JPH04117370A - (4s,5r)-4-cyclohexylmethyl-oxazolidin-2-one derivative - Google Patents

Abstract

NEW MATERIAL:A (4S,5R)-4-cyclohexylmethyl-5-[(S)-1-hydroxyethyl]-oxazolidin-2- one derivative expressed by formula I (R<1> is H or amide-protecting group; R<2> is isopropyl or morpholin-4-yl). USE:A synthetic intermediate for antihypertensive agents having human renin inhibitory activity. PREPARATION:A compound expressed by formula II (R<3> us amide-protecting group) and an isopropylmagnesium halide expressed by formula III X is Cl, Br or I) are subjected to ring opening reaction of the epoxide ring in the presence of copper iodide in a solvent such as THF at -30 to +50 deg.C and deprotection, as necessary, is then carried out to afford the compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to compounds represented by the general formula (1) (wherein R1 represents a hydrogen atom or a protecting group for an amide group, and R2 represents an isopropyl group or a morpholin-4-yl group). (4S, 5R) 4-cyclohexylmethyl-5 to ((S)-1 human xoethyl:-oxadurinone) represented by (4S, 5R)-4-cyclohexylmethyl 5-((S
)-oxazuridin-2-one derivatives. (4S
, 5R)-4-cyclohexyl-5-((S)-1-hydroxyethyl)oxazolidine derivatives are produced by the general formula (nl) (E
(2S, 3R, 4S)-2-- (I[l) (wherein R2 represents an isopropyl group or a morpholin 4-yl group)
Amino-1-cyclobekyl-6-mef-3,4-heptadiol or (2S3R,4S:)-4-amino-5-noclobekyl, 1-(morpholine-4-
yl) can be derived into 2,3-pencunol (see reference side below).

Represented by general formula (1) (2 S, 3 R, 45
)2-Amino-1-cyclohequinol-6-methyl3.4
-hebutanediol and (2S,3R43)-4-amino-5-cyclohexyl-1(morpholin-4-yl)-2,3-pentanenol are respectively used as antihypertensive drugs due to their human renin inhibitory activity. Useful formulas (TV
) (In the formula, the carbon atom marked with (R) has the (R) configuration, and the carbon atom marked with (S) has the (S) configuration I.) and the formula Carbon atoms are of the (R)-configuration, and carbon atoms marked with (S) are of the (S)-configuration. ) can be used as a raw material for producing peptide-like compounds represented by (J, Med, Chem, 31°2264,
2277 (1988), FEBS Letter
s, 230.38 (1988), Bioche
m, Biophys, Res, Commun,,
15shi999 (1989), and Tetrah
edron Letters31, 1569 (199
0),).

[Conventional technology]

Conventionally, optically active (2S) is a raw material for manufacturing useful pharmaceuticals.
,3R,4S)-2-amino-1-cyclohekinru6
-Methyl-3,4-heptanediol is synthesized by the -ittig reaction of (S)-2-t-butoxycarboxamide-3cyclohexolprobanal. Cis-dihydroxylation of l-cyclohexyl-6-methyl-hebutan-3-ene (J, MedChem, 31.2
264 (1988), ) 2) (S) -2-
(23)-2, synthesized by 1,2-addition of vinylmagnesium halide to t-butoxycarboxamido-3-cyclohequinleprobanal followed by epoxidation.
-t-butoxycarboxamide 1-cyclohexyl-4,
Iodide of 5-epoxy-3hydroxy-pentane 1M (
1) Opening of the epoxide ring with isopropylmagnesium halide in the presence of J, Org, Che
m,, 53°6109 (1988), ) or 3) (S)-2-t-butoxycarboxamide-3
- 12-Addition of 2-methylpropylmagnesium iodide to the cyanohydrin derivative prepared from cyclohexylpropanal followed by hydrolysis S, thereby synthesizing the compound (2S)-2-t-phthoquinolpoamito 1cyclohexyl-3- Reduction of hydroquine-6-methylhebutan-4-one with sodium borohydride (J, Org
, Chem, 53.6109 (1988), )
・It is also produced by optically active (233R
, 4S)-4-amino-5-cyclohequinyl 1-(morpholin-4-yl 1)-2,3-bentanediol is 4
) 3-0-hensyl-1 prepared from D-glucose,
It was produced from 2-0-isopropylidene-α-D-ribopentodialdo-1,4-furanose by applying Wittig reaction, Mitsunobu reaction, etc. (Tetrahe
drone Letters, 3L1569 (199
0),). However, in method 1) -ittig
The stereoselectivity of the reaction and cis-dihydroxylation is low; 2)
Method (3) has low stereoselectivity for 12-addition of Grignard reagent and epoxidation, method (3) has low stereoselectivity for production of cyanohydrin derivatives and reduction of ketones with sodium borohydride, and The method is multi-step and uses reactions that are difficult to implement industrially, such as the Mitsunobu reaction.
(2S,3R,4S)-2-amino-l-cyclohexyl-6-methyl-3,4-hebutanediol and (2S,3R,4S)-4amino-5-cyclohequinyl 1 - It has been very difficult to industrially produce (morpholin 4-yl)-2,3-bentanediol.

[Problem to be solved by the invention]

The present inventors have discovered the above-mentioned - which is a useful pharmaceutical product intermediate.
(2S, 3R43)-2-, represented by the linear formula (III)
Amino-1-cyclohexyl-6methyl-3,4-hebutanediol and (2S3R,4S)-4-amino-
5-cyclohexyl 1-(morpholin-4-yl)-2
, 3-bentanediol with high stereoselectivity and efficiency.
The inventors have discovered that the compound of the present invention represented by n) can be an excellent intermediate for its production, and have completed the present invention.

[Means to solve the problem]

(4S, 5R) 4-cyclohexylmethyl-5-C(S)-1hydroxyethyl]-oxazolidin-2-one derivative represented by the above-mentioned -line formula (1) and the above-mentioned -way formula (It) The (4S5R14-cyclohexylmethyl-5-((S)oxiran-2-yl)-oxazzuridin-2one derivative) can be produced according to the following synthetic steps.

L-OR2 (1st process) 士H2 (〜■) (4th process) /He- (5th process) ↓ (6th process) φ Do) (XV) Do~) (9th process) ↓ ( 10th step) (Ic) (Id) In the formula C, R1
' is an amide group-protecting group, R2 is a hydroxyl-protecting group, R3
゛ is a protecting group for an amino group, imino group, or amide group, R
4 is an unsubstituted or halogen-substituted chain or branched alkyl group having 1 to 6 carbon atoms or a substituted or unsubstituted aryl group, and 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 (Vl) is condensed with an amine derivative represented by the general formula (■) to obtain an imine derivative represented by the -line formula (■). It is manufactured.

-IiG The aldehyde derivative represented by formula (Vl) is (2
It can be easily synthesized from 3,3S)-tartaric acid by a known method (J, Med, Chem, ', 14
(1964).

Chemistry Letters, Yu982.92
9. , and “Modern 5ynthetic
Methocl,” ed, by R.

5cheffold, 0tto 5alle Ver.
Lay, Frankfurt am Main, Vo
l, 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, third, and fourth steps described later, and can be removed in the fifth 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, hensyl group, p-methoxyhensyl group, p-nitrohensyl group, 0. Substituted or unsubstituted arylmethyl groups such as p-dimethoxyhensyl group, henzhydryl group, di(p-methoxyphenyl)methyl group, trityl group, t-butyldimethylsilyl group, t-
Silyl groups such as butyldiphenylsilyl are exemplified, and Hensyl is preferably used. These hydroxyl protecting groups are introduced into the aldehyde derivative represented by the general formula (Vl) by a known method.

(Protective Groups in Org.
anic 5ynthesisJohn Wiley
& 5ons, New York, 1981 pp.
lo 86).

The amine derivatives used in this step include substituents of the amino group not only in this step but also in the second, third, fourth, and
A material that stably exists in the fifth, sixth, seventh and eighth steps and can be removed in the ninth and tenth steps without damaging other parts is selected. Examples of amine m1 bodies that meet this requirement include benzylamine, p-methoxyhensylamine, p-nitrobenzylamine, 0. Examples include substituted or unsubstituted arylmethylamines such as p-dimethoxybenzylamine, benzhydrylamine, di<p-methoxyphenyl)methylamine, and tritylamine, and hensylamine is preferably used.

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

As the dehydration side, any substance can be used as long as it does not participate in the reaction, but preferably anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium sulfate, 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, and hexane, diethyl ether, tetrahydrofuran, dioxane, etc. - Ether solvents such as dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, and carbon tetrachloride are used. The reaction is -20
It progresses smoothly between ℃ and 50℃.

[Second step] In this step, a cyclohenoquinormagunsium halide represented by the general formula (IX) is added to the imine derivative represented by the -line formula (■), and a halogen represented by the general formula (X) is added. The reaction was carried out in the presence of cerium chloride, and (4R, 5R
) -4-: (S)-(1amino-2-cyclohexyl)ethylni-13-dioxolane derivative is produced.

In this step, an equivalent amount of anhydrous cerium halide represented by the general formula (X) and anhydrous cerium halide represented by the general formula (X) are added to
After reacting at 0° C. to 0° C. for 10 minutes to 1 hour, the imine derivative represented by the general formula (■) is added to the resulting reaction solution to carry out a 12-addition reaction.

The 12-addition reaction to the imine derivative represented by the general formula (■) proceeds with high stereoselectivity, and the 1.3-dioxolane derivative is a single reaction product. obtained as. In this 1,2-addition reaction, -linear equation (
The cyclobexylmethylmagnesium halide represented by IX) and the cerium halide represented by -111Q (X) are each in an amount of about 1 to 10 equivalents, more preferably, relative to the imine derivative represented by the general formula (■). , each used in an amount of 5 equivalents. As the solvent 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 preferably, Ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 12-dimethoxyethane are used singly or as a mixed solvent. 1.2 The addition reaction proceeds smoothly at -80°C to 50°C.

[Third step] In this step, (4R,5R)- expressed by the -wire formula (Xl)
The amine group on the 4-position substituent of the 4-((S)-(1-amino-2-cyclohexyl)ethyl)-1,3-dioxolane derivative is alkoxycarbonylated, and then 1.3
- (4S, 5R)-4-cyclohexylmethyl 5-'((R)-1-hydroxyethyl]-oxazolidin-2-one represented by general formula (Xn) by intramolecular ring closure reaction after dioxolane ring cleavage) It is used to produce derivatives.

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 bromoformate), and hensyloxycarbonyl chloride (hensyl chloroformate). Examples include lower alkoxycarbonyl chloride and arylmethoxycarbonyl halide, 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, 18-diazabicyclo:5.4.0'J undec-
7ene (DBU), 1 4-diazabidichloro 22.2
] Octane (DABCO) and other organic bases are exemplified, 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℃ to 3
Proceeds smoothly at 0°C.

The next cleavage of the 1,3-dioxolane ring is carried out under acidic conditions by a known method (ProtectiveGro
ups in Organic 5ynthesis+
” John Wiley & 5ons, New Y
ork, 198L pp124 128. ), preferably in a 60-90% acetic acid aqueous solution by heating from 60°C to 100°C. Represented by the general formula (Xn) (4S,
5R)-4-cyclohexylmethyl-5-((Ril-
The preparation of hydroxyethyltheoxazolidin-2-one derivatives is carried out using a base in a solvent. Examples of the base used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, pyridine, and
(NN-dimethylamino)pyridine, 1.8 diazabicyclo f5. 4. 0] Undeku-7=en (DBU
), 1 4-diazavinchro(2,22]octane (D
Organic bases such as ABCO) are exemplified, but preferably,
Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide are used. Any solvent can be used as long as it does not participate in the reaction, but alcoholic solvents such as methanol, ethanol, propatool, isopropanol, and butanol are preferably used. Intramolecular ring closure reaction is 0
It progresses smoothly between ℃ and 50℃.

[Fourth step] This step is represented by the -wire formula (XIII) (4S5R
)-4-cyclohexylmethyl-5-1: (R) 1-sulfonyloxyethyl gooxazolidin-2-one derivative is produced. The sulfonylation rules used in this step include methanesulfonyl chloride, methanesulfonyl bromide, methanesulfonyl iodide, ethanesulfonyl chloride, propanesulfonyl chloride, trifluoromethanesulfonyl chloride, heynesulfonyl chloride, heynesulfonyl bromide, and heynesulfonyl chloride. p-Toluenesulfonyl, p-bromide
Examples include sulfonyl halides such as toluenesulfonyl, preferably methanesulfonyl chloride and p chloride.
-Toluenesulfonyl is used. Sulfonylation is carried out in the presence of a base, and the bases used include triethylamine, diisopropylethylamine, pyridine,
Examples include organic bases such as 4-dimethylaminopyridine, 1,8-diazabicyclo[540]undec-7-ene (DBU), and 1,4diazabicyclo(2,2,2)octane (DABCO), but preferably , pyridine is used. The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably halogenated hydrocarbon medium M'4 such as dichloromethane or chloroform, diethyl ether, Ether solvents such as tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are used. In addition, using a large excess of organic base such as pyridine used in the reaction,
It can also be used as a solvent. The reaction takes place from -20°C to 40°C.
Proceeds smoothly at ℃.

[Fifth step] This step is performed using the general formula (X I[l) (4S, 5R
)-4-Cyclohexylmethyl-5-((R) The protecting group for the hydroxyl group on the 5-position substituent of the 1-sulfonyloxyethylgooxazolidin-2-one derivative was removed, and the -linear formula (
(4S5R)-4-cyclohexylmethyl-5-C(R)(2-hydroxy-1-sulfonyloxy)ethyltuoxazolidin-2-one derivative represented by XIV) is produced. Removal of the hydroxyl protecting group is carried out by a known method depending on the type of protecting group used.

(llProtective Groups in O
rganic 5ynthesisJohn Wile
y & 5ons, Netn York, 981.
pplo-86,) For example, when the protecting group for the hydroxyl group is a Hensyl group, the Hensyl group can be removed by hydrolysis using palladium hydroxide supported on carbon as a catalyst. In this case, the reaction is carried out under a hydrogen atmosphere of 1 to 5 atmospheres in an alcoholic solvent such as methanol, ethanol, propatool, isopropanol, butanol, etc.
It progresses smoothly between ℃ and 50℃.

[Sixth step] This step is expressed by the -wire equation (XIV) (4S5Ri
A 4-cyclohexylmethyl-5-((R)(2-hydroxy-1-sulfonyloxy)ethylcuoxazolidin-2-one derivative is treated with a base to form a compound of the present invention represented by general formula (n). (43.5R)-4-Cyclohexylmethyl-5-((S)-oxiran-2-yl)oxazolidin-2-one derivative is produced.The base used is lithium hydroxide, sodium hydroxide. , alkali metal hydroxides such as potassium hydroxide, alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride, sodium amide,
Alkali metal amides such as potassium amide, alkali metal alkoxides such as lithium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide, potassium butoxide, lithium benzyl oxide, sodium hensyl oxide, etc. are exemplified, but alkali metal alkoxides are preferably used, and sodium methoxide is more preferably used. The base has the general formula (XrV)
(435R)-4-cyclohexylmethyl-
It is used in an amount of 1 to 10 equivalents based on the 5-((R)(2-hydroxy-1-sulfonyloxy)ethylcouoxazolidin-2-one derivative.The reaction is carried out in a solvent, and the solvent used is one that is involved in the reaction. Any solvent can be used as long as it does not react, but ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are preferably used.The reaction proceeds smoothly at -20°C to 40°C. do.

[Step 7] This step is represented by the general formula (It) (43.5 R)
4-Cyclohexylmethyl-5-C(S)-oxirane-2-yltuoxazolidin-2-one derivative is reacted with isopropylmagnesium halide represented by -line formula (XV) in the presence of copper (1) iodide. The epoxide ring is opened to form (4S,5R)-4-cyclohexylmethyl-5 represented by the general formula (Ia), which is the compound of the present invention.
-((R)=(1-hydroxy-3-methyl)butylshioxazolidin-2-one derivative is produced.The isopropylmagnesium halide represented by the -line formula (XV) is isopropylmagnesium chloride. , isopropylmagnesium bromide, and isopropylmagnesium iodide, but isopropylmagnesium chloride is preferably used.
) iodination of catalytic amount of isopropylmagnesium halide in a solvent! After reacting with i[1'l at -30°C to 50°C for 1 minute to 1 hour, the resulting reaction solution contains (4S, 5R)-4-cyclohexylmethyl-5- represented by general formula (n). ((S)-Oxiran-2yl]-oxazolidin-2-one derivative is added. The reaction proceeds with high stereoselectivity and is represented by the -line formula (Ia) (4S,5R)4 -cyclohexylmethyl-5-((S)(1-hydroxy-3-methyl)
A butylcyoxazolidin-2-one derivative is obtained as a single product. - Isopropylmagnesium halide and copper iodide (1) represented by the linear formula (XV) are -
For the (4S, 5R)-4cyclohexylmethyl-5-((S)-oxirane-2-yltuoxazolidin-2-one derivative represented by the linear formula (n), 1 to
10 equivalents and 0.05 to 0.5 equivalents, more preferably 3 equivalents and 0.15 equivalents, respectively. Isobrobyl magnosium halide and iodide &Pl [I
The ring-opening of the epoxide ring, which is carried out subsequent to the reaction with [] and the anealing, is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but diethyl is preferably used. Ether solvents such as ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane are used singly or as a mixed solvent. The ring-opening reaction of the epoxide ring proceeds smoothly at -30°C to 50°C.

[Eighth step] This step is expressed by the -wire formula (n) (4S, 5R)
-4-cyclohexylmethyl-5-((S)oxiran-2-yldi-oxazolidin-2one derivative is reacted with morpholine to open the epoxide ring, and the compound of the present invention is represented by the general formula (Ib). (4S, 5R) -
A 4-cyclohexylmethyl-5-[(S)-1-hydroxy-2(morpholin-4-yl)ethyltuoxazolidin-2-one derivative is produced.

The reaction is (4S,,5R)4- represented by general formula (II)
Cyclohexylmethyl-5-<(S)-oxirane-
This is carried out using 1 to 5 equivalents, more preferably 2 equivalents of morpholine to the 2-yl:-oxazolidin-2-one derivative. The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but alcohol-based solvents such as methanol, propatool, isopropanol, butanol, and t-butanol are preferable. A solvent is used. The reaction is from -20℃ to 50℃
proceed smoothly.

[Ninth step] This step is performed by (4S5R) − represented by the -wire formula (I a).
4-Cyclohexylmethyl-5-C(S)-(1-hydroxy-3-methyl)butylcyoxazolidine-2-
By removing the protecting group of the amide group present at the 3-position of the on derivative, the compound of the present invention represented by formula (IC) (43
．． 5R)-4cyclohexylmethyl-5-((S)-(
1-Hydroxy-3-methyl)butylcyoxazolidin-2-one derivatives are produced.

Removal of the protecting group for the amide group is carried out by a known method depending on the type of protecting group used.

(Protective Groups in Org.
anic 5ynthesisJohn Wiley
& 5ons, New York, 981 pp.
272275,). For example, when the protecting group for the amide group is a Hensyl group, the (43.5R)-4cyclohexylmethyl- The reaction is carried out by dissolving the 5-'((S)-(1-hydroxy-3-methyl)butylcyoxazolidin-2-one derivative.
Proceeds smoothly at 0°C.

[Step 10] In this step, (43,5R)-4 represented by the general formula (from)
-cyclohexylmethyl-5-((S)-1-hydroxy-2-(morpholin-4-yl)ethyltuoxazolidine derivative) by removing the protecting group of the amide group present at the 3-position of the compound of the present invention. (Id) (43
,5R)-4cyclohexylmethyl-5-((S)-1
-Hydroxy-2-(morpholin-4-yl)ethyl]
This is to produce oxazolidin-2-one.

Removal of the protecting group for the amide group is carried out in exactly the same manner as in the ninth step.

(4S5R)-4-cyclohexylmethyl-5-((S)l-hydroxyethyl)-oxazolidin-2one, which is a compound of the present invention produced by the above synthesis process and is represented by the above-mentioned -linear formula (1). The derivative is synthesized by the above-mentioned -line formula (III), which is a raw material for the production of the peptide-like compound represented by the above-mentioned formula (IV) or (V), which is useful as a therapeutic agent for hypertension due to its human renin inhibitory activity, through the following synthetic steps.
)-2-amino-1- represented by (2S,3R,4S)
Can be efficiently induced into cyclohexyl-6-methyl-3,4-hebutanediol and (2S,3R,4S)-4-amino-5-cyclohexyl-1-(morpholine-4-1l)-23-bentanediol. .

(1c) (ld) -゛・H (I[la) (I[lb)
[Step 11] In this step, the compound of the present invention, (4S, 5R)-4-cyclohexylmethyl-5-(
(S)-(1-hydroxy-3-methyl)butylshioxazolidin-2-one is hydrolyzed to produce (2S, 3R) represented by formula (nla).

4S)-2-Amino-1-cyclohexyl-6-methyl-3,4-hebutanediol is produced.

The hydrolysis is carried out under acidic conditions, preferably with the formula (l c
)-4-cyclohexylmethyl-5-((S)-(1-hydroxy-3-methyl)butylshioxazolidin-2one represented by ) in 10-37% hydrochloric acid from 50°C to 120°C. This is done by adding .

10-37% hydrochloric acid: Y, represented by formula (lc) (43.
5R)-4-cyclohexylmethyl-5-((S)-(
1-Hydroxy-3-methyl)butyl:-oxazolidine-2one 5 to 20 times per 100 mg are used. After hydrolysis, if the reaction solution is condensed to dryness with QQ,
(2S, 3R, 4S)-2amino-1-cyclohexylmethyl-6-methyl3.4-
Heptanediol is obtained as the hydrochloride salt.

[Step 12] In this step, (43.5R)-4-cyclohexylmethyl-5-(
Hydrolyzing (S)-(1-hydroxy-2(morpholin-4-yl)ethylgooxazolidin-2-one,
(2S, 3R, 4S)-4- represented by formula (IIIb)
Amino-5-cyclohexyl-1-(morpholine-4-
yl) 2,3-bentanediol is produced.

Hydrolysis is carried out under acidic conditions in exactly the same way as in the 11th step. If the reaction solution is condensed to dryness 4 times, it will be expressed as nib (
2S, 3R, 4S)-4-amino-5cyclohexyl-
1-(morpholin-4-yl)2,3-pencunediol is obtained as the dihydrochloride.

The present invention will be described in detail below with reference to Examples and Reference Examples, but the present invention is not limited thereto. In addition, in the reference examples and examples, the following abbreviations are used.

Bn: Henzyl group Boc: t-butoxycarbonyl group Reference Example I Oxalyl chloride (1.4 ml 1.16.1 mmol) was dissolved in dichloromethane 97 (34 ml), and dimethyl sulfoxide (2.3 ml 1.32.4 mmol) was dissolved at -78°C. )
A dichloromethane solution (6 ml) was added and stirred for 10 minutes. Subsequently, the method described in the literature (J, Med, Ch
em, 7.14 (1964).

and Chemistry Letters+ 198
2+ 929. 4- synthesized from 7 (23,35)-tartaric acid according to ).

Hensyl-2,3-〇-isopropylidene-D threitol ([α 0-7.96 (C=0.91.chloroform)) (1.99g, 7.89mmol)
A dichloromethane solution (7s+1) of
mmol) and further stirred for 1 hour. The temperature was gradually raised, and when it reached 0°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 acid maggot, it was concentrated under reduced pressure, and the residue was distilled on a Kugelrohr to give 4-0-hensyl-2,3-0-isoprepylidene-D-threos as a pale yellow oil ( 1,79g,
91%).

HNMR (CDC13) δ: 1.40.1.47 (6
ft, sx2. CLX2), 3.50 3.77(2
)1. m, cHzO), 4.07 4.39 (211,
m, CHCH), 4.59 (2H, s, C) IzPh
), 7.31(5H5,C6)1s), 9.72(
IH, brs, CHO).

Reference example 2 4-0-hensyl-2,3-0-isopropylidene-D
-Threose (505 mg, 2.02 mmol) was dissolved in toluene (10 ml), and hensylamine (
2.06 mmol) and anhydrous magnesium sulfate (602 mg, 5.00 mmol) were added and stirred for 1.5 hours.

After heating to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude (4R
,5R) -4-((N-hensyl)iminomethyl]-
5-benzyloxymethyl-2,2dimethyl-1,3-
Dioxolane was obtained as a pale yellow oil (701 mg, quantitative yield). This product was immediately used in the next reaction step.

'H-N? 1R (CDC13) δ: 1.44 (6H,
sx2. CL×2) 3.49-3.73 (2H, m,
CH20), 4.12-4.45(2)1+e, CI
CFI), 4.45 4.81 (4H,m,cl(zP
hX2) 7.10 7.37 (10H, n, CJsX2
)7.79 (IH,brd,J=5Hz,C11=N)
.

Reference example 3 Cerium chloride heptahydrate (4,00g, 10.7001
) was prepared by heating cerium chloride under reduced pressure at 130 to 140°C for 5 hours.
0 ml), 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, 10.11I11.10.1 mmol) was added and stirred for 30 minutes.

The crude (4R,5R)-4-(
(N-benzyl)iminomethyl-5-hensyloxymethyl-2,2-dimethyl-1,3-dioxolane (7
A tetrahydrofuran solution (10 ml) of 011I (1 g, 2.02 mmol) was added dropwise. After stirring for 2 hours, the temperature was gradually raised, and the mixture was further stirred at room temperature for 12 hours. The reaction solution was poured into saturated sodium bicarbonate 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 1
00: 1-501) and purified with (4R,5R)-4
-C(S)1-hensylamino-2-cyclohexylethyl]-5-hensyloxymethyl-2,2-dimethyl-1,3-dioxolane in colorless oil (660 mg,
75% (from 4-○-hensyl-2.3-0-isopropylidene-D-threose)).

[α]! '+12.3' (C=1.22.
1l:l hozrem) H-N? IIl (CDC13)δ
:0.77-1.73 (13H, m, CJllCHHz)
1.40, 1.42 (6H, sX2.CIIzX2),
2.66 2.74 (IH, m, BnNCH) 3.
56 (IH, dd, J=10.3, 5.5) 1zone
proton of CLO), 3.57(])
l, dd, J=10.3°4.4Hz, one p
roton of CHZO) + 3.75(1)1
+dJ=13.1Hz, one proton of
NCI (zPh), 3.85 (IH, (1, J=13.
11 (Z, one proton of NCFL
, Ph) 3.88 (LH, dd, J=7.9.4.0H
z, CHCHCHJ) 4.24 (lit, ddd,
J・7.94.56 (2H, s, 0CH2Ph) C, II, x 2).

IR (neat): 2930.2870cm MS (m/
z):438(CM+1]') High resolution MS: C2B)1411NO3(CM+1)"
Calculated value: 438.3005 Measured value: 438.2987 5.5, 4.4Hz, CHC) fcFlzo) 7.19
Reference example 4 CO2 e O2Me (4R,5R)-4-((S)-1-benzylamino-
2-Cyclohexylmethyl-5-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (262
mg, 0.598m5o1. ) was dissolved in tetrahydrofuran (6.5 ml) and water-cooled with potassium carbonate (435 ml).
+*g, 3.15mmol) and methoxycarbonyl chloride (methyl chloroformate) (0.24ml1.3.llm
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 subjected to column chromatography (
Purified with silica gel, toluene-ethyl acetate 100; l), (4R,5R)-4C(S)-1-(N-hensyl-N-methoxycarbonyl)amino-2-cyclohexylethyl]5-benzyloxymethyl -22-dimethyl 1,3-dioxolane in colorless oil (288+g97
%) was obtained.

[αI4.9'(C=1.05.Chloroform)'HNMR (CDC13) δ:0.40-2.10
(13H, sheath, C0tCHs).

1.38 (6H, SX2.CI (3X2), 3.69
(311,s,C0tCL)4.61C4H,s,CH
zPhX2>= 3.46 4.50 (5H, m.

NCHCHCHCHHzO), 7.27(5H,S,C
6H3), 7.33 (5H,s, C61(S).

IR(neat): 2950 2B75 1690
cm-'MS (m/z): 495 (M"),
480.437.274(4R,5R)-4-((S)
-1-(N-benzyl-N-methoxycarbonyl)amino-2-cyclohexylethyl]-5-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (2
42 mg, 0.487 mmol) was dissolved in 80% acetic acid aqueous solution (12 ml), heated and stirred at 80°C for 5 hours, and then concentrated under reduced pressure to obtain crude (2R,3R,43)-4-(N
Hensyl-N-methoxycarbonyl)amino-1 hensyloxy-5-cyclohexyl-2,3bentanediol was obtained. This product was immediately used in the next reaction step.

'HNMR (CDC13) δ: 0.45 1.90 (1
38,m, CaH++CHz) 3.73(3H,s,C
0tCHs), 7.27 (51,s, CJs) 7.3
2 (5H, s, Ca1ls).

Crude (2R,3R,43)-4-(N-benzyl-N
-methoxycarbonyl)amino-1-benzyloxy-
10 5-cyclohexyl-2,3-bentanediol
% aqueous potassium solution dissolved in 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 10:1), (4S, 5R)
-3-hensyl-4-7 clohequinylmethyl-5-C
(R)-(2-hensyloxy-1-hydroxy)ethyldi-oxazolidin-2one in colorless oil (189 g
, 92% (2 steps)).

[αview'-29.7° (C=1.25.Chloroform).

'H-NMR (CDC13) δ: 0.67 1.70 (
13H, m, CJ++CHz) 2.33 (IH, brs
, OH), 3.53 (IH, dd, J=9.6, 7.
3Hz, one proton of C! ho),
3.58(1)1. dd J=9.635.1Hz+
One proton of CHtO) + 3.6
43.75 (2H4, Ndan1 (CHCdanCHzO),
4.09 (IH, d, J=15.3)+2. one
proton of NC)lzPh)+4.20(
1)1. dd, J□5.0, 2.8Hz, CHCI(C
HtO), 4.52 (2H.

s, 0 CHzPh), 4.79 (IH, J=15.3
Hz, one protonof NCH*Ph),
7.24-7.38 (10H, at, C, Flsx2)
.

IR(neat): 3300.2940 2875
1735C@MS (m/z): 423 (M
”), 332.302 284° high resolution MS:
Calculate as CzbHsco NO4 (M') Directly: 42
3,2407 Measured value 423.2431 Reference example 5 (43,5R)-3-hensyl-4-cyclohexylmethyl-5-((R)-(2-hensyloxy-1-hydroxy)ethylcouoxazolidin-2-one ( 306
+sg, 0.723 mmol) in pyridine (25o1
) and cooled with water to dissolve methanesulfonyl chloride (70μm
, 0.904 m*ol) and stirred at the same temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was subjected to column chromatography (silica gel; hexane-ethyl acetate 4:1-3:
2) to obtain (43,5R)-3-benzyl-4-
Cyclohexylmethyl-5-((R)-(2-benzyloxy-1-methanesulfonyloxy)ethylcouoxazolidin-2-one was dissolved in colorless oil (347sg96%).
) was obtained.

'H-N gate R (CDCh) δ: 0.7-1.7 (131-1, m, C, 11,,
CL), 2.87(3)1. sSO2Me) 3.6
5 (28, m, C) IN, one proton of
CtlzOBn), 3.70 (LH, dd, J=4.
9,10.6tlz, oneproton of C
1 (20Bn), 4.12 (IH, d, J = 15.1
)1zone proton of NCI(zPh)
, 4.38(LH, dd, J=4.0X21(z,
CHOCo 4.47(II(,d,J=11.7f
tzone proton of CHzPh), 4
．． 52 (18, dj=11.7Hz, one pro
ton of CH2Ph), 4.68 (IH, mC
HO5O□Me), 4.71 (IH, d, J=15.
1tlz oneproton of NCHzPh)
, 7.24-7.38 (10tl, maromati
c protons) IR (neat): 3050.2950.2B75.
1760.1180922, 702c closed-1 MS (m/z): 501 (M'), 410 ([M
-Bnl), 404 Reference Example 6 (4S,5R)-3-hensyl-4-cyclohexylmethyl-5-C(R)-(2-hensyloxy-1-methanesulfonyloxy)ethyldioxazolidin-2-one (645 mg , 1.29n+mol) was dissolved in methanol (5ml) and 20% palladium hydroxide-carbon (
80 mg) was added thereto, and the mixture was stirred for 2 days under room salt under a hydrogen atmosphere of 1 atm. After filtering off the catalyst, the solvent was concentrated under reduced pressure to obtain (43
,5R)-3-hensyl-4-cyclohexylmethyl-
5-C(R)-(2hensyloxy-1-methanesulfonyloxy)ethylcouoxazolidin-2-one was obtained as a colorless oil (517++ g, 98%).

) 1-N gate R (CDCIi) δ: 0.7-1.7 (13H, m, CbH,, CHz>
, 2.34 (IHtJ=5.DH2,0)1), 2
．． 87(3)1. s, 5OJe), 3.66CIHm
, cHNBn), 3.84(2H,m,cLo)l)
, 4.09 (lH, dJ=14.9Hz, one p
roton of NCHzPh), 4.40 (1f
t, dd, J=3.4, 4.5Hz, CHOC=O),
4.60 (iftddd, J=3.4.4.7,6
．． 3Hz, C)IO3OzMe], 4.75(11
d, J=15.011z, one proton
of NCH, Ph), 7.3-7.4 (511
, m, aromatic protons) IR(ne
at): 3200-3700 br, 2945 2
855 17401442.1175,915.702
cm: 41HM'), 314(CM-C61(+I
C) 1g)”).

218.91 Phylum S (n/z) Example 1 (4S,5R)-3-hensyl-4-cyclohexylmethyl-5-((R)-(2-hensyloxy-1-methanesulfonyloxy)ethyldioxazolidine- 2-one (515++ g, 1.25 mmol) was dissolved in tetrahydrofuran (10 ml), and sodium methoxide (560 mg, 10.4 mmol) was added under water cooling.
Ix and stirred at the same temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed successively with 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; hexane-ethyl acetate 19:1-43:1).
, S R) -3-hensyl-4cyclohexylmethyl-5-((S)-oxiran-2-ylcyoxazolidin-2-one) as a colorless oil (370 mg, 94%)
obtained as.

"α]!'-7.64' (C=0.706.C
HCl,)H-NMfl(CDCh) δ:0.7-1.7(131(,Sho,C,l(,,C
)1m), 2.68 (ILddJ=2.5+4.7
Hz, one proton of CI+20)+
2.84 (IH, dd, J=4.0.4.7Hz, o
ne proton of C11zO) 2.94 (1
1 (, ddd, J Mi 2.5, 4.0, 6.1Hz, CI
(OCL) 3.50(1)1 ddd, J=3.9,4
．． 29.8Hz, Ct (NBn) 3.84 (IH, dd
, J=4.2.6.11 (z, CHOC=0), 4
．． 05 (IH, d, J=15.2Hz, one pro
ton of NCLPh) 4.83 (IH+d+J=
15.2Hz, one proton of NCHtP
h), 7.25 to 7.83 (5H, m, aromati
cprotons) TR (neat): 2950.2B55,1760
．． 1422, 1240°702c wheel: 315 (M”), 218 (CM-C, 1lllC
1").

MS (m/z) Example 2 (43,5R) -3-hensyl-4-cyclohexylmethyl-5-((S)-oxirane-2yl)-oxazolidin-2-one (70,5mg0.224-so o1
) was dissolved in methanol (1.5 ml), morpholine (40 μ+, 0.459 nmol) was added at room temperature, and the mixture was stirred at the same temperature for 1 day. The reaction solution was diluted with ethyl acetate, washed successively with 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; hexane-ethyl acetate 1 nia) to give (43,5R)-3-hensyl-4
-Cyclohexylmethyl-5-((S)-1-hydroxy-2-(morpholin-4-yl)ethylcouoxazolidin-2-one in colorless caramel (84,4B, 94
%).

[α:E'55.2' (C=0.782.
CHClz) 11-11MR (CDC11) δ: 0.7-1.7 (1311, m, C6H11CH2
), 2.34 (tH, ddJ=10.0, 12.51
1z, one proton of CH,N O)2
．． 39 (2H, I! I, two protons of
NC) 12 CH20) 2.55 (IH, dd, J=
3.5.12.5Hz, one proton of C
LL N O) 2.58 (2H, w+, two protons of
NCjjlCHzO)3.53(LH,ddd,J=
3.5, 7.2, 10.0Hz, CHOH) 3.59 (
18,m, CI(NBn), 3.68(4H,m,C
H2QC)lx)3.96(IH,ddj=3.6,7
．． 2Hz, C)lOc=o), 4.05(l)l,d
+J=15.1Hz, one proton of
NC) IzPh) 4.81 (IH, d, J=15.1!
(z, One proton of NCHlPh)
, 7.26-7.38 (5N, m, aromatic
protons) IR (neat): 3200~3700br, 29
48.2855.1755°1442.1120.70
2cm-' MS (#l/2): 401 ((M1)'')
+340.258. 100 ((=N O) ”) Example 3 Metallic sodium (approximately 50 mg
) and further stirred at 78°C to (4S, 5R) 3-benzyl-4-cyclohexylmethyl-5((S)-1-hydroxy-2-(morpholin-4-yl)ethylcouoxazolidin-2-one (84 ,4B, 0.210m5o
An ether solution of 1) was added and the mixture was refluxed for 2 hours. After adding ammonium chloride to the reaction solution, ammonia was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.

The residue obtained by concentration under reduced pressure was subjected to column chromatography (silica gel; hexane-ethyl acetate 1:4-ethyl acetate).
to give (4S,5R)-4-cyclohexylmethyl-5-((S)-1-hydroxy-2-(morpholin-4-yl)ethyl)oxazolidin-2-one as colorless crystals (50.8m878 %).This material was recrystallized from ethyl acetate to obtain an analytical sample.

Sheath p, 173-174℃ [α]! '79.8' (C=0.694.
(JIC1+)' H-NMR (CDCl s) δ: 0.8 to 1.8 (13H, m, cJ,, CHz),
2.39(1)1. ddJ=9.9.12.611z
, one proton of C4-N O)2.4
6(2)1. m, two protons of NC
HzCHzO) 2.66 (IHdd, J=3.6,12
．． 6Hz, one proton of NCHCH20
>, 3.71 (4H, Cabinet, CHzOCHz), 3.
79(11(ddd, J=3.6,7.1,9.9Hz
, Cdan OH), 3.92 (IH, m.

CHNH), 3.97 (LH, dd, J=4.7,
7.1 Hz, CHOC=O).

5.54(IH,br Ntl>IR(CHCh): 2940,2B55.174
0. 1118. 109109O'MS(+m/z)
: 313 (CM + 1) ”), 1
30. 100 elemental analysis: C+JtsN*Oa ・0
．． 2) Calculated as 1zO (!: C, 60, 81;)
1,9.06; N, 8.87% analysis value F C, 60
,89; l(,9,09,N, 8.72% Reference Example 7 (4S,5R)-4-cyclohexylmethyl 5-(
(S) -1-hydroxy-2- (morpholine-4-
yl)ethyl]-oxazolidine-2one (37.2m
g, 0.119 mmol) in 37% hydrochloric acid (3 tl) L
This was dissolved and heated under reflux at 100°C for 3 days. The solvent was concentrated under reduced pressure to obtain (2S.3R,4S)-4-amino-5-cyclohexyl-1-(morpholin-4yl)-2.3-bentanediol 2 hydrochloride in a colorless caramel (48.4B).
, quantitative yield).

1H-Nj (DgO) δ: 0.7-1.7 (13H, m.CII+.clIt
), 3.10 (211, + two protons
of NCHzCHtO)+3.18(It(,d
d+J=10.5+13.5Hz, one proto
n of C) 12 N O) 3, 22 (1) 1, dd
, J=2.843.5Hz, one proton o
fCjil N O), 3.46 (3H+w+, Ct
lNH. two protonsof NChCHzO
), 3.56(If(, dd.J・2.6.7.0)l
zC)IOH-C)IOH:1. 3.75 (2tl
, m, two proton. s of CH20CHHz
) + 3.98 (2H, m.two protons
ofCHgOCHz), 4.06(IH.ddd
, J=2.8,7.0.10.5HzC and OHCH2) 'C NMR (DzO) 28, 27. 2B. 31, 28.65. 3
5.17, 35.2535, 63. 39.80
, 51.93. 53.80. 56.246
2, 13, 66, 28, 67, 98, 72
．． 99MS (SIMS) 287 ((M +
1-28Cl)'')+200 For the purpose of further structural confirmation, this was dissolved in pyridine (0.3 tl), and acetic anhydride (0.1 tl) and a catalytic amount of dimethylaminopyridine were added.6. The mixture was stirred for 5 hours.The solvent was concentrated under reduced pressure, and the resulting residue was subjected to column chromatography (silica gel: ethyl acetate-chloroform-methanol 10:1).
) to give (2S,3R.4S)-4-acetylamino-5cyclohexyl-2,3-diacetoxy-1 (
Morpholin-4-yl)-pentane in pale yellow caramel (
48.5mg. 99% (2 steps).

;α]6°-48.7° (C =0.986, CH
Ch) 11 NMR (CDC13) δ: 0.8-1.8 (138.m, CJ++C)1z)
11.96 (31(, s.

Ac), 2.05 (311.s, Ac), 2.10
(31(,s,Ac)2, 10(3H,s.Ac),
2.46 (IH.dd.J=6.5.13.2HzC)
lJcHz), 2.60 (IH, ild.J=5.
8,13.2tlz,oneproton of CH
z-N O), 3.65 (48, t, J=4.6Hz
CH20C)12), 4.52(+, 餉.CI(N
) lAc), 5.11 (IHddj=3.2, 6.
0Hz, CHOAc) + 5.15 (IH, dddJ
=5.8 6.0 6.5)1z,CHOAc),
5.34(l)1. d.

J=10.1Hz. Nl() IR(CHCh): 2940, 2860, 1740
, 1680. 13721116cm-' MS (m/z): 413 (CM + 1)
'), 369, 293. 184 Example 4 Iodide w4 (7 mg. 0.037ffia+ol
) was suspended in ether (2 ml) and diluted with isopropylmagnesium chloride-ether solution (1M solution,
After adding 0.7 tl, 0.7 mv Aol) and stirring at the same temperature for 10 minutes, (4S5R1-3-benzyl-
4-Cyclohexylmethyl-5-C(S)-oxiran-2-yl)-oxazolidin-2-one (73.4m
0.233 mmol of ether solution was added thereto, and the mixture was stirred at the same temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel; hexane ether 2:1) to give (4S,5R)3-benzyl-4-cyclohexylmethyl-5- ((S)-(
1-Hydroxy-3-methyl)butyltuoxazolidin-2-one in colorless caramel (51.8 mg, 62%
) was obtained.

[αSee'-35,0''' (c=0.982.C)
ICh))I NMR (CDCI*) δ: 0.84 (3H, d, J・6.6Hz, CH3)
, 0.9H3)1. dJ=6.7H2,CH3),
0.7-1.7 (16H, m, CaHzCflzCHz
CH(CHa)z), 350(IH,m, CHNBn
), 3.67 (ltlm, (JIOH), 4.03
(Ill, dd, J=4.2HzX2.CtlOC=
O) 4.07 (IH, d, J=15.2Hz, NBn)
, 4.80 (ILdJ=15.2Hz, NBn),
7.24-7.38 (58, maro+natic p
rotons)IR(C)IcIs): 2940.2
850.1740.14421092cXie-1 MS (m/z): 359 (M”), 262.17
6,91 Example 5 Metallic sodium (approximately 50 mg
) was added, and (4S, 5R)3- was further heated at -78°C.
Hensyl-4-cyclohexylmethyl-5C(S)-(
An ether solution of 1-hydroxy-3-methyl)butylcyoxazolidin-2-one (118 mg, 0.328 Bol) was added and the mixture was refluxed for 2 hours.

After adding ammonium chloride to the reaction solution, ammonia was distilled off, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and anhydrous.

Dry with magnesium. The residue obtained by concentration under reduced pressure was purified by column chromatography (silica gel; hexane-ethyl acetate 4:1 → 3:2) to obtain (4S,5R)-
4-Cyclohexylmethyl-5((S)-(1-hydroxy-3-methyl)butylcyoxazolidin-2-one was obtained as colorless crystals (44.9 mg, 51%).

This product was recrystallized from ethyl acetate to obtain an analytical sample.

Shore, 162.0-162.5℃ [α viewing 0-81.2@(C=0.739.CHCh)
11-NMR (CDCl2) δ: 0.93 (3) 1. d, J==6.6Hz, CH
a), 0.97 (3H, dJ = 6.7) 1z, CH
3), 0.8-1.9 (16H, m, C-tlzcH
zChCH(CHs)z), 2.40(IH,br,
0)l), 3.92 (2Hm CHNH,CHOH)
, 4.02(1)1. dd, J=3. 'l, 5.4H
zCHOC=0), 5.45(18,br,NH)I
R (CJICh): 2940.2855.175B,
1092c part MS (lIl/z): 270 (CM
+ 1) "").

251 (CM-11!O)'''), 212.122
．． 86 elemental analysis: C+5HtJOz・0. Calculated value as lHg0: C, 66,44; H, 10,11;
N, 5.16% analysis value; C, 66,51; )[,10
, 10; N, 5.12% Reference Example 8 (4S, 5R)-4-cyclohexylmethyl 5- ((
S)-1-hydroxy-3-methyl)butyl]-oxazzuridin-2-one (42.8mg0, 159mmol
) was dissolved in 37% hydrochloric acid (4 ml) and heated under reflux at 100°C overnight. The solvent was concentrated under reduced pressure to obtain (2S 3R,4
S)-2-amino-1-cyclohexyl-6-methyl-
Add 3,4-hebutanediol hydrochloride to colorless caramel (47
, 0 mg, quantitative yield).

HNMR (020) δ: 0.85 (3H, d, J = 6.6t (z, cHs)
, 0.89 (3tl, dJ=6.7Hz CHs>,
0.8-1.8 (16H, II, C41'1.ICH
2CHzCH(Clt3)t), 3.56(20,
11,CHOH,C)lNH2)3.82(11,m,
MS (SIMS): 244 (CM+1-HCl3
”) + 126.55 For the purpose of further structural confirmation, this product was dissolved in chloroform (l ml) and diluted with
er t-butyludicarbonate (70.0mg,
0.321 mmol) and triethylamine (67p
I, 0.481+nmol) and stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate.

The residue obtained by concentration under reduced pressure was subjected to column chromatography (
(2S3RAS)-2-(tert-butyloxycarbonyl)amino-1-cyclohexyl-6-
Methyl 3,4-bentanediol as colorless crystals (45,9
+ng84%, 2 steps). This product was recrystallized from cyclohexane to obtain an analytical sample.

mp: 134-135°C [Literature value: mp 130-131°C, (J, Or
g, Chem.

53, 6109 (1988), )) [αkoot”67.4 ° (C=1.17.CII
Ch) [Literature value: Lα]P-64,91' (C
=2.20. CHCl3) (J, Org, Chem;
, 53.6109 (19gg) , ) ]NH
NMR (CDCl2) δ: 0.8-1.5 (15H, m, C-) 111CHz
, CHzCH(C)lz)z)0.89(3H,d,J
=6.6)1z, Cf13), 0.95(3)1.
dJ=6.7Hz, CHz), 1.45(9H,s,
tBu), 1.94(IHll, CI((CH3)
Z), 3.20(1)1. m), 3.33(lH,
mCHOHC)INW), 4.04(1)1. Theory, C
HII)l), 4.16(II(,dJ=4.3H
z, 0) I), 4.54 (III, d, J=9.0t
lz, NH) This 'H-NMR spectrum is based on the literature (J,
Org, Chem, 536109 (1988), )
I was completely defeated by the one described.

'H-N? lR(CD3CN) δ: 0.85(3)1. d, J=6.6) 1z, CH
s), 0.92(3)1. d.

J=6.7Hz), 1.42(9)1. s, tBu)
, 0.8-1.95 (168, m, CthH++CL
, CHiC)l(C)Is)z), 2.80(IHb
r, OH), 3.01 (IH, brd, J=8.3H
z, CHO) IcHN■) 3.22 (1B, brt, J
=9.2Hz, CHOHCFlt), 3.90(IH
m, CHNI(), 3.98(LH,br,OH),
5.20(II(,brd.

J=9.1Hz, Nu) IR (CHCIs): 3450.2940.1680
．． 15021160c+@-? ! 5(lI/z): 344(CM+1'J
'), 288.266, 5T Procedures Master's Authorization (Spontaneous) June 11, 1991

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents a hydrogen atom or a protecting group for an amide group, and R^2 represents an isopropyl group or a morpholin-4-yl group. )-(4S,5R)-4-cyclohexylmethyl-5-[(S)-1-hydroxyethyl]-oxazolidin-2-one derivative. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^3 represents a protecting group for the amide group.) (4S,5R)-4-cyclohexylmethyl-5-[
(S)-Oxiran-2-yl]-oxazolidine-2
-one derivative.