPh), 7.24-
7.38 (IOH, II, C6) ISX2).

IR (neat): 3300 2940.2875.
1735cm-'MS (m/z): 423 (M")
, 332, 302.284° High resolution MS: Czb
Total X value as H3JOa (M”): 423.240
7 Measured value: 423.2431 (45,5R)-3-benzyl-4-cyclohexylmethyl~5- ((R)-(2-benzyloxy-1-hydroxy)ethylcouoxazolidin-2-one (15
8■, 0.372 mmol) in methanol (3 ml)
A catalytic amount of 20% palladium hydroxide on carbon was added thereto, and the mixture was stirred overnight under room salt under a hydrogen atmosphere of 1 atm. After filtering off the catalyst, the solvent was concentrated under reduced pressure to give (4S 5R)-3-
Benzyl-4-cyclohexylmethyl-5-((R,)
-(1,2-dihydroxy)ethylcouoxazolidin-2-one was obtained as colorless crystals (125 µm, quantitative yield). This product was recrystallized from ethyl acetate-hexane to obtain an analytical sample.

-p, 101 102℃ [α]P-43,1' (C=0.594.rit7
o#rum).

NMR (CDCI x>δ: 0.7-1.8 (138
, II, C4H6+CHz), 2.20 (1B, t
, J=5.9) 1z, CH, OH) 2.65 (18
d J=6.6HzC)IOH), 3.55(I
H4, C and OH), 3.64 (1M, si, C) I
N), 3.72 (2H, dd, J=5.8.5.5
H2, CH20H), 4.10 (IH, d, J=15.
31] z, one proton of NC
HzPh), 4.20 (IH, d, J=5.13.
3Hz, NCHCHCHCH, O), 4.79 (IH,
d, J=15.3Hz, oneproton of
NCHzPh), 7.2-7.4 (5H, m, CJs)
.

Summer R (KBr): 3440. 3250. 29
30. 28B5. 1720 14401042
．． 702cm-' MS (m/z): 333 (M"), 236, 17
6.91° Elemental analysis: Calculated value as C, J2.8O4: C, 68,44; II, 8.16; N, 4
．． 20χ analysis value: C, 68, 22, H, 8, 25;
N, 4.19χ Reference Example 4 (4S 5R) 3-benzylcyclohexylmethyl-50oxy)ethyl] ((R)-(1,2-dihydroxazolidin-2-one (162■, 0.485 mmol) in a mixed solvent of carbon tetrachloride-acetonitrile-water (2:2:3) (6
, 3 ml) and a catalytic amount of ruthenium chloride trihydrate and sodium metaperiodate (512 μ, 2.4 O−
sol) and stirred at room temperature for 2 hours, the reaction mixture was extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate.

It was concentrated under reduced pressure to obtain crude (4S,5R)-3-benzyl-4-cyclohexylmethyl-oxazolidin-2-one-5-carboxylic acid.

Crude (4S,5R)-3-benzyl-4-cyclohexylmethyl-oxazolidin-2-one-5-carboxylic acid was dissolved in a mixed solvent of benzene-methanol (4:l) (3s
+1), added an excess amount of trimethylsilyldiazomethane (10% hexane solution) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, hexane-ethyl acetate).
9:1-4:l) and purified with methyl (43,5R)
-3benzyl-4-cyclohexylmethyl-oxazolidin-2-one-5-carboxylate as a colorless oil (
117■, 73% (2 steps)).

[α: 0-21°5' (C=1.92. Chloroform).

NMR (CDC13) δ: 0.7-1.7 (13H, m
,C,lI,,CH2), 3.58(18,ddd,
J=9.8.3.8.3.8) 1z, CHN), 3.
78 (385COtCH3), 4.04 (18, d, J
=15.3Hz, One proton or NCH
zPh), 4.55 (Ill, d, J=3.8Hz,
CHCOzMe), 4.83 (IHd, J=15.
3flz, one proton of N
C) lzPh), 7.2-7.4 (5H beard, C6
H3).

rR(neat): 2950. 2870.
1775. 1760 (sh) 1240.702cm-
'MS(-/z):33HM''), 234.
205. 91° Reference Example 5 Methyl (4S, 5R)-3-benzyl-4-cyclohexylmethyl-oxazolidin-2-onecarboxylate (127μ, 0.384mmol) was dissolved in methanol (
0.6ml) and 2M sodium hydroxide aqueous solution (
41) was added thereto, and the mixture was stirred at 90°C overnight. Next, pH1
After adding 1M hydrochloric acid to the solution, the solvent was concentrated under reduced pressure.

Methanol was added to the residue, insoluble materials were filtered off, and the mixture was concentrated under reduced pressure to obtain crude (2R,3S)-3-hensylamino-4-cyclohexyl 2-hydroquinobutyric acid hydrochloride. This product was immediately used in the next reaction step.

Crude (2R,3S)-3-benzylamino 4-cyclohexyl-2-hydroxybutyrate hydrochloride was dissolved in methanol (6
ml), a catalytic amount of 20% palladium hydroxide-carbon was added thereto, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere of 1 atm.

After removing the catalyst, the solvent was concentrated under reduced pressure and the resulting residue was diluted with 6M
Hydrochloric acid (41) was added and the mixture was stirred at 100°C for 2 hours. The solvent was concentrated under reduced pressure to obtain crude (2R,3S)-3-amino-
4-cyclohexyl-2-hydroxybutyric acid hydrochloride was obtained.

This was treated with ion exchange resin AG50W-X2 (H" type) (water - 25% ammonia water), and the effluent from the column was concentrated under reduced pressure. The obtained residue was dissolved in 1M hydrochloric acid and the solvent was removed under reduced pressure. Concentration gave pure (2R,3S)-3-amino-4-cyclohexyl 2-hydroxy##hydrochloride as colorless crystals (69.0 x 76%).This was recrystallized from water and analyzed. Got the sample.

8p, 191-192°C [α]P-13.6° (C=0.633. I M
salt MI) 11MR(0,0)δ:0.8-1.8(
13L (CJ+ICL), 3.67 (IH, di,
J=7.3. 3.5Hz, NCH,
4.34 (IH, d, J = 3.EHz, Cdan 0
H)

Claims (2)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents the protecting group for the amino group, R^2 represents the protecting group for the hydroxyl group. 5R)-4
-[(S)-(1-amino-2-cyclohexyl)ethyl]-1,3-dioxolane derivative. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents a protecting group for the imino group, and R^2 represents a protecting group for the hydroxyl group.) , General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a chlorine, bromine, or iodine atom. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 is amino (4R,5R)-4 represents a protecting group for the group, and R^2 represents a protecting group for the hydroxyl group.
- A method for producing a [(S)-(1-amino-2-cyclohexyl)ethyl]-1,3-dioxolane derivative.