JPH09216856A - Amino alcohol derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amino alcohol derivative having activity on stimulating or controlling the biosynthesis of a glycolipid, antitumor activity, and activities suppressing cancer metastasis and stimulating the growth of neurocyte, and useful as a synthetic intermediate of a PDMT analog. SOLUTION: A 2-acylaminoalcohol expressed by formula I (the mark *indicates an asymmetric carbon; R<1> is an alkyl, a cycloalkyl, etc.; R<2> is a group of formula II, etc.; R<11> is a 3-18C alkyl or alkenyl), e.g. (1S,2S)-2- benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester. A compound of formula I is obtained by reacting an aminopropanol derivative expressed by formula III (P<1> is an alkyl or an amino-protecting group; Y is a leaving group) with an amine, removing the P<1> group from the reaction product to obtain an amino alcohol derivative and further reacting the amino alcohol derivative with carboxylic acid or its reactive derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 2-acylaminoalcohol derivative having an action of promoting or inhibiting the biosynthesis of glycolipids and an action of antivirus, antitumor, cancer metastasis and nerve cell growth. The present invention relates to a novel amino alcohol derivative useful for producing the derivative.

[0002]

BACKGROUND OF THE INVENTION 2-decanoylamino-3-morpholino-1-phenyl-1-propanol represented by the following formula, which is a 2-acylaminoalcohol derivative (hereinafter referred to as PDMP
Is abbreviated. )

[0003]

Embedded image

Has a glycolipid biosynthesis control activity, but the activity is greatly different among the four types of stereoisomers.
Therefore, the separation of the optically active isomers was performed by condensing decanoylaminoacetophenone with morpholine by the Mannich reaction and then reducing with sodium borohydride to obtain PDMP as a mixture of four stereoisomers, followed by crystallization. The diastereomer is resolved by the method and the racemate is optically resolved by the crystallization method (J. L.
ipid. Res., 28, 565-571, 1987 and Advancesin Lipid
Research, 26, 183-213, 1993).

[0005]

DISCLOSURE OF THE INVENTION The present invention aims to provide a method for highly efficiently obtaining optically active isomers of PDMP having a plurality of asymmetric centers and its analogs from a chiral compound as a raw material. It is intended to provide a stereoselective synthetic method which does not require a complicated optical resolution step. Another object of the present invention is to provide a novel amino alcohol derivative useful for the production of PDMP and its analogs.

The inventors of the present application have conducted research to develop a more convenient and general stereoselective method for producing PDMP and its analogs, and as a result, have two asymmetric centers in the molecule in advance. , N-protection in which the amino group is protected by a urethane-type protecting group, which is inexpensively supplied as a reagent for peptide synthesis.
By using 2-aminopropanediol as the main starting material and an asymmetric source, and establishing a synthetic route consisting of reactions that proceed with steric retention, PDMP or all of its analogs can be stereoselectively stereoselectively produced. The present invention has been completed by finding that it can be synthesized and confirming a novel amino alcohol derivative as an intermediate in the synthetic route.

That is, the gist of the present invention is as follows. General formula (1)

Embedded image Y—CH ₂ —C ^* H (NHP ¹ ) —C ^* H (OH) —R ¹ (1) (wherein ^* represents an asymmetric carbon, P ¹ is an alkyl group or An amino propanol derivative represented by R ² H (in the formula, R ² is an amino protecting group, R ¹ is an alkyl group, a cycloalkyl group or an aryl group, and Y is a leaving group).
Is a group represented by the following formulas (I) to (VI). ) Is reacted with an amine represented by the general formula (2)

Embedded image R ² —CH ₂ —C ^* H (NHP ¹ ) —C ^* H (OH) —R ¹ (2) (wherein P ¹ , R ¹ and R ² have the same meanings as described above) in the amino alcohol derivative synthesis shown, the desorbed the P ¹ from the compound of the general formula (3)

Embedded image R ² —CH ₂ —C ^* H (NH ₂ ) —C ^* H (OH) —R ¹ ... (3) (in the formula, R ¹ and R ² are as defined above). An amino alcohol derivative was synthesized, and then R ¹¹ COOH (wherein R ¹¹ has 3 to 18 carbon atoms which may have a hydroxyl group).
Represents an alkyl group or an alkenyl group. ) Is reacted with a carboxylic acid represented by

Embedded image R ² —CH ₂ —C ^* H (NHCOR ¹¹ ) —C ^* H (OH) —R ¹ ... (4) (wherein R ¹ , R ² and R ¹¹ are as defined above) A method for producing a 2-acylaminoalcohol derivative comprising obtaining a 2-acylaminoalcohol derivative represented by

[0008]

Embedded image

[Wherein R ³ and R ⁴ are the same or different,
A hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy lower alkyl group, a lower alkoxyalkyl group, an amino lower alkyl group, a cycloalkyl group, a hydroxycycloalkyl group, an aralkyl group or a piperazino group which may be substituted with a lower alkyl group. the stands, R ⁵ is a hydrogen atom, hydroxy group, lower alkyl group, a lower alkoxy group, a hydroxy-lower alkyl group, a carboxyl group, lower alkoxycarbonyl group, an aralkyl group, a piperidino group, an acyloxy group, an amino group and an amino-lower alkyl group 1 or 2 or more same or different substituents selected, R ⁶ represents a hydrogen atom or 1 or 2 or more same or different substituents same as R ^5, and R ⁷ may be interrupted by oxygen. represents a lower alkylene group, R ⁸ and R ⁹ are the same or different, a hydrogen atom, lower Or represents an alkyl group or a hydroxy lower alkyl group, or R ⁸ and R ⁹ represents a lower alkyl group which may be substituted piperidino group or a morpholino group together with the nitrogen atom to which they are attached, m is 2
Represents an integer of 6, p represents 2 or 3, and X represents the following formula (VI
Represents I) or (VIII).

[0010]

Embedded image

(Wherein R ¹⁰ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxycarbonyl group or a pyridyl group)] and an aminoalcohol represented by the general formula (2) described in claim 5. Derivatives and claim 1
1 relates to the aminoalcohol derivative represented by the general formula (3).

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
PDMP and its analogs, which have been found as biosynthesis regulators for glycolipids, are an interesting group of compounds having other physiological actions such as antivirus, antitumor, cancer metastasis suppression, and nerve cell growth promoting action. Structurally, they have 2-aminoalcohol as a basic skeleton and have at least two asymmetric carbons in the molecule, but the four stereoisomers resulting from them have different actions, so that PDMP and its analogs have In order to study the relationship between structure and activity and to develop highly active analogs, it was essential to develop a method for stereoselectively synthesizing these four isomers.

As described above, one of the present inventions uses, as a main starting material, a 2-aminopropanediol derivative having two asymmetric carbon atoms in the molecule and an amino group protected with a urethane type protecting group. The present invention relates to a method for stereoselectively synthesizing four stereoisomers of PDMP analogs, which is based on the following new findings. 1) Use a chiral compound having two asymmetric carbon atoms in the molecule as a starting material. 2) Introduce a leaving group (mesyl group, etc.) into only the primary hydroxyl group from the primary and secondary hydroxyl groups. After that, the mesyl group was replaced with a primary or secondary amine, and 3) all reaction steps were constituted by steric retention, thereby enabling stereoselective synthesis of PDMP.

The present invention will be described below according to the synthetic route shown in FIG. In the present invention, "lower" means that the carbon number is 1 to 6. In the method of the present invention,
The optically active aminopropanol derivative represented by the general formula (1) is used as a starting material. In the formula, R ¹ represents an alkyl group having 6 to 15 carbon atoms, a cycloalkyl group, or an aryl group such as phenyl, preferably the same or different selected from lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl and nitro. A phenyl group which may be substituted with 1 to 3 substituents,
For example, a phenyl group, a dimethoxyphenyl group, a dihydroxyphenyl group, and the like, more preferably a phenyl group. P ¹ is an alkyl group having 3 to 18 carbon atoms such as a decyl group, nitro, halogen, lower alkoxy,
A benzyloxycarbonyl group optionally substituted with a lower alkoxyphenylazo or phenylazo group, or a linear, branched or cyclic carbon number 1 optionally substituted with a fluorenyl or methylsulfonyl group
To 15 are amino-protecting groups such as an alkoxycarbonyl group containing an alkyl group, specifically, a benzyloxycarbonyl group or a substituted benzyloxycarbonyl group such as p-nitrobenzyloxycarbonyl group, p-bromobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group and the like; alkoxycarbonyl group such as t-butoxycarbonyl group, cyclopentyloxycarbonyl group, octyloxycarbonyl group and the like, or substituted alkoxycarbonyl group such as 9- Fluorenylmethoxycarbonyl group, methylsulfonylethoxycarbonyl group and the like; and other amino protecting groups such as benzenesulfonyl group and the like. Y represents a leaving group, specifically, methanesulfonyl (mesyl), trihalogenomethanesulfonyl, for example, trifluoromethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, p-bromobenzenesulfonyl group or the like.

The aminopropanol derivative is prepared by reacting the optically active N-protected-2-aminopropanediol represented by (Compound a) in FIG. 1 in a solvent such as pyridine or in an anhydrous solvent such as dichloromethane in the presence of pyridine. From ice-cooling to room temperature, for example, methanesulfonyl chloride (Ms-C
It can be produced by methanesulfonylating (mesylating) only the primary hydroxyl group of the diol by treating with l) (step 1). After isolation of this product, optionally without isolation, it is treated as such with the amine of formula R ² H in the organic solvent, such as ethyl alcohol or N, N-dimethylformamide, as the starting material. It can lead to the compounds shown in 2) (step 2). This amine is represented by R ² H, in which R ² represents the above formulas (I) to (VI), and in the formulas (I) to (VI), the cycloalkyl group or the hydroxycycloalkyl group has 3 carbon atoms. Is 8 and the carbon number of the aralkyl group is 6 to 20. R ² is preferably a morpholino group; a lower alkylamino group; a morpholino lower alkyl group; a cycloalkylamino group which may be substituted with a hydroxy group; a pyrrolidino group which may be substituted with a hydroxy group or a hydroxy lower alkyl group; A piperazino group optionally substituted with a lower alkyl group, a bis (hydroxy lower alkyl) amino group; and a piperidino group optionally substituted with a hydroxy group or a hydroxy lower alkyl group, more preferably a morpholino group or a pyrrolidino group. It is a base.

In step 3, the alkyl group or amino-protecting group which protects the amino group is removed by a conventional method such as catalytic reduction, acid treatment, base treatment or the like to obtain the compound represented by the general formula (3). The amino group formed is then converted to the formula R ¹¹ C
A carboxylic acid represented by OOH or a reactive derivative thereof,
For example, the desired 2-acylaminoalcohol derivative represented by the general formula (4) can be obtained by acylation with an acid halide or acid anhydride of a carboxylic acid (step 4). In this formula, R ¹¹ has 3 to 18 carbon atoms
The above alkyl group or alkenyl group may have a hydroxyl group at the 2 or 3 position. When the acyl group (R ¹¹ CO—) to be introduced has 10 carbon atoms, specifically, decanoyl chloride or decanoic anhydride is used as the acylating agent. Alternatively, the compound represented by the general formula (3) is converted to a carboxylic acid having 8 to 16 carbon atoms (R ¹¹ COO
H) and a condensing agent usually used for an amide bond reaction can be reacted to lead to the desired 2-acylaminoalcohol derivative represented by the general formula (4) (step 4). Specifically, octanoic acid is used as the carboxylic acid,
Fatty acids such as 2-hydroxyoctanoic acid, decanoic acid, 2-hydroxydecanoic acid, dodecanoic acid, 2-hydroxydodecanoic acid, myristic acid, 2-hydroxymyristic acid, palmitic acid, 2-hydroxypalmitic acid and hydroxy-substituted fatty acids are used. Known condensing agents such as dicyclohexylcarbodiimide and water-soluble carbodiimide are used as the condensing agent. Specific examples of the water-soluble carbodiimide include 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC).

A preferred embodiment of the novel aminoalcohol derivative represented by the general formula (2) obtained in the above production process is that in the general formula (2), R ¹ is an alkyl group, a cycloalkyl group, or a lower alkyl, A phenyl group which may be substituted with 1 to 3 same or different substituents selected from lower alkoxy, hydroxy, hydroxy lower alkyl and nitro, and P ¹ is nitro, halogen, lower alkoxy, lower alkoxy phenylazo Alternatively, an amino protecting group selected from a benzyloxycarbonyl group optionally substituted with a phenylazo group and an alkoxycarbonyl group containing a linear, branched or cyclic alkyl group optionally substituted with a fluorenyl or methylsulfonyl group. Or carbon number 3 to 1
8 is an alkyl group and R ² is an amino alcohol derivative having the same meaning as defined in claim 1.

Another preferred embodiment is the general formula (2)
Wherein R ¹ is an alkyl group having 6 to 15 carbon atoms, a cyclohexyl group or a phenyl group, and P ¹ is an amino protecting group or a decyl group selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group and an octyloxycarbonyl group. R ² is a morpholino group; a lower alkylamino group; a morpholino lower alkylamino group; a cycloalkylamino group optionally substituted with a hydroxy group; a pyrrolidino group optionally substituted with a hydroxy group or a hydroxy lower alkyl group. A piperazino group optionally substituted with a lower alkyl group; a bis (hydroxy lower alkyl) amino group; and an amino group selected from a piperidino group optionally substituted with a hydroxy group or a hydroxy lower alkyl group It is an amino alcohol derivative

A further preferred embodiment is that, in the general formula (2), R ¹ is a phenyl group, P ¹ is a benzyloxycarbonyl group, and R ² is a morpholino group, a pyrrolidino group, a hydroxypyrrolidino group, a hydroxypyrin. Peridino group, N-methylpiperazino group, diethanolamino group,
Or a hydroxycyclohexylamino group, an aminoalcohol derivative having a configuration of (1S, 2S), or R ¹ in the general formula (2) is a phenyl group and P ¹ is a benzyloxycarbonyl group. R ² is a morpholino group, a pyrrolidino group, a piperidino group, a cyclohexylamino group or a cyclopentylamino group, and is an aminoalcohol derivative having a configuration of (1R, 2R).

A preferred embodiment of the novel aminoalcohol derivative represented by the general formula (3) obtained in the above production process is that in the general formula (3), R ¹ has 6 to 6 carbon atoms.
15 is an alkyl group, a cyclohexyl group or a phenyl group, R ² is a morpholino group; a lower alkylamino group; a morpholino lower alkylamino group; a cycloalkylamino group which may be substituted with a hydroxy group; a hydroxy group or a hydroxy lower group. Pyrrolidino group optionally substituted with alkyl group; Piperazino group optionally substituted with lower alkyl group; Bis (hydroxy lower alkyl) amino group; and Piperidino optionally substituted with hydroxy group or hydroxy lower alkyl group An amino alcohol derivative consisting of an amino group selected from the group.

In the method of the present invention, the product may be isolated in each step of the production process, but in some cases, the product is obtained by using the optically active diol which is the starting material of the general formula (1) as a starting material. The desired 2-acylaminoalcohol derivative represented by the general formula (4) can also be obtained by gradually performing the above stepwise reaction without isolation.

The starting material of the amino alcohol derivative of the general formula (1), N-protected-2-
As a method for synthesizing aminopropanediols, a method of reducing aminoketones (J. Org. Chem., 54, 1866 (198
9)), a method of treating an N- (diphenylmethylene) amino acid ester with diisobutylaluminum hydride and then a Grignard reagent (J.Org.Chem., 57, 5469 (1992)),
Method of reacting N-protected-aminoaldehyde or N-protected-amino acid acid chloride with an organometallic reagent (J. Am. Chem.
Soc., 95, 4098 (1973)), asymmetric aldol reaction of 2-oxazolidinone with aldehyde (J. Am. Chem. Soc., 1
08, 6757 (1986)) (Evans method), asymmetric aldol reaction of chiral imidazolidinone and oxazolidinone with aldehyde (Helv. Chem. Acta, 70, 237 (1987)) and the like are known. On the other hand, as a method for synthesizing N-protected-α-aminoketones, which are raw materials for N-protected-2-aminopropanediol, N-protected-α-amino acid is used as a starting material to convert the carboxyl group of the amino acid into an acid chloride. After conversion, a method of reacting with benzene and Friedel-Crafts (J.Am.C
hem.Soc., 103, 6157 (1981)), a method in which the carboxyl group of the amino acid is treated with an alkyllithium reagent to form a lithium salt, and then reacted with a Grignard reagent is known (J.Org.Chem. ., 54, 1866 (1989)).

[0023]

INDUSTRIAL APPLICABILITY According to the method of the present invention, an N-protected-2-aminopropanol derivative as a raw material is used as a raw material to efficiently and efficiently obtain an optically active substance of PDMP having a plurality of asymmetric centers and its analogs. Can be combined without the need for division. That is, since all four stereoisomers of PDMP analogs can be stereoselectively synthesized, the present invention is extremely useful. The novel amino alcohol derivative of the present invention is
It has multiple asymmetric centers and is extremely useful as a synthetic intermediate for PDMP analogs.

[0024]

EXAMPLES Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples unless it exceeds the gist. In the examples below, Me
OH, AcOEt, AcOH, and DMF represent methanol, ethyl acetate, acetic acid, and N, N-dimethylformamide, respectively.

Example 1 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (1S, 2S) -2-benzyloxycarbonylamino- 1-phenyl-1,3-propanediol (21.2
g, 70.3 mmol) in pyridine (350 ml), and melt on ice with methanesulfonyl chloride (5.6 m).
1, 72.3 mmol) was added dropwise over 5 minutes. After stirring for 30 minutes on an ice bath, the mixture was stirred overnight at room temperature. After confirming the completion of the reaction by TLC (chloroform: methanol = 20: 1), the solvent was distilled off, ethyl acetate (500 ml) was added, and 1N-HCl (250 ml ×
3) After washing with a saturated saline solution (250 ml), the solution was dried over sodium sulfate, and the solvent was distilled off. The precipitated crystals were washed with ethyl acetate: hexane = 1: 1 to give the title substance as white crystals (25.3 g, yield 95.0%). TLC Rf 0.55 (CHCl ₃ : MeOH = 20: 1), 0.83 (AcOEt), 0.62 (He
xane: AcOEt = 1: 2) ¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (10H, m, aromatic), 5.30
(1H, d, J = 7.81H _Z , NH), 5.02 (2H, s, C H ₂ -O-CO), 4.99 (1H,
d, J = 3.91H _Z , C H -OH), 4.43-4.39,4.22-4.12 (3H, m, NC H -C
H ₂ ), 2.98 (3H, s, SO ₃ CH ₃ )

Example 2 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (1S, 2S) -2-benzyloxycarbonylamino- 1-phenyl-1,3-propanediol (15.4
g, 51.0 mmol) with methylene chloride (150 ml)
Dissolved in pyridine (12.1 ml, 149.6 mmo
l) was added, and then methanesulfonyl chloride (4.5 ml, 58.1 mmol) was added dropwise over 5 minutes on an ice bath. After stirring for 30 minutes on an ice bath, the mixture was stirred overnight at room temperature. TLC (chloroform:
Methanol = 20: 1, hexane: ethyl acetate = 1:
After confirming in 1), water (100 ml) and chloroform (50 ml) were added, and the organic layer was washed successively with 1N-hydrochloric acid, water, saturated sodium hydrogen carbonate solution and 100 ml each of water, dried over sodium sulfate and filtered. did. The solvent was distilled off, and hexane: ethyl acetate = 2: 1 (100 ml).
Was added and left overnight. The precipitated crystals were collected by filtration and washed with hexane: ethyl acetate = 2: 1 to give the title substance (16.56 g, yield 85.7%) as white crystals.

Example 3 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1 , 3-Propanediol-3-methanesulfonyl ester (9.68 g, 25.5 mmo
l) is dissolved in ethanol (50 ml), morpholine (9.8 ml, 112.6 mmol) is added at room temperature, and 4
Stirred at 0 ° C. for 3 days. TL that the reaction is finished
C (chloroform: methanol = 20: 1, hexane:
After confirming with ethyl acetate = 1: 2, ethyl acetate), the solvent was distilled off, and water (50 ml) and ethyl acetate (150 ml) were added.
Was added, and the organic layer was washed successively with saturated sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and filtered. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give the title substance as a colorless oil (3.61 g, yield 38.1).
%) Was obtained. TLC Rf 0.32 (CHCl ₃ : MeOH = 20: 1), 0.12 (Hexane: AcOEt = 1:
2) ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (10H, m, aromatic), 5.04
(2H, s, CH ₂ O-CO), 5.00 (1H, d, J = 3.41Hz, H-1), 4.11 (1H,
m, H-2), 3.72 (4H, m, (CH 2) 2 O), 2.68-2.47 (6H, m, (CH 2)
₃ N)

Example 4 Synthesis of (1R, 2R) -2-benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl-1 , 3-Propanediol-3-methanesulfonyl ester (1.21 g, 3.19 mmo
l) was dissolved in N, N-dimethylformamide (6 ml), and morpholine (1.11 g, 12.8 mmol) was dissolved at room temperature.
l) was added and the mixture was stirred at 40 ° C for 24 hours. The completion of the reaction was confirmed by TLC (chloroform: methanol =
20: 1, hexane: ethyl acetate = 1: 2, ethyl acetate) and then a saturated sodium hydrogen carbonate solution (70%).
ml) and ethyl acetate (100 ml), and the organic layer was washed successively with water and saturated saline, dried over sodium sulfate, and filtered. The solvent is distilled off, and the residue is subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 2).
The title compound (507.5 mg, yield 43.0%) was obtained as a colorless oil.

Example 5 (1S, 2S) -2-amino-
Synthesis of 3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (438.8 mg, 1.19 mmol) in methanol (10 ml). ), 10% palladium on carbon (12
(6.5 mg, 10.0 mol%) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After confirming the completion of the reaction by TLC (chloroform: methanol = 9: 1 and 7: 3), palladium carbon was removed by filtration. The filtrate was concentrated to give the title compound (275.6 mg, yield 98.5%) as a colorless oil. TLC Rf 0.48,0.24 (CHCl ₃ : MeOH = 7: 3) (tailing), 0.68 (CH
Cl ₃ : MeOH: aqNH ₃ = 4: 1: trace) ¹ H-NMR (CD ₃ OD) δ: 7.36-7.26 (5H, m, aromatic), 4.47 (1
H, d, J = 6.60Hz, H-1), 3.65 (4H, m, (CH ₂ ) ₂ O), 3.21-3.14 (1
H, m, H-2), 2.51-2.43, 2.32-2.24, 2.11-2.05 (6H, m, (CH
₂ ) ₃ N)

Example 6 (1S, 2S) -2-amino-
Synthesis of 3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (3.82 g, 10.3 mmol) in methanol (10
ml) and ammonium formate (2.6 g, 41.
3 mmol), 10% palladium carbon (888.5 m)
g, 8.09 mol%) was added, and the mixture was stirred overnight at room temperature. After confirming the completion of the reaction by TLC (chloroform: methanol = 9: 1 and 7: 3), palladium carbon was removed by filtration. The filtrate was concentrated to give the colorless oily title compound (2.34 g, yield 99.0%).

Example 7 Synthesis of (1S, 2S) -2-decanoylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-amino-3-morpholino-1-phenyl-1 -Propanol (1.33g, 4.0mmo
l) was dissolved in methanol (4 ml) and decanoyl chloride (0.82 ml, 4.0 mm) was added under ice cooling in the presence of triethylamine (668.0 μl, 4.8 mmol).
ol). After 30 minutes, after confirming by TLC (ethyl acetate, chloroform: methanol = 20: 1, chloroform: methanol = 7: 3) that the reaction was almost completed, methanol (30 ml) was added and the mixture was allowed to stand for 90 minutes. . The reaction solution was concentrated under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and ethyl acetate (50 ml) was added.
Extracted. The organic layer was mixed with water (20 ml) and saturated saline (2
(0 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an oil (853.5 mg). The obtained oily substance was purified by silica gel column chromatography (ethyl acetate) to give the title substance as a colorless oil (930.5 mg,
Yield 59.6%) was obtained. TLC Rf 0.62 (CHCl ₃ : MeOH = 9: 1), 0.26 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (5H, m, aromatic), 5.87 (1
H, d, J = 7.26Hz, NH), 4.95 (1H, d, J = 3.63Hz, H-1), 4.28 (1
H, m, H-2), 3.72 (4H, m, (CH ₂ ) ₂ O), 2.63-2.44 (6H, m, (CH ₂ )
₃ N), 2.09 (2H, m, CO-C H ₂ -CH ₂ ), 1.50 (2H, m, CO-CH ₂ -C H ₂ ),
1.24 (12H, brs, (C H ₂ ) ₆ CH ₃ ), 0.88 (3H, t, CH ₃ )

Example 8 Synthesis of (1S, 2S) -2-decanoylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-amino-3-morpholino-1-phenyl-1 -Propanol (84.9 mg, 0.270
mmol) in tetrahydrofuran (4 ml),
Triethylamine (80.0 μl, 0.575 mmo
l) in the presence of decanoic anhydride (109.2 m) under ice cooling.
g, 0.334 mmol) was added, and the mixture was stirred at room temperature for one day. TLC (ethyl acetate, chloroform: methanol =
After confirming that the reaction was almost completed with 20: 1, chloroform: methanol = 7: 3), ethyl acetate (30 ml) and a saturated sodium hydrogen carbonate solution (20 m) were used.
l) was added, and the organic layer was mixed with water (20 ml) and saturated saline (2
(0 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an oil (130.8 mg). The obtained oily substance was purified by silica gel column chromatography (ethyl acetate) to obtain the colorless oily title substance (37.2 mg, yield 40.5%).

Example 9 Synthesis of (1S, 2S) -2-decanoylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1, 3-Propanediol-3-methanesulfonyl ester (9.5 g, 25.1 mmol)
Was dissolved in ethanol (50 ml) on an oil bath (40 ° C.), morpholine (8.7 ml, 100 mmol) was added, and the mixture was stirred at 40 ° C. for 3 days. TLC (n-hexane:
After confirming that the reaction was almost completed with ethyl acetate = 1: 2), the solvent was distilled off under reduced pressure. Ethyl acetate (100 ml) was added to the reaction residue, and the precipitated crystals were removed by filtration. The filtrate was saturated sodium hydrogen carbonate solution (50 m
l), water (50 ml × 2) and saturated saline (50 ml), and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance (13.7 g). Methanol (50 ml), 10% palladium on carbon (2.3 g,
8.6 mol%) was added, and the mixture was vigorously stirred under a hydrogen atmosphere overnight. After confirming the completion of the reaction by TLC (ethyl acetate, chloroform: methanol = 9: 1, chloroform: methanol = 7: 3), palladium carbon was removed by filtration. The filtrate was concentrated to an oil (9.33).
g) was obtained. This oil was dissolved in methanol (25 ml) and triethylamine (4.2 ml, 30 mmol).
And decanoyl chloride (5.15 m
1, 25 mmol) was added dropwise. After 30 minutes, after confirming by TLC (ethyl acetate, chloroform: methanol = 20: 1, chloroform: methanol = 7: 3) that the reaction was almost completed, methanol (20 ml) was added, and the mixture was left for 30 minutes. . The reaction solution was concentrated under reduced pressure, saturated sodium hydrogen carbonate solution (50 ml) was added, and the mixture was extracted with ethyl acetate (150 ml). The organic layer is water (40 ml x
3), washed with saturated saline (40 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an oil (9.73 g). The obtained oily substance was purified by silica gel column chromatography (ethyl acetate) to obtain the colorless oily title compound (4.35 g, yield 44.6%).

Example 10 (1S, 2S, 2'S) -2
-(2'-hydroxydecanoylamino) -3-morpholino-1-phenyl-1-propanol and (1S,
Synthesis of 2S, 2'R) -2- (2'-Hydroxydecanoylamino) -3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-Amino-3-morpholino-1-phenyl- 1-Propanol (141.5 mg, 0.60
0 mmol) was dissolved in methylene chloride (6 ml), and 2-
Hydroxydecanoic acid (100 mg, 0.531 mmo
l), N-hydroxysuccinimide (150.8 m
g, 1.131 mmol) and stirred at room temperature for 15 minutes, and then on an ice bath, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (134.0 m)
g, 0.699 mmol) was added and the mixture was stirred overnight. TL
C (ethyl acetate, chloroform: methanol = 20:
After confirming that the reaction is almost complete in 1),
Ethyl acetate (30 ml) was added, and the organic layer was added with 5% aqueous citric acid solution (15 ml) and saturated sodium hydrogen carbonate solution (1
(5 ml) and water (15 ml), and the extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate,
Purified with chloroform: methanol = 20: 1), the colorless oily title compound ((1S, 2S, 2'S)) was obtained in 15.6.
mg, 20.0 mg of (1S, 2S, 2′R) compound was obtained. The absolute configuration of the title compound was identified by using (2R) -2-hydroxydecanoic acid as a starting material and performing the same synthesis.

(1S, 2S, 2'S) -2- (2'-Hydroxydecanoylamino) -3-morpholino-1-phenyl-1-propanol TLC Rf 0.38 (AcOEt) ¹ H-NMR (CDCl ₃ ). δ: 7.36-7.25 (5H, m, aromatic), 6.82 (1
H, d, J = 7.81Hz, NH), 4.96 (1H, d, J = 3.41Hz, H-1), 4.3 (1H,
m, H-2), 3.99 (1H, dd, J = 3.90,3.91Hz, H-2 '), 3.71 (4H, t,
(CH ₂ ) ₂ O), 2.64-2.49 (6H, m, (CH ₂ ) ₃ N), 1.70-1.65 (1H, m,
CH (OH) -C H ₂ (A)), 1.50-1.43 (1H, m, CH (OH) -C H ₂ (B)), 1.3
1-1.20 (12H, m, (C H ₂ ) _6- CH ₃ ), 0.88 (3H, t, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 174.3, 140.8, 128.4, 127.7, 12
6.0, 75.2, 72.0, 66.9, 59.9, 54.4, 51.0, 34.8, 31.
8,29.4,29.2,24.8,22.6,14.1 (1S, 2S, 2'R) -2- (2'-hydroxydecanoylamino) -3-morpholino-1-phenyl-1-
Propanol TLC Rf 0.20 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.25 (5H, m, aromatic), 6.88 (1
H, d, J = 8.3Hz, NH), 5.00 (1H, d, J = 3.41Hz, H-1), 4.3 (1H,
m, H-2), 4.03 (1H, dd, J = 3.90,3.42Hz, H-2 '), 3.72 (4H, t,
(CH ₂ ) ₂ O), 2.67-2.53 (6H, m, (CH ₂ ) ₃ N), 1.66-1.61 (1H, m,
CH (OH) -C H ₂ (A)), 1.50-1.45 (1H, m, CH (OH) -C H ₂ (B)), 1.32
-1.20 (12H, m, (C H ₂ ) ₆ CH ₃ ), 0.88 (3H, t, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 174.0, 140.8, 128.4, 127.7, 12
6.0, 75.2, 72.2, 66.9, 60.1, 54.4, 50.8, 34.8, 31.
8, 29.4, 29.3, 29.2, 24.6, 22.6, 14.1

Example 11 Synthesis of (1S, 2S) -2-decanoylamino-3- (N-methylpiperazino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1- Phenyl-1,3-propanediol-3-methanesulfonyl ester (1.81 g, 4.78 mmo
l) was dissolved in ethanol, N-methylpiperazine (1.92 g, 19.2 mmol) was added, and the mixture was mixed at 40 ° C. for 3 times.
Stirred for days. After completion of the reaction, the solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. Next, the extract was dissolved in methanol and mixed with 10
% Palladium carbon was added, and hydrogen gas was introduced with vigorous stirring. After completion of the reaction, palladium carbon was removed by filtration, the solvent was distilled off under reduced pressure, methanol was added to the reaction residue,
Decanoyl chloride was added in the presence of triethylamine on an ice bath. After completion of the reaction, the solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and the solvent was evaporated. Next, the extract was purified by silica gel column chromatography (chloroform: methanol = 9: 1),
The title substance (10.0 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.25 (5H, m, aromatic), 5.91 (1
H, d, J = 7.3Hz, NH), 4.95 (1H, d, J = 3.4Hz, H-1), 4.29 (1H, m, H
-2), 2.78-2.36 (10H, m, H-3, H-2 ', H-3', H-4 ', H-5'), 2.32
(3H, t, N-CH ₃ ), 2.30-2.27 (1H, m, COC H ₂ (A)), 2.11-2.08 (1
H, m, COC H ₂ (B)), 1.63-1.60 (1H, m, CO-CH ₂ -C H ₂ (A)), 1.53-
1.48 (1H, m, CO-CH ₂ -C H ₂ (B)), 1.25 (12H, brs, (C H ₂ ) ₆ CH ₃ ),
0.88 (3H, t, CH ₃ )

Example 12 Synthesis of (1S, 2S) -2-decanoylamino-3-((2S) -2-hydroxymethylpyrrolidino) -1-phenyl-1-propanol According to the method of Example 11, Instead of N-methylpiperazine, (2S) -2-hydroxymethylpyrrolidine was used to perform the same synthesis, and the title substance (89.
6 mg). ¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (5H, m, aromatic), 6.13 (1
H, d, J = 6.3Hz, NH), 4.99 (1H, d, J = 3.4Hz, H-1), 4.14 (1H, m, H
-2), 3.71-3.67 (1H, m, H-6'A), 3.57-3.53 (1H, m, H-6'B), 3.
29-3.24 (1H, m, H-5'A), 3.14-3.09 (1H, m, H-3A), 2.83-2.78
(1H, m, H-3B), 2.76 (1H, m, H-2 '), 2.38-2.32 (1H, m, H-5')
B), 2.14-2.03 (2H, m, COCH ₂ ), 1.92-1.83 (1H, m, H-3'A), 1.8
0-1.73 (2H, m, H-4 '), 1.70-1.62 (1H, m, H-3'B), 1.50-1.43
(2H, m, CO-CH 2 -C H 2), 1.22 (12H, brs, (C H 2) 6 CH 3), 0.88 (3H,
t, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 174.1, 141.1, 128.3, 127.5, 12
5.7, 75.6, 66.4, 63.6, 57.6, 56.1, 54.1, 36.7, 31.
8, 29.4, 29.3, 29.2, 29.0, 27.0, 25.6, 23.9, 22.
6, 14.1

Example 13 (1S, 2S) -2-decanoylamino-3- (3-hydroxypyrrolidino) -1-
Synthesis of Phenyl-1-propanol According to the method of Example 11, 3-hydroxypyrrolidine was used in place of N-methylpiperazine, and synthesis was performed in the same manner to give the title substance as a colorless oil (diastereomer ratio 1:
1 mixture, 88.3 mg) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m, aromatic), 5.91 (0.
5H, d, J = 7.3Hz, NH), 5.88 (0.5H, d, J = 7.3Hz, NH), 5.0 (1H, H-
1), 4.40 (1H, m, H-3 '), 4.23 (1H, m, H-2), 3.06-3.01 (1H, m, H
-5'A), 3.00-2.70 (3H, m, H-3, H-2'A), 2.67-2.63 (1H, m, H-
2'B), 2.54-2.45 (1H, m, H-5'B), 2.21-2.12 (1H, m, H-4'A),
2.11-2.00 (2H, m, COC H ₂ ), 1.79-1.74 (1H, m, H-4'B), 1.50-
1.44 (2H, m, CO- CH 2 -C H 2), 1.22 (12H, brs, (C H 2) 6 CH 3), 0.88
(3H, t, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 173.6, 141.0, 140.9, 128.3, 12
7.5, 127.4, 125.9, 75.3, 75.1, 71.1, 71.0, 63.7, 5
7.6, 53.6, 53.5, 52.6, 36.7, 34.7, 31.8, 29.4, 29.
3, 29.2, 29.0, 25.6, 22.6, 14.0

Example 14 Synthesis of (1S, 2S) -2-decanoylamino-3-pyrrolidino-1-phenyl-1-propanol According to the method of Example 11, pyrrolidine was used instead of N-methylpiperazine. , Was obtained in the same manner as above to give the title substance (92.2 mg) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.23 (5H, m, aromatic), 5.91 (1
H, d, J = 7.8Hz, NH), 5.05 (1H, d, J = 3.4Hz, H-1), 4.26 (1H, m, H
-2), 2.86 (2H, d, J = 5.4Hz, H-3), 2.70 (4H, m, H-2 ', H-5'), 2.
07 (2H, m, COCH ₂ ), 1.81 (4H, m, H-3 ', H-4'), 1.47 (2H, m, CO-C
_{H 2 -C H 2), 1.3-1.1} (12H, m, (C H 2) 6 CH 3), 0.88 (3H, t, CH 3) 13 C-NMR (CDCl 3) δ: 173.5,141.0,128.2 , 127.4, 12
5.9, 75.4, 57.9, 55.2, 52.3, 36.7, 31.8, 29.3, 29.
2, 29.0, 25.6, 23.6, 22.6, 14.0

Example 15 (1S, 2S) -2-decanoylamino-3- (3-hydroxymethylpiperidino)
Synthesis of -1-phenyl-1-propanol According to the method of Example 11, 3-hydroxymethylpiperidine was used instead of N-methylpiperazine, and synthesis was performed in the same manner to give the title substance as a colorless oil (diastereomer). A mixture with a ratio of 1: 1 was obtained (246.5 mg). ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m, aromatic), 5.96 (0.
5H, d, J = 7.8Hz, NH), 5.94 (0.5H, d, J = 7.8Hz, NH), 4.96 (0.5
H, d, J = 3.4Hz, H-1), 4.94 (0.5H, d, J = 3.4Hz, H-1), 4.33-4.2
6 (1H, m, H-2), 3.59-3.51 (1H, m), 3.50-3.42 (1H, m), 3.00-
2.83 (2H, m), 2.59 (1H, dd, H-3A), 2.48 (1H, dd, H-3B), 2.3-
2.0 (2H, m), 2.07 (2H, m, COC H ₂ ), 1.9-1.5 (4H, m), 1.48 (2H,
_{m, CO-CH 2 -C H} 2), 1.4-1.1 (12H, m, (C H 2) 6 CH 3), 1.10-1.00 (1
H, m), 0.88 (3H , t, CH 3)

Example 16 Synthesis of (1S, 2S) -3-cyclohexylamino-2-decanoylamino-1-phenyl-1-propanol According to the method of Example 11, cyclohexylamine was used instead of N-methylpiperazine. Was synthesized in the same manner as above to obtain the title substance (40.6 mg) as a colorless oily substance. ¹ H-NMR (CDCl ₃ ) δ: 7.4-7.2 (5H, m, aromatic), 6.64 (1H, d,
J = 7.3Hz, NH), 5.14 (1H, d, J = 2.5Hz, H-1), 4.37 (1H, m, H-
2) 、 3.34 (1H, dd, J = 4.9,12.7Hz, H-3A) 、 3.13 (1H, dd, J = 5.
4,16.3Hz, H-3B), 2.77 (1H, m, (CH ₂ ) ₂ C H NH), 2.2-2.0 (4H,
m), 1.76 (2H, d, J = 12.7Hz), 1.63 (1H, d, J = 10.7Hz), 1.5-
1.0 (19H, m), 0.88 (3H, t, J = 6.8Hz, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 173.7, 141.1, 128.3, 127.3, 12
5.5, 75.9, 57.0, 53.2, 49.1, 36.8, 33.2, 33.0, 31.
8, 29.4, 29.3, 29.2, 29.0, 25.8, 25.7, 24.8, 22.
6, 14.1

Example 17 Synthesis of (1S, 2S) -2-decanoylamino-3- (4-hydroxycyclohexylamino) -1-phenyl-1-propanol According to the method of Example 11, N-methylpiperazine was prepared. Instead, 4-hydroxycyclohexylamine was used to perform the same synthesis, and the title substance (12.0 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.4-7.2 (5H, m, aromatic), 6.36 (1H, d,
J = 6.8Hz, NH), 5.13 (1H, d, J = 2.0Hz, H-1), 4.31 (1H, m, H-
2), 3.61 (1H, m, CH ₂ C H OH), 3.34 (1H, dd, J = 4.4,12.7Hz, H-
3A), 3.06 (1H, dd, J = 4.9,12.7Hz, H-3B), 2.73 (1H, m, CH ₂ C
H NH), 2.2-1.9 (6H, m), 1.5-1.0 (18H, m), 0.88 (3H, t, J =
6.8Hz, CH ₃ )

Example 18 Synthesis of (1S, 2S) -2-decanoylamino-3- (2- (N-morpholino) ethylamino-1-phenyl-1-propanol) According to the method of Example 11, Instead of N-methylpiperazine, 2- (N-morpholino) ethylamine was used for synthesis in the same manner to give the title substance (91.7 m) as a colorless oil.
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.4-7.2 (5H, m, aromatic), 6.02 (1H, d,
J = 7.3Hz, NH), 4.64 (1H, d, J = 2.4Hz, H-1), 4.28 (1H, m, H-
2), 3.80 (1H, dd, J = 9.8,14.2Hz), 3.68 (4H, t, J = 4.4Hz, CH
₂ -O-CH ₂ ), 3.50 (2H, m), 3.30 (1H, dd, J = 5.9,14.2Hz), 2.
7-2.5 (2H, m), 2.48 (4H, t, J = 4.4Hz, CH ₂ NCH ₂ ), 2.4-2.3 (2
H, m), 2.00 (2H, m, COCH ₂ ), 1.65 (2H, m), 1.5-1.0 (14H, m,
(C H ₂ ) ₇ CH ₃ ), 0.88 (3H, t, J = 6.8Hz, CH ₃ )

Example 19 (1S, 2S) -2- (2-
Synthesis of (hydroxy-n-octanoylamino) -3-morpholino-1-phenyl-1-propanol According to the method of Example 11, morpholine was used instead of N-methylpiperazine, and the synthesis was carried out in the same manner. (1S,
2S) -2-Amino-3-morpholino-1-phenyl-
1-Propanol was obtained. The present compound (99.2 mg,
0.42 mmol) in methylene chloride, and at room temperature,
2-hydroxy-n-octanoic acid (80.0 mg,
0.50 mmol), N-hydroxysuccinimide (1
(02.1 mg, 0.42 mmol) was added, and 1-ethyl-3- (3-dimethylaminopropyl) under ice cooling.
Carbodiimide hydrochloride (118.1 mg, 0.62 m)
mol) was added and the mixture was stirred as it was. After completion of the reaction, chloroform was added, and the organic layer was washed successively with 5% citric acid aqueous solution, saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate and filtered, and the solvent was evaporated. The reaction residue was purified by silica gel column chromatography (ethyl acetate) to give the title substance (15.4 mg) as a colorless oil as one diastereomer and the other diastereomer (16.9 mg).

{One diastereomer} TLC Rf 0.
2 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m, aromatic), 6.75 (1H,
d, J = 7.3Hz, NH), 5.00 (1H, d, J = 3.4Hz, H-1), 4.3 (1H, m, H-
2), 4.02,4.01,4.00,3.99 (1H, dd , CO-C H -OH), 3.74,3.7
3,3.72 (4H, t, CH ₂ OCH ₂ ), 2.69-2.52 (6H, m, CH ₂ N (CH ₂ ) ₂ ),
1.72-1.66 (1H, m, CH (OH) C H ₂ (A)), 1.51-1.43 (1H, m, CH (O
H) C H ₂ (B)), 1.30-1.20 (8H, m, (C H ₂ ) ₄ CH ₃ ), 0.87 (3H, t, CH
₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 174.1, 140.8, 128.4, 127.7, 12
6.0, 75.3, 72.0, 66.9, 60.0, 54.5, 51.1, 34.9, 31.
6,29.0, 24.7, 22.5, 14.0 {other diastereomer} TLC Rf 0.1 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m, aromatic), 6.85 (1H,
d, J = 7.8Hz, NH), 5.01 (1H, d, J = 3.4Hz, H-1), 4.3 (1H, m, H-
2), 4.06,4.05,4.04,4.03 (1H, dd , CO-C H -OH), 3.74,3.7
3,3.72 (4H, t, CH ₂ OCH ₂ ), 2.68-2.51 (6H, m, CH ₂ N (CH ₂ ) ₂ ),
1.68-1.64 (1H, m, CH (OH) C H ₂ (A)), 1.51-1.46 (1H, m, CH (O
H) C H ₂ (B)), 1.30-1.20 (8H, m, (C H ₂ ) ₄ CH ₃ ), 0.88 (3H, t, CH
₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 173.9, 140.8, 128.4, 127.7, 12
6.0, 75.2, 72.2, 66.9, 60.1, 54.4, 50.8, 34.8, 31.
6, 29.0, 24.5, 22.5, 14.0

Example 20 (1R, 2S) -2-decanoylamino-3- (4-hydroxypiperidino) -1-
Synthesis of Phenyl-1-propanol According to the method of Example 11, replacing (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester And (1R, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3
-Methanesulfonyl ester was used, and 4-hydroxypiperidine was used instead of N-methylpiperazine to carry out the same synthesis, and the title substance (204.
2 mg). TLC Rf 0.24 (CHCl ₃ : MeOH: AcOH = 9: 1: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.26 (5H, m, aromatic), 6.29 (1H,
d, J = 4.3Hz, NH), 4.83 (1H, d, J = 5.0Hz, H-1), 4.25 (1H, m, H
-2), 3.76 (1H, m, H-4 '), 2.90-2.78 (2H, br, H-2'A), 2.70
-2.56 (2H, m, H-3), 2.38-2.35 (2H, br, H-2'B), 2.01-1.91
(2H, br, H-3'A), 2.16-2.10 (2H, m, COCH ₂ ), 1.67-1.57 (4
H, m, H-3'B, COCH ₂ C H ₂ ), 1.24 (12H, brs, (C H ₂ ) ₆ CH ₃ ), 0.88
(3H, t, CH ₃ ) MS (FAB) 405 (M + H) ⁺

Example 21 (1S, 2R) -2-decanoylamino-3- (4-hydroxypiperidino) -1-
Synthesis of Phenyl-1-propanol According to the method of Example 20, instead of (1R, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester In addition, (1S, 2R) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3
Using methanesulfonyl ester, a similar synthesis was carried out to obtain the title substance (160.5 mg) as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: In agreement with the data of Example 20.

Example 22 (1R, 2R) -2-decanoylamino-3- (4-hydroxypiperidino) -1-
Synthesis of Phenyl-1-propanol According to the method of Example 20, instead of (1R, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester And (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3
Using methanesulfonyl ester, a similar synthesis was carried out to obtain the title substance (184.2 mg) as a colorless oil. TLC Rf 0.20 (CHCl ₃ : MeOH: AcOH = 9: 1: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.23 (5H, m, aromatic), 6.77 (1H,
d, J = 7.6Hz, NH), 4.95 (1H, d, J = 3.6Hz, H-1), 4.41 (1H, m, H
-2), 3.78 (1H, m, H-4 '), 3.06-3.03 (2H, br, H-2'A), 2.86
(2H, m, H-3), 2.80-2.70 (2H, br, H-2'B), 2.10-2.00 (4H,
m, H-3'A, COCH ₂ ), 1.76 (2H, m, H-3'B), 1.45 (2H, m, COCH ₂ C
_{H 2), 1.24 (12H,} brs, (C H 2) 6 CH 3), 0.88 (3H, t, CH 3) 13 C-NMR (CDCl 3) δ: 174.8,141.0,128.8,128.1,12
6.4, 74.5, 65.1, 58.2, 51.2, 50.9, 50.7, 36.9, 32.
6, 32.3, 29.9, 29.8, 29.7, 29.6, 26.0, 23.0, 14.6 MS (FAB) 405 (M + H) ⁺

Example 23 (1R, 2S) -2-decanoylamino-3-diethylamino-1-phenyl-1-
Synthesis of propanol According to the method of Example 11, (1R, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester was replaced with (1R , 2S) -2-Benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3
-Methanesulfonyl ester was used, diethylamine was used instead of N-methylpiperazine, and synthesis was performed in the same manner to obtain the title substance (L-erythro form). TLC Rf 0.59 (CHCl ₃ : MeOH: AcOH = 9: 1: 1), 0.32 (CHCl ₃ : Me
OH: AcOH = 95: 5: 10) ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.23 (5H, m, aromatic), 5.87 (1H,
d, J = 4.0Hz, NH), 4.75 (1H, d, J = 6.3Hz, H-1), 4.17 (1H, m, H
-2), 2.97-2.50 (6H, m, CH ₂ N (CH ₂ ) ₂ ), 2.04 (2H, m, COC
H ₂ ), 1.45 (2H, COCH ₂ C H ₂ ), 1.24 (12H, brs, (C H ₂ ) ₆ CH ₃ ),
1.05 (6H, brt, N (CH ₂ CH ₃ ) ₂ ), 0.88 (3H, t, (CH ₂ ) ₆ CH ₃ ) MS (FAB) 377 (M + H) ⁺

Example 24 (1S, 2R) -2-decanoylamino-3-diethylamino-1-phenyl-1-
Synthesis of propanol According to the method of Example 11, instead of (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester, (1S, 2S) was used. , 2R) -2-Benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3
-Methanesulfonyl ester was used, diethylamine was used instead of N-methylpiperazine, and synthesis was performed in the same manner to obtain the title substance (D-erythro form). ¹ H-NMR (CDCl ₃ ) δ: In agreement with the data of Example 23.

Example 25 (1R, 2S) -2-hexa
Noylamino-3- (4-hydroxypiperidino) -1
Synthesis of -phenyl-1-propanol According to the method of Example 20, instead of decanoyl chloride
Hexanoyl chloride was used for
The title material (250.5 mg) was obtained as a colored solid.¹ H-NMR (CDCl_Three) δ: 7.36-7.26 (5H, m, aromatic), 5.95 (1H,
d, J = 4.3Hz, NH), 4.80 (1H, d, J = 5.0Hz, H-1), 4.22 (1H, m, H
-2), 3.72 (1H, m, H-4 '), 2.90-2.78 (2H, br, H-2'A), 2.70
-2.56 (2H, m, H-3), 2.38-2.35 (2H, br, H-2'B), 2.01-1.91
(2H, br, H-3'A), 2.16-2.10 (2H, m, COCH_Two), 1.67-1.57 (4
H, m, H-3'B, COCH_TwoCH _Two) ， 1.24 (4H, brs, (CH _Two)_TwoCH_Three), 0.88
(3H, t, CH_Three)

Example 26 (1R, 2S) -2-Octanoylamino-3- (4-hydroxypiperidino) -1
Synthesis of -phenyl-1-propanol According to the method of Example 20, octanoyl chloride was used instead of decanoyl chloride, and synthesis was performed in the same manner to obtain the title substance (230.2 mg) as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.26 (5H, m, aromatic), 6.09 (1H,
d, J = 4.3Hz, NH), 4.80 (1H, d, J = 5.0Hz, H-1), 4.21 (1H, m, H
-2), 3.70 (1H, m, H-4 '), 2.90-2.78 (2H, br, H-2'A), 2.70
-2.56 (2H, m, H-3), 2.38-2.35 (2H, br, H-2'B), 2.01-1.91
(2H, br, H-3'A), 2.16-2.10 (2H, m, COCH ₂ ), 1.67-1.57 (4
H, m, H-3'B, COCH ₂ C H ₂ ), 1.24 (8H, brs, (C H ₂ ) ₄ CH ₃ ), 0.88
(3H, t, CH ₃ )

Example 27 (1R, 2S) -2-Dodecanoylamino-3- (4-hydroxypiperidino) -1
Synthesis of -phenyl-1-propanol According to the method of Example 20, dodecanoyl chloride was used instead of decanoyl chloride, and synthesis was performed in the same manner to obtain the title substance (265.0 mg) as a white solid. ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.26 (5H, m, aromatic), 5.97 (1H,
d, J = 4.3Hz, NH), 4.80 (1H, d, J = 5.0Hz, H-1), 4.22 (1H, m, H
-2), 3.72 (1H, m, H-4 '), 2.90-2.78 (2H, br, H-2'A), 2.70
-2.56 (2H, m, H-3), 2.38-2.35 (2H, br, H-2'B), 2.01-1.91
(2H, br, H-3'A), 2.16-2.10 (2H, m, COCH ₂ ), 1.67-1.57 (4
H, m, H-3'B, COCH ₂ C H ₂ ), 1.24 (16H, brs, (C H ₂ ) ₈ CH ₃ ), 0.88
(3H, t, CH ₃ )

Examples 28 to 30 The following stereoisomers were synthesized in the same manner as in Examples 25 to 27. The yield is as follows. Example 28: (1S, 2R) -2-Hexanoylamino-3- (4-hydroxypiperidino) -1-phenyl-
Yield: 245.0 mg Example 29: (1S, 2R) -2-Octanoylamino-3- (4-hydroxypiperidino) -1-phenyl-
1-Propanol; Yield: 233.5 mg Example 30: (1S, 2R) -2-Dodecanoylamino-3- (4-hydroxypiperidino) -1-phenyl-
1-Propanol; Yield: 215.0 mg

Example 31 Synthesis of (1R, 2R) -2-benzyloxycarbonylamino-3-pyrrolidino-1-phenyl-1-propanol (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl-1 , 3-Propanediol-3-methanesulfonyl ester (1.52 g, 4.01 mmo
l) was dissolved in DMF (8 ml) and pyrrolidine (1.1) was dissolved.
4g, 16.03 mmol) and add 1 at 40-50 ° C.
After stirring for 8 hours, ethyl acetate (100 ml) was added,
The organic layer was washed successively with a saturated sodium hydrogen carbonate solution (70 ml), water (70 ml), and a saturated saline solution (70 ml).
After drying over sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title compound as a colorless oil (1.21 g, yield 85.5%). TLC Rf 0.20 (CHCl ₃ : MeOH = 20: 1), 0.20 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.24 (10H, m, aromatic), 5.06-
5.02 (2H, m, CH ₂ -O-CO), 4.99 (1H, d, J = 3.91Hz, H-1), 4.07
(1H, m, H-2 ), 2.9-2.6 (6H, m, (CH 2) 3 N), 1.83-1.74 (4H, m,
H-3 ′, H-4 ′) ¹³ C-NMR (CDCl ₃ ) δ: 156.0, 140.8, 136.5, 128.4, 12
8.2, 128.0, 127.8, 127.4, 126.1, 75.7, 66.6, 58.
1,55.2,53.4,23.6

Example 32 Synthesis of (1R, 2R) -2-benzyloxycarbonylamino-3-cyclopentylamino-1-phenyl-1-propanol (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl- 1,3-Propanediol-3-methanesulfonyl ester (1.21 g, 3.19 mmo
1) was dissolved in DMF (6 ml), cyclopentylamine (1.09 g, 12.8 mmol) was added, and 40-5
After stirring at 0 ° C. for 32 hours, cyclopentylamine (0.51 g, 5.99 mmol) was further added, and 40 to 5
Stirred overnight at 0 ° C. TL that the reaction is almost complete
After confirming with C (ethyl acetate), ethyl acetate (100 m
l) was added and the organic layer was saturated with sodium hydrogen carbonate solution (7
(0 ml), water (70 ml) and saturated saline (70 ml), and the extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title substance as a colorless oil (534.4 mg, yield 4
5.7%) was obtained. TLC Rf 0.17 (CHCl ₃ : MeOH = 20: 1), 0.10 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.35-7.23 (10H, m, aromatic), 5.34
(1H, d, CONH), 5.08 (1H, s, H-1), 4.98 (2H, m, CH ₂ -O-CO),
3.94 (1H, m, H-2), 3.24 (1H, m, H-3A), 3.08 (1H, m, H-2 '),
2.85 (1H, dd, J = 2.93,12.21Hz, H-3B), 2.04-1.93, 1.87-
1.79, 1.73-1.55, 1.51-1.30 (8H, m, H-3 ', H-4', H-5 ', H-
6 ') ¹³ C-NMR (CDCl ₃ ) δ: 160.7, 141.0, 136.4, 128.4, 12
8.2, 128.0, 127.8, 127.3, 125.6, 76.3, 66.6, 59.
9, 54.7, 53.5, 49.9, 34.1, 33.2, 33.1, 32.7, 23.
8, 23.6, 23.4

Example 33 Synthesis of (1R, 2R) -2-benzyloxycarbonylamino-3-piperidino-1-phenyl-1-propanol (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl-1 , 3-Propanediol-3-methanesulfonyl ester (1.21 g, 3.19 mmo
l) was dissolved in DMF (6 ml) and piperidine (1.0
9g, 12.8 mmol) and added at 40-50 ° C for 24 hours.
Stirred for hours. TLC indicates that the reaction is almost complete.
(Ethyl acetate, chloroform: methanol = 20: 1)
After confirming with, ethyl acetate (100 ml) was added, and the organic layer was washed with a saturated sodium hydrogen carbonate solution (70 ml) and water (7 ml).
0 ml) and saturated brine (70 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless oil (795.4 m
g, yield: 68.0%). TLC Rf 0.20 (CHCl ₃ : MeOH = 20: 1), 0.17 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (10H, m, aromatic), 5.04
(2H, s, CH ₂ -O-CO), 5.01 (1H, d, J = 3.42Hz, H-1), 4.94 (1H,
d, J = 7.33Hz, NH), 4.15 (1H, m, H-2), 2.64-2.45 (6H, m, (CH
₂ ) ₃ N), 1.68-1.54 (4H, m, H-3 ', H-5'), 1.5-1.4 (2H, m, H-
4 ′) ¹³ C-NMR (CDCl ₃ ) δ: 155.9, 140.8, 136.4, 128.5, 12
8.3, 128.1, 127.9, 127.4, 126.3, 75.7, 66.7, 60.
5, 55.8, 51.7, 26.1, 23.9

Example 34 Synthesis of (1R, 2R) -2-benzyloxycarbonylamino-3-cyclohexylamino-1-phenyl-1-propanol (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl- 1,3-Propanediol-3-methanesulfonyl ester (1.21 g, 3.19 mmo
l) was dissolved in DMF (6 ml), cyclohexylamine (1.29 g, 13.0 mmol) was added, and 40-5
After stirring at 0 ° C. for 2 days, cyclohexylamine (0.62 g, 6.25 mmol) was added, and the temperature was 40 to 50 ° C.
It was stirred overnight. TLC indicates that the reaction is almost complete.
(Ethyl acetate, chloroform: methanol = 20: 1)
After confirming with, ethyl acetate (100 ml) was added, and the organic layer was washed with a saturated sodium hydrogen carbonate solution (70 ml) and water (7 ml).
0 ml) and saturated brine (70 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a colorless oil (750.0 m
g, yield 61.5%) was obtained. TLC Rf 0.19 (CHCl ₃ : MeOH = 20: 1), 0.12 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.35-7.22 (10H, m, aromatic), 5.32
(1H, d, J = 7.32Hz, CONH), 5.07 (1H, s, H-1), 4.98 (2H, m, CH ₂
-O-CO), 3.94 (1H, m, H-2), 3.26 (1H, m, H-3A), 2.88 (1H, d
d, J = 2.44,12.69Hz, H-3B), 2.44 (1H, m, H-2 '), 1.95-1.8
6, 1.77-1.68, 1.63-1.60, 1.42-1.02 (10H, m, H-3 ', H-
4 ', H-5', H-6 ', H-7') ¹³ C-NMR (CDCl ₃ ) δ: 156.2, 141.0, 136.4, 128.4, 12
8.2, 128.0, 127.8, 127.3, 125.7, 76.3, 66.6, 56.
8, 54.7, 49.6, 47.0, 34.7, 33.5, 33.3, 33.0, 25.
9, 25.4, 25.0, 24.8, 24.7

Example 35 Synthesis of (1S, 2S) -2-t-butoxycarbonylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-t-butoxy according to the method of Example 1. After mesylating carbonylamino-1-phenyl-1,3-propanediol, the morpholine substitution reaction was carried out according to the method of Example 3, and as a result, the title substance was obtained as a colorless oil in a yield of 63%. TLC Rf 0.36 (CHCl ₃ : MeOH = 20: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (5H, m, aromatic), 4.98 (1
H, d, J = 3.91Hz, H-1), 4.05 (1H, m, H-2), 3.74 (4H, m, (CH 2)
₂ O), 2.64-2.59 (5H, m, H-2 ', H-6', H-3A), 2.46 (1H, dd, J =
4.89,13.19Hz, H-3B), 1.38 (9H, s, (CH 3) 3)

Example 36 (1S, 2S) -2-t-Butoxycarbonylamino-3-morpholino-1-phenyl-1-propanol was used as a starting material (1S, 2S) -2.
-Decanoylamino-3-morpholino-1-phenyl-
Synthesis of 1-propanol (1S, 2S) -2-t-
Butoxycarbonylamino-3-morpholino-1-phenyl-1-propanol (49.9 mg, 0.149 m
mol) in methylene chloride (1 ml), and under ice cooling,
Trifluoroacetic acid (1 ml) was added and stirred. After 30 minutes, TLC (chloroform:
After confirming with methanol = 9: 1, ether (3m
1) was added, and the solvent was distilled off under reduced pressure. The resulting colorless oil was acylated according to Example 7 to give the title substance as a colorless oil (48.8 mg, yield 82.2%).

Example 37 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3- (N-methylpiperazino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1 -Phenyl-1,3-propanediol-3-methanesulfonyl ester (1.81 g, 4.78 mmo
l) was dissolved in ethanol (40 ml), sodium iodide (712.8 mg, 4.75 mmol) and N-methylpiperazine (1.92 g, 19.2 mmol) were added, and the mixture was stirred at 50 ° C for 5 days. After confirming the reaction status by TLC (chloroform: methanol = 9: 1), the solvent was distilled off, water (50 ml) and ethyl acetate (100 ml) were added, and the organic layer was washed with water and saturated saline in this order. Dry over sodium sulfate and filter. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title compound (2) as a colorless oil.
42.2 mg, yield 13.2%). TLC Rf 0.38 (CHCl ₃ : MeOH = 9: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.26 (10H, m, aromatic), 5.04
(2H, s, CH ₂ -O-CO), 5.00 (1H, d, J = 3.41Hz, H-1), 4.97 (1H,
d, NH), 4.12 (1H , m, H-2), 2.70-2.49 (10H, m, (CH 2) 3 N, (CH
_{2) 2 N), 2.28 (} 3H, s, CH 3 -N) 13 C-NMR (CDCl 3) δ: 156.0,140.7,136.4,128.5,12
8.3, 128.1, 127.9, 127.5, 126.2, 75.3, 66.8, 59.
6, 55.1, 54.1, 52.1, 45.9

Example 38 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3-((2S) -2-hydroxymethylpyrrolidino) -1-phenyl-1-propanol (2S) -2-hydroxy Methylpyrrolidine (323.
3 mg, 3.20 mmol) in ethanol (12 ml)
And (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-p-bromobenzenesulfonyl ester (782
mg, 1.50 mmol) in methylene chloride (3 m
It was dripped at l). The mixture was stirred at 45 ° C for 2 days.
After confirmation by LC (chloroform: methanol = 9: 1, ethyl acetate: 2-propanol = 2: 1), the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate: 2-propanol = 7: 3). Purification
Title substance as colorless oil (79.5 mg, 13.8% yield)
I got TLC Rf 0.25 (CHCl ₃ : MeOH = 9: 1), 0.39 (AcOEt: (CH ₃ ) ₂ CHOH
= 2: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.51-7.23 (10H, m, aromatic), 5.32
(1H, br, NH), 4.99 (3H, m, H-1, CH ₂ -O-CO), 3.93 (1H, m, H-
2), 3.67,3.66,3.64,3.63 (1H, dd , C H 2 (A) -OH), 3.51 (1H,
dd, J = 4.40,11.23Hz, C H 2 (B) -OH), 3.28-3.23 (1H, m, H-5 '
A), 3.08 (1H, dd, J = 5.86,13.19Hz, H-3A), 2.81 (1H, dd, J =
2.93, 13.18Hz, H-3B), 2.71 (1H, m, H-2 '), 2.34-2.28 (1H,
m, H-5'B), 1.90-1.59 (4H, m, H-3 ', H-4') ¹³ C-NMR (CDCl ₃ ) δ: 156.5, 141.0, 136.5, 128.4, 12
8.3, 128.0, 127.8, 127.5, 125.8, 75.4, 66.6, 66.
4, 63.7, 58.0, 56.2, 55.4, 27.0, 23.8

Example 39 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3- (3-hydroxypyrrolidino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino -1-Phenyl-1,3-propanediol-3-methanesulfonyl ester (2.60 g, 6.86 mmo
l) was dissolved in ethanol (20 ml), 3-hydroxypyrrolidine (1.19 g, 13.68 mmol) was added, and the mixture was stirred at 45 ° C for 5 days. After confirming the reaction status by TLC (chloroform: methanol = 9: 1), the solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1, ethyl acetate: methanol = 9: 1). And the title substance (5
27.1 mg, yield 20.8%). TLC Rf 0.25 (CHCl ₃ : MeOH = 9: 1), 0.35 (AcOEt: MeOH = 4: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.41-7.24 (10H, m, aromatic), 5.26
(0.7H, d, J = 7.82Hz, NH, from one diastereomer),
5.20 (0.3H, d, NH, derived from the other diastereomer), 5.
00 (3H, s, H- 1, CH 2 -O-CO), 4.34 (0.7H, m, H-3 ', derived from one of the diastereomers), 4.28 (0.3H, m, H-3', From the other diastereomer), 4.02 (1H, m, H-2), 3.04-2.99, 2.89
-2.42 (6H, m, (CH 2) 3 N), 2.20-2.07 (1H, m, H-4'A), 1.80-
1.68 (1H, m, H-4′B) ¹³ C-NMR (CDCl ₃ ) δ: 156.5, 141.2, 141.1, 136.7, 12
8.8, 128.6, 128.3, 128.2, 127.8, 126.4, 75.4, 75.
2, 71.3, 67.0, 64.0, 58.0, 54.2, 54.1, 53.8, 34.9

Example 40 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3-pyrrolidino-1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1 , 3-Propanediol-3-methanesulfonyl ester (1.21 g, 3.19 mmo
l) was dissolved in DMF (6 ml) and pyrrolidine (0.9
1 g, 12.8 mmol), and the mixture was stirred at 40 ° C. for 24 hours. Then, ethyl acetate (100 ml) was added, and the organic layer was washed with a saturated sodium hydrogen carbonate solution (70 ml) and water (70 ml).
1), washed successively with saturated saline (70 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title substance (983.1 mg, yield 87.0%) as a colorless oil. TLC Rf 0.20 (CHCl ₃ : MeOH = 20: 1), 0.20 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: In agreement with the data shown in Example 31. ¹³ C-NMR (CDCl ₃ ) δ: In agreement with the data shown in Example 31.

Example 41 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3- (3-hydroxymethylpiperidino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxy Carbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (2.43 g, 6.41 mmo
l) was dissolved in ethanol (20 ml), and 3-hydroxymethylpiperidine (1.47 g, 12.78 mmol) was dissolved.
l) was added and the mixture was stirred at 45 ° C for 5 days. Reaction status TL
After confirming with C (chloroform: methanol = 9: 1), the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1, ethyl acetate: methanol = 20: 1), and colorless. The title material was obtained as an oil (293.3 mg, 11.5%). TLC Rf 0.42 (CHCl ₃ : MeOH = 9: 1), 0.16 (AcOEt: MeOH = 20: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (10H, m, aromatic), 5.03
(2H, s, CH ₂ -O-CO), 4.994 (0.5H, d, J = 7.81Hz, H-1, from one diastereomer), 4.986 (0.5H, d, J = 8.30Hz, H -1,
From the other diastereomer), 4.15-4.09 (1H, m, H-
2), 3.56-3.45 (2H, m , C H 2 -OH), 3.00-2.91, 2.75, 2.25-
2.00 (4H, m, H-2 ', H-6'), 2.65-2.59 (1H, m, H-3A), 2.49-
2.45 (1H, m, H-3B), 1.82 (1H, m, H-3 '), 1.75-1.65, 1.63-
1.53, 1.09-1.04 (4H, m, H-4 ′, H-5 ′) ¹³ C-NMR (CDCl ₃ ) δ: 156.2, 156.1, 140.7, 136.4, 12
8.5, 128.3, 128.1, 127.9, 127.5, 126.2, 75.4, 75.
3, 66.7, 65.7, 65.6, 60.4, 60.3, 60.2, 58.2, 57.
5, 55.7, 55.1, 52.0, 38.8, 38.7, 26.6, 24.7, 14.2

Example 42 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonyl Amino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (273.6 mg, 0.722 m
mol) was dissolved in ethanol (3 ml), and sodium iodide (119.2 mg, 0.795 mmol),
Hydroxypiperidine (171.5 mg, 1.70 mm
ol) was added and the mixture was stirred at room temperature for 4 days. Reaction status TL
After confirming with C (chloroform: methanol = 9: 1), 4-hydroxypiperidine (157.0 mg, 1.
55 mmol), and the mixture was further stirred at 45 ° C. for 2 days. The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title substance as a colorless oil (112.6 mg, yield 4).
0.6%) was obtained. TLC Rf 0.24 (CHCl ₃ : MeOH = 9: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (10H, m, aromatic), 5.03
(3H, m, CH ₂ -O-CO, NH), 5.00 (1H, d, J = 2.93Hz, H-1), 4.11
(1H, m, H-2), 3.71 (1H, m, H-4 '), 2.91, 2.82, 2.64, 2.4
8,2.32 (6H, m, (CH 2) 3 N), 1.89 (2H, m, H-3'A, H-5'A), 1.6
4-1.56 (2H, m, H- 3'B, H-5'B) 13 C-NMR (CDCl 3) δ: 156.1,140.7,136.4,128.5,12
8.3, 128.1, 127.9, 127.5, 126.2, 75.4, 66.9, 66.
8, 66.7, 59.5, 52.2, 51.9, 34.4

Example 43 Synthesis of (1S, 2R) -2-benzyloxycarbonylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol (1S, 2R) -2-benzyloxycarbonyl Amino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (270.0 mg, 0.712 m
mol) in ethanol (3 ml), 4-hydroxypiperidine (287.8 mg, 2.85 mmol)
Was added and stirred at 45 ° C. for 2 days. TLC for reaction status
(Chloroform: methanol = 9: 1),
The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and the title substance as a colorless oil (170.9 mg, yield 62.
5%). TLC Rf 0.24 (CHCl ₃ : MeOH = 9: 1)

Example 44 Synthesis of (1R, 2S) -2-benzyloxycarbonylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol (1R, 2S) -2-benzyloxycarbonyl Amino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (273.6 mg, 0.722 m
mol) in ethanol (3 ml), 4-hydroxypiperidine (291.7 mg, 2.89 mmol)
Was added and stirred at 45 ° C. for 2 days. TLC for reaction status
(Chloroform: methanol = 9: 1),
The solvent was evaporated, the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1), and the title substance as a colorless oil (184.3 mg, yield 66.
5%). TLC Rf 0.24 (CHCl ₃ : MeOH = 9: 1)

Example 45 Synthesis of (1R, 2R) -2-benzyloxycarbonylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol (1R, 2R) -2-benzyloxycarbonyl Amino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (295.6 mg, 0.780 m
mol) was dissolved in ethanol (3 ml), and 4-hydroxypiperidine (315.1 mg, 3.12 mmol) was dissolved.
Was added and stirred at 45 ° C. for 2 days. TLC for reaction status
(Chloroform: methanol = 9: 1),
The solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title substance as a colorless oil (179.7 mg, yield 60.50 mg).
0%). TLC Rf 0.24 (CHCl ₃ : MeOH = 9: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.25 (10H, m, aromatic), 5.03
(3H, m, CH ₂ -O-CO, NH), 5.00 (1H, d, J = 2.93Hz, H-1), 4.11
(1H, m, H-2), 3.71 (1H, m, H-4 '), 2.91, 2.82, 2.64, 2.4
8,2.32 (6H, m, (CH 2) 3 N), 1.89 (2H, m, H-3'A, H-5'A), 1.6
4-1.56 (2H, m, H- 3'B, H-5'B) 13 C-NMR (CDCl 3) δ: 156.1,140.7,136.4,128.5,12
8.3, 128.1, 127.9, 127.5, 126.2, 75.4, 66.9, 66.
8, 66.7, 59.5, 52.2, 51.9, 34.4

Example 46 (1S, 2S) -2-Benzyloxycarbonylamino-3-diethanolamino-
Synthesis of 1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester (1.50 g, 3.96 mmo)
1) was dissolved in ethanol (30 ml), diethanolamine (1.69 g, 16.1 mmol) was added, and 45
The mixture was stirred at 0 ° C for 5 days. After confirming the reaction status by TLC (chloroform: methanol = 9: 1), the solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give the title compound as a colorless oil (81 0.1 mg, yield 5.3%) was obtained. TLC Rf 0.38 (CHCl ₃ : MeOH = 9: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.31-7.21 (10H, m, aromatic), 5.48
(1H, d, J = 8.79Hz, NH), 5.04 (1H, d, J = 2.44Hz, H-1), 4.95
(2H, m, CH ₂ -O-CO), 3.89 (1H, m, H-2), 3.64-3.54 (4H, m, N
(CH ₂ -C H ₂ -OH) ₂ ), 2.79, 2.71-2.53 (6H, m, (CH ₂ ) ₃ N) ¹³ C-NMR (CDCl ₃ ) δ: 156.9, 141.5, 136.4, 128.4, 12
8.3, 128.0, 127.8, 127.4, 125.9, 72.6, 66.7, 59.
9, 57.5, 57.3, 55.5

Example 47 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3 (4-hydroxycyclohexylamino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino- 1-phenyl-1,3-propanediol-3-methanesulfonyl ester (1.21 g, 3.19 mmo
l) was dissolved in N, N-dimethylformamide (6 ml) and trans-4-aminocyclohexanol (1.
47 g, 12.76 mmol) was added, and the mixture was stirred at 50 ° C. for 3 days. After confirming the reaction status by TLC (chloroform: methanol = 9: 1), ethyl acetate (100 ml)
Was added, and the organic layer was added to a saturated sodium hydrogen carbonate solution (70 m
l), water (70 ml) and saturated saline (70 ml) were successively washed, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 9: 1), and the title substance as white crystals (571.5 mg, yield 45.
0%). TLC Rf 0.18 (CHCl ₃ : MeOH = 4: 1), 0.16 (AcOEt: MeOH = 4: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.34-7.23 (10H, m, aromatic), 5.33
(1H, d, NH), 5.07 (1H, s, H-1), 4.98 (2H, m, CH ₂ -O-CO), 3.
96 (1H, m, H-2), 3.60 (1H, m, H-4 '), 3.25 (1H, m, H-3A), 2.
89 (1H, m, H-3B), 2.48 (1H, m, H-1 '), 1.97 (4H, m, H-2'A, H-
3'A, H-5'A, H-6'A), 1.33-1.14 (4H, m, H-2'B, H-3'B, H-5 '
B, H-6'B) ¹³ C-NMR (CDCl ₃ ) δ: 156.2, 140.8, 136.3, 128.5, 12
8.3, 128.1, 127.8, 127.4, 125.6, 75.8, 70.0, 66.
7, 56.2, 54.7, 49.7, 33.7, 30.9, 30.7

Example 48 Synthesis of (1S, 2S) -2-octyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-Amino-3-morpholino-1-phenyl- 1-Propanol (627.7 mg, 2.66)
mmol) in methanol (10 ml), and at room temperature triethylamine (0.518 ml, 3.723 m)
mol), then chloroformic acid n-octyl ester (0.625 ml, 3.192 mmol) was added on an ice bath, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, methanol (5 ml) was added and the mixture was stirred for 20 minutes, then the solvent was evaporated under reduced pressure, ethyl acetate (100 ml) was added, and the organic layer was saturated sodium hydrogen carbonate solution, water and saturated saline each 70%.
The organic layer was dried over sodium sulfate and then filtered, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by a silica gel column (elution solvent; hexane: ethyl acetate = 1: 2) to give the title substance as a colorless oil (814.5 m
g, yield 78.1%) was obtained. TLC Rf 0.21 (Hexane: AcOEt = 1: 2), 0.32 (CHCl ₃ : MeOH = 2
0: 1), 0.36 (AcOEt) ¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (5H, m, aromatic), 4.99 (1H,
d, J = 3.42Hz, H-1), 4.08 (1H, m, H-2), 3.98 (2H, m, COOC
_{H 2), 3.73 (4H,} m, (CH 2) 2 O), 2.66-2.45 (6H, m, CH 2 N (C
H ₂ ) ₂ ), 1.54 (2H, m, COOCH ₂ C H ₂ ), 1.27 (10H, m, (C H ₂ ) ₅ C
H ₃ ), 0.88 (3H, t, CH ₂ C H ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 156.5, 140.7, 128.3, 127.6, 12
6.2, 75.4, 66.9, 65.3, 60.1, 54.4, 52.0, 31.7, 29.
2, 29.0, 28.9, 25.7, 22.6, 14.0

Example 49 Synthesis of (1R, 2R) -2-octyloxycarbonylamino-3-pyrrolidino-1-phenyl-1-propanol (1R, 2R) -2-amino-3-pyrrolidino-1-phenyl- 1-Propanol (250.2 mg, 1.11
mmol) in methanol (5 ml).
Triethylamine (0.186 ml, 1.337 mmol
After l) was added, n-octyl chloroformate (0.240 ml, 1.226 mmol) was added on an ice bath, and the mixture was stirred at room temperature. After 90 minutes, triethylamine (0.186 ml, 1.337 mmol), n-octyl chloroformate (0.240 ml, 1.226 m)
mol) and stirred at room temperature. After 20 hours, the solvent was distilled off under reduced pressure, ethyl acetate (100 ml) was added, and the organic layer was sequentially washed with 70 ml of a saturated sodium hydrogen carbonate solution, water and saturated saline, and dried over sodium sulfate.
After filtration, the solvent was distilled off under reduced pressure. The obtained crude product is purified by silica gel column chromatography (elution solvent;
Chloroform: methanol = 20: 1) to give the title substance as a colorless oil (99.5 mg, yield 23.8%). TLC Rf 0.28 (AcOEt: MeOH = 4: 1), 0.30 (CHCl ₃ : MeOH = 9: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.36-7.24 (5H, m, aromatic), 5.05 (1H,
d, J = 2.93Hz, H-1), 4.9 (1H, d, NH), 4.04 (1H, m, H-2), 3.9
6 (2H, m, COOCH ₂ ), 2.91-2.68 (6H, m, CH ₂ N (CH ₂ ) ₂ ), 1.80 (4
H, m, H-3 ' , H-4'), 1.52 (2H, m, COOCH 2 C H 2), 1.26 (10H, m,
(C H ₂ ) ₅ CH ₃ ), 0.88 (3H, t, CH ₂ C H ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 156.4, 140.9, 128.2, 127.3, 12
6.1, 75.6, 65.1, 58.1, 55.2, 53.3, 31.7, 29.1, 28.
9, 25.7, 23.6, 22.6, 14.0

Example 50 Synthesis of (1R, 2R) -2-decylamino-3-pyrrolidino-1-phenyl-1-propanol (1R, 2R) -2-decanoylamino-3-pyrrolidino-1-phenyl-1 -Propanol (181.8m
g, 0.486 mmol) in methylene chloride (5 ml) and lithium aluminum hydride (15 ml) at room temperature.
3.0 mg, 4.032 mmol) was added, and 35-40
After refluxing at 2.5 ° C. for 2.5 hours, 1N hydrochloric acid (15 m
l), and the mixture was stirred for 30 minutes. Then, a saturated sodium hydrogen carbonate solution (70 ml) and chloroform (100 ml) were added, and the organic layer was washed successively with water and saturated brine (70 ml each), dried over sodium sulfate, and filtered. Then, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (elution solvent: chloroform: methanol = 20: 1, ethyl acetate: methanol = 2:
1), the title substance as a colorless oil (121.2 mg, yield 6)
9.3%). TLC Rf 0.39 (CHCl ₃ : MeOH = 9: 1), 0.19 (AcOEt: MeOH = 2: 1) ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.22 (5H, m, aromatic), 4.68 (1H,
d, J = 3.90Hz, H-1), 2.99 (1H, m, H-2), 2.63-2.42 (8H, m, CH
₂ N (CH ₂ ) ₂ , NHC H ₂ ), 1.77 (4H, m, H-3 ', H-4'), 1.41-1.24
(16H, m, (C H 2) 8 CH 3), 0.88 (3H, t, CH 3) 13 C-NMR (CDCl 3) δ: 143.1,128.1,127.0,126.2,73.
9, 61.2, 57.6, 54.5, 48.5, 31.9, 30.2, 29.7, 29.
6, 29.4, 29.3, 27.1, 23.6, 22.7, 14.1

Example 51 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3-morpholino-1-cyclohexyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1-cyclohexyl-1 , 3-Propanediol-3
-Methanesulfonyl ester (369.0 mg, 0.9
58 mmol) of methylene chloride: methanol mixture (2:
1,5 ml), and at room temperature, morpholine (0.25
ml, 2.88 mmol) was added, and the mixture was stirred at 40 ° C.
After 20 hours, morpholine (0.083 ml, 0.958
mmol) was added, and the mixture was stirred at 40 ° C. for another 2 days. After confirming the completion of the reaction by TLC (hexane: ethyl acetate = 1: 2), the solvent was evaporated under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and the mixture was extracted with chloroform (30 ml × 3). The organic layer was dried over sodium sulfate and then filtered. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 1: 2) gave the title substance (61.1 mg, yield 17.0%) as a colorless oil. TLC Rf 0.36 (CHCl ₃ : MeOH = 20: 1), 0.18 (Hexane: AcOEt = 1:
2) ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.26 (5H, m, aromatic), 5.11 (2
H, m, CH ₂ O-CO), 4.98 (1H, br, NH), 3.85 (1H, m, H-2), 3.67
(4H, m, (CH ₂ ) ₂ O), 3.44 (1H, m, H-1), 2.67-2.48 (6H, m, (CH
₂ ) ₃ N), 1.86, 1.75, 1.66, 1.53, 1.38, 1.29-1.11 (11
H, m) ¹³ C-NMR (CDCl ₃ ) δ: 155.8, 136.4, 128.5, 128.2, 12
8.0, 127.9, 79.6, 67.0, 66.8, 66.3, 60.9, 54.2, 4
7.9, 40.6, 29.5, 27.1, 26.4, 26.0, 25.8

Example 52 (1S, 2S) -2-decanoylamino-3-morpholino-1-cyclohexyl-1
-Synthesis of propanol (1S, 2S) -2-benzyloxycarbonylamino-3-morpholino-1-cyclohexyl-1-propanol (62.9 mg, 0.167 mmol) was dissolved in methanol (2 ml) and 10% palladium carbon ( 17.
(5 mg, 9.83 mol%) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After confirming the completion of the reaction by TLC (chloroform: methanol = 9: 1 and hexane: ethyl acetate = 1: 3), palladium carbon was removed by filtration, and the filtrate was concentrated to give an oil (45 0.0 mg) was obtained. This oil was dissolved in methanol (1 ml) and triethylamine (34.8 μl, 0.250 mmol).
And decanoyl chloride (41.0μ
1, 0.200 mmol) was added dropwise. 2 hours later, TL
C (ethyl acetate, ethyl acetate: methanol = 20: 1)
After confirming that the reaction was completed in step 1, methanol (5 ml) was added, and the mixture was left for 20 minutes. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (ethyl acetate: methanol = 40: 1) to obtain the title substance (25.3 mg, yield 38.3%) as a colorless oil. TLC Rf 0.32 (CHCl ₃ : MeOH = 20: 1), 0.28 (Toluene: Acetone
= 3: 1) ¹ H-NMR (CDCl ₃ ) δ: 5.63 (1H, d, J = 8.30Hz, NH), 4.13 (1H,
m, H-2), 3.69 (4H, m, (CH ₂ ) ₂ O), 3.44 (1H, m, H-1), 2.66
2.49 (6H, m, (CH ₂ ) ₃ N), 2.20-2.14 (2H, m, CO-CH ₂ ), 1.88-
1.56, 1.34-1.11 (25H, m), 0.88 (3H, t, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 172.7, 77.6, 66.9, 60.6, 54.3,
46.5, 40.9, 36.9, 31.8, 29.5, 29.4, 29.3, 26.4, 2
6.1, 25.8, 22.6, 14.1

Example 53 Synthesis of (2S, 3S) -2-benzyloxycarbonylamino-1-morpholino-3-octadecanol (2S, 3S) -2-benzyloxycarbonylamino-1,3-octadecanediol- 1-Methanesulfonyl ester (514.4 mg, 1.003 mmol) was dissolved in a methylene chloride: methanol mixture (2: 1, 5 ml), and morpholine (348 μl, 4.00 mm) was added at room temperature.
ol) was added and the mixture was stirred at 40 ° C. After 3 days, morpholine (100 μl, 1.15 mmol) was added and another 3
After stirring at 40 ° C. for a day, the reaction solvent was evaporated under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and the mixture was extracted with chloroform (30 ml). The organic layer was dried over sodium sulfate and then filtered. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate = 1: 3) gave the title compound (50.7 mg, yield 10.1%) as a colorless oil. TLC Rf 0.35 (n-Hexane: AcOEt = 1: 3) ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.26 (5H, m, aromatic), 5.11 (2
H, m, CH ₂ O-CO), 4.99 (1H, br, NH), 4.46-4.11 (1H, m, H-4
A), 3.68 (6H, m, (CH ₂ ) ₂ O, H-4B, OH), 3.38 (1H, m, H-3), 2.
66-2.54 (6H, m, (CH ₂ ) ₃ N), 1.50, 1.25 (26H, m, (C H ₂ ) ₁₃ C
_{H 3), 0.88 (3H,} t, CH 3)

Example 54 Synthesis of (2S, 3S) -2-decanoylamino-1-morpholino-3-octadecanol (2S, 3S) -2-Benzyloxycarbonylamino-1-morpholino-3-octadeca Noor (59.2m
g, 0.117 mmol) was dissolved in a methylene chloride: methanol mixture (1: 1, 2 ml), 10% palladium carbon (21.3 mg, 17.0 mol%) was added, and the mixture was stirred under a hydrogen atmosphere. After 3 hours, palladium carbon was removed by filtration, and the filtrate was concentrated to give white crystals (39.7 mg). This white crystal (39.7 mg, 0.107 mmo
l) is a mixture of methylene chloride and methanol (1: 1, 2 m
1) and dissolved in triethylamine (39.0 μl, 0.
280 mmol) was added, and decanoyl chloride (48.0 μl, 0.234 mmol) was added dropwise under ice cooling.
After stirring at room temperature for 20 hours, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 40: 1) to give the title compound as a colorless oil (1
3.9 mg, yield 22.6%) were obtained. TLC Rf 0.44 (CHCl ₃ : MeOH = 20: 1), 0.36 (AcOEt: MeOH = 40:
1) ¹ H-NMR (CDCl ₃ ) δ: 5.80 (1H, d, J = 6.84Hz, NH), 3.95 (1H,
m, H-2), 3.69 (4H, m, (CH ₂ ) ₂ O), 3.58 (1H, m, H-3), 2.55 (6
H, m, (CH ₂ ) ₃ N), 2.19 (2H, m, CO-CH ₂ ), 1.62, 1.41, 1.25
(42H, m), 0.88 ( 6H, m, CH 3) 13 C-NMR (CDCl 3) δ: 173.5,74.9,66.8,60.1,54.0,
50.4, 36.8, 34.0, 31.9, 31.8, 29.7, 29.6, 29.4, 2
9.3, 29.2, 25.8, 22.7, 14.1

Example 55 Synthesis of (2S, 3S) -2-benzyloxycarbonylamino-1-morpholino-3-tridecanol (2S, 3S) -2-benzyloxycarbonylamino-1,3-tridecanediol-1 -Methanesulfonyl ester (556.2 mg, 1.256 mmol) in a tetrahydrofuran: ethanol mixture (1: 1, 4 ml)
And morpholine (330 μl, 3.79) at room temperature.
mmol) was added and the mixture was stirred at 40 ° C. After 3 days, morpholine (165 μl, 1.90 mmol) was added, and after stirring at 40 ° C. for another 3 days, the reaction solvent was evaporated under reduced pressure, and saturated sodium hydrogen carbonate solution (20 ml) was added,
It was extracted with chloroform (30 ml × 3), the organic layer was dried over sodium sulfate, and then filtered. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (n-
Purification with hexane: ethyl acetate = 1: 2) gave the title compound (27.1 mg, yield 5.0%) as a colorless oil. TLC Rf 0.29 (CHCl ₃ : MeOH = 20: 1), 0.28 (n-Hexane: AcOEt =
1: 2) ¹ H-NMR (CDCl ₃ ) δ: 7.39-7.25 (5H, m, aromatic), 5.11 (2
H, m, CH ₂ O-CO), 4.95 (1H, br, NH), 4.47-4.16 (1H, m, H-4
A), 3.85-3.62 (6H, m, (CH ₂ ) ₂ O, H-4B, OH), 3.41 (1H, m, H-
3), 2.63-2.41 (6H, m, (CH ₂ ) ₃ N), 1.52-1.42, 1.26 (16H,
m, (C H ₂ ) ₈ CH ₃ ), 0.88 (3H, t, CH ₃ )

Example 56 Synthesis of (2S, 3S) -2-decanoylamino-1-morpholino-3-tridecanol (2S, 3S) -2-benzyloxycarbonylamino-1-morpholino-3-tridecanol (25. 0m
g, 57.6 μmol) was dissolved in methanol (1 ml), and 10% palladium carbon (16.5 mg, 26.9 m) was added.
ol%) was added and the mixture was stirred under a hydrogen atmosphere. Two hours later,
Palladium carbon was removed by filtration, and the filtrate was concentrated to give white crystals (18.4 mg). This white crystal (17.3m
g, 57.6 μmol) was dissolved in methanol (0.5 ml) and triethylamine (20.0 μl, 0.143
mmol) and decanoyl chloride (2
4.0 μl, 0.117 mmol) was added dropwise. After 1 hour, methanol was added and the mixture was allowed to stand for 15 hours, then the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate), and the title substance (10.
4 mg, yield 39.8%) was obtained. TLC Rf 0.41 (CHCl ₃ : MeOH = 20: 1), 0.29 (AcOEt: MeOH = 40:
1) ¹ H-NMR (CDCl ₃ ) δ: 5.80 (1H, d, J = 6.34Hz, NH), 3.95 (1H,
m, H-2), 3.69 (4H, m, (CH ₂ ) ₂ O), 3.58 (1H, m, H-3), 2.60-
2.55 (6H, m, (CH ₂ ) ₃ N), 2.19 (2H, m, CO-CH ₂ ), 1.62, 1.4
1,1.26 (32H, m), 0.88 (6H, m, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 173.5, 74.9, 66.8, 60.1, 54.0,
50.4, 36.8, 34.0, 31.9, 31.8, 29.7, 29.6, 29.5, 2
9.3, 25.8, 22.7, 14.1

Example 57 Synthesis of (2S, 3S) -2-benzyloxycarbonylamino-1-morpholino-3-nonanol (2S, 3S) -2-benzyloxycarbonylamino-1,3-nonanediol-1- Methanesulfonyl ester (715.7 mg, 1.850 mmol) was dissolved in a methylene chloride: methanol mixture (2: 1, 10 ml), and morpholine (480 μl, 5.51 mmo) was added at room temperature.
1) was added, and the mixture was stirred at 40 ° C. Two days later, morpholine (160 μl, 1.84 mmol) was added and another 2
After stirring at 40 ° C. for 30 days, the reaction solvent was evaporated under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and the mixture was extracted with chloroform (30 ml × 3). The organic layer was dried over sodium sulfate and then filtered. . After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to obtain the title compound (76.1 mg, yield 10.9%) as a colorless oil. . TLC Rf 0.53 (CHCl ₃ : MeOH = 20: 1), 0.29 (n-Hexane: AcOEt =
(1: 2)

Example 58 Synthesis of (2S, 3S) -2-decanoylamino-1-morpholino-3-nonanol (2S, 3S) -2-benzyloxycarbonylamino-1-morpholino-3-nonanol (68. 1 mg,
0.180 mmol) was dissolved in methanol (2 ml) and 10% palladium carbon (36.8 mg, 19.2 m) was added.
ol%) was added and the mixture was stirred under a hydrogen atmosphere. After 15 hours, palladium carbon was removed by filtration, and the filtrate was concentrated to give a colorless oil (55.9 mg). This colorless oil (4
3.9 mg, 0.180 mmol) in methanol (1 m
l) and dissolved in triethylamine (37.6 μl, 0.
270 mmol) was added, and decanoyl chloride (48.0 μl, 0.234 mmol) was added dropwise under ice cooling.
After stirring at room temperature for 18 hours, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1), and the title substance (6.
0 mg, yield 8.4%) was obtained. TLC Rf 0.42 (CHCl ₃ : MeOH = 20: 1), 0.44 (AcOEt: MeOH = 20:
1) ¹ H-NMR (CDCl ₃ ) δ: 5.80 (1H, d, J = 6.35Hz, NH), 3.95 (1H,
m, H-2), 3.69 (4H, m, (CH ₂ ) ₂ O), 3.59 (1H, m, H-3), 2.55 (6
H, m, (CH ₂ ) ₃ N), 2.19 (2H, m, CO-CH ₂ ), 1.62, 1.41, 1.2
9, 1.28, 1.26 (24H, m), 0.88 (6H, m, CH ₃ ) ¹³ C-NMR (CDCl ₃ ) δ: 173.5, 74.9, 66.9, 60.1, 54.0,
50.4, 36.8, 34.0, 31.8, 29.5, 29.4, 29.3, 25.8, 2
5.7, 22.6, 14.1

[Brief description of drawings]

FIG. 1 is a schematic diagram showing a synthetic route of the method of the present invention.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location C07C 271/48 9451-4H C07C 271/48 309/66 7419-4H 309/66 C07D 295/12 C07D 295/12 ZA

Claims (12)

[Claims] 1. A general formula (1) ## STR1 ## ^{_{Y-CH 2 -C * H (}} NHP 1) -C * H (OH) -R 1 ··· (1) ( wherein ^* asymmetric represents a carbon, P ¹ represents an alkyl group or an amino-protecting group, R ¹ represents an alkyl group, a cycloalkyl group or an aryl group, Y is an aminopropanol derivative represented by the representative.) the leaving group, R ² H (in the formula, R ²
Is a group represented by the following formulas (I) to (VI). (2) R ² —CH ₂ —C ^* H (NHP ¹ ) —C ^* H (OH) —R ¹ ... (2) (wherein , P ¹ , R ¹ and R ² have the same meanings as defined above, and P ¹ is eliminated from the compound to give a compound of the general formula (3) R ² —CH ₂ — _{^{C * H (NH 2) -C}} * H (OH) -R 1 ··· (3) ( wherein, R ¹ and R ² are as defined above) to synthesize an amino alcohol derivative represented by, then R ¹¹ COOH (In the formula, R ¹¹ has 3 to 18 carbon atoms which may have a hydroxyl group.
Represents an alkyl group or an alkenyl group. ) Is reacted with a carboxylic acid represented by the formula (4) or a reactive derivative thereof, and R ² —CH ₂ —C ^* H (NHCOR ¹¹ ) —C ^* H (OH) —R ¹ ... (4) A method for producing a 2-acylaminoalcohol derivative, which comprises obtaining a 2-acylaminoalcohol derivative represented by the formula (wherein R ¹ , R ² and R ¹¹ are as defined above). Embedded image [Wherein R ³ and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy lower alkyl group, a lower alkoxyalkyl group, an amino lower alkyl group, a cycloalkyl group, a hydroxycycloalkyl group, An aralkyl group or a piperazino group which may be substituted with a lower alkyl group is represented, and R ⁵ is a hydrogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group, a hydroxy lower alkyl group, a carboxyl group, a lower alkoxycarbonyl group, an aralkyl group. , A piperidino group, an acyloxy group, an amino group and an amino lower alkyl group 1
Or two or more same or different substituents, R ⁶ represents a hydrogen atom or one or more same or different substituents same as R ^5, and R ⁷ represents a lower alkylene group which may be interrupted by oxygen. R ⁸ and R ⁹ are the same or different and represent a hydrogen atom, a lower alkyl group or a hydroxy lower alkyl group, or R ⁸ and R ⁹ are substituted with a lower alkyl group together with the nitrogen atom to which they are bonded. Optionally represents a piperidino group or a morpholino group, m represents an integer of 2 to 6, p represents 2 or 3, and X represents the following formula (VII) or (VIII)
Represents [Chemical 6] (In the formula, R ¹⁰ is a hydrogen atom, a lower alkyl group, an acyl group,
Represents a lower alkoxycarbonyl group or a pyridyl group)]. 2. The method according to claim 1, wherein R ^{1 of the} compound represented by the general formula (1) is selected from an alkyl group, a cycloalkyl group, or lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl and nitro. A phenyl group which may be substituted with 1 to 3 same or different substituents, wherein P ¹ is nitro, halogen,
Lower alkoxy, lower alkoxy benzyloxycarbonyl group which may be substituted by phenylazo or phenylazo group, or alkoxycarbonyl containing linear, branched or cyclic alkyl group which may be substituted by fluorenyl or methylsulfonyl group A method for producing a 2-acylaminoalcohol derivative, which is an amino-protecting group selected from the group or an alkyl group having 3 to 18 carbon atoms. 3. The method according to claim 1, wherein R ^{1 of the} compound represented by the general formula (1) is phenyl, dimethoxyphenyl or dihydroxyphenyl, and the amine represented by R ² H is morpholine. And 2
-A method for producing an acylamino alcohol derivative. 4. The method according to claim 1, wherein R ^{1 of the} compound represented by the general formula (1) is an alkyl group having 6 to 15 carbon atoms, a cyclohexyl group or a phenyl group, and R ²
The amine represented by H is a lower alkylamine; a morpholino lower alkylamine; a cycloalkylamine which may be substituted with a hydroxy group; a pyrrolidine which may be substituted with a hydroxy group or a hydroxy lower alkyl group; Optionally selected from piperazine; bis (hydroxy lower alkyl) amine; and piperidine optionally substituted with a hydroxy group or a hydroxy lower alkyl group.
-A method for producing an acylamino alcohol derivative. 5. An amino alcohol derivative represented by the following general formula (2). Embedded image R ² —CH ₂ —C ^* H (NHP ¹ ) —C ^* H (OH) —R ¹ (2) (In the formula, ^* represents an asymmetric carbon and P ¹ , R ¹ And R ² has the same meaning as defined in claim 1.) 6. In the general formula (2), R ¹ is an alkyl group, a cycloalkyl group, or 1 to 3 substituents which are the same or different and are selected from lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl and nitro. A phenyl group which may be substituted with P ¹ , and P ¹ is substituted with a benzyloxycarbonyl group which may be substituted with a nitro, halogen, lower alkoxy, lower alkoxy phenylazo or phenylazo group, and a fluorenyl group or a methylsulfonyl group. Straight chain, which may be
An amino protecting group selected from alkoxycarbonyl groups containing a branched or cyclic alkyl group, or having 3 carbon atoms
The amino alcohol derivative according to claim 5, which is an alkyl group of -18. 7. In the general formula (2), R ¹ has 6 to 6 carbon atoms.
15 is an alkyl group, a cyclohexyl group or a phenyl group, P ¹ is an amino protecting group or a decyl group selected from a benzyloxycarbonyl group, a t-butoxycarbonyl group and an octyloxycarbonyl group, and R 1
² is a morpholino group; a lower alkylamino group; a morpholino lower alkylamino group; a cycloalkylamino group which may be substituted with a hydroxy group; a pyrrolidino group which may be substituted with a hydroxy group or a hydroxy lower alkyl group; a lower alkyl A piperazino group optionally substituted with a group; a bis (hydroxy lower alkyl) amino group;
And an amino group selected from a piperidino group which may be substituted with a hydroxy group or a hydroxy lower alkyl group, and the amino alcohol derivative according to claim 5. 8. In the general formula (2), R ¹ is a phenyl group, P ¹ is a benzyloxycarbonyl group, and R ²
Is a morpholino group, a pyrrolidino group, a hydroxypyrrolidino group, a hydroxypiperidino group, an N-methylpiperazino group, a diethanolamino group, or a hydroxycyclohexylamino group, the configuration of which is (1S, 2S).
The amino alcohol derivative according to claim 5, wherein 9. In the general formula (2), R ¹ is a phenyl group, P ¹ is a benzyloxycarbonyl group, and R ²
Is a morpholino group, a pyrrolidino group, a piperidino group, a cyclohexylamino group or a cyclopentylamino group, and the steric configuration is (1R, 2R). 10. General formula (1) embedded image Y—CH ₂ —C ^* H (NHP ¹ ) —C ^* H (OH) —R ¹ ... (1) (wherein ^* is asymmetric represents a carbon, P ¹ represents an alkyl group or an amino-protecting group, R ¹ represents an alkyl group, a cycloalkyl group or an aryl group, Y is an aminopropanol derivative represented by the representative.) the leaving group, R ² H (in the formula, R ²
Is as defined in claim 1. (2) R ² —CH ₂ —C ^* H (NHP ¹ ) —C ^* H (OH) —R ¹ ... (2) (wherein , P ¹ , R ¹ and R ² have the same meanings as defined above, and the amino alcohol derivative represented by the above is obtained. 10. The method for producing an amino alcohol derivative according to claim 5, wherein 11. An aminoalcohol derivative represented by the general formula (3). Embedded image R ² —CH ₂ —C ^* H (NH ₂ ) —C ^* H (OH) —R ¹ (3) (wherein ^* represents an asymmetric carbon, and R ¹ and R ² Is claim 1
Has the same meaning as the definition described in. ) 12. In the general formula (3), R ¹ has 6 carbon atoms.
To 15 alkyl group, cyclohexyl group or phenyl group, R ² is morpholino group; lower alkylamino group; morpholino lower alkylamino group; cycloalkylamino group optionally substituted with hydroxy group; hydroxy group or hydroxy group. Pyrrolidino group optionally substituted with lower alkyl group; Piperazino group optionally substituted with lower alkyl group; bis (hydroxy lower alkyl) amino group; and optionally substituted with hydroxy group or hydroxy lower alkyl group The amino alcohol derivative according to claim 11, which is an amino group selected from a piperidino group.