JP2007204495A - Method for producing aminoalcohol derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing stereoselectively a propanol derivative having a 2-acylamino group from an aminopropanol derivative whose amino group is protected, through several processes. <P>SOLUTION: This method for producing the 2-acylaminopropanol compound comprises mesylating a 2-aminopropanediol compound whose amino group is protected, reacting the product with an amine compound, releasing the amino-protecting group from the obtained 2-aminopropanol compound, and then reacting the product with an acylating agent or a carboxylic acid-amine condensing agent. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing a 2-acylaminoalcohol derivative having an action of promoting or suppressing biosynthesis of glycolipid and an action of antiviral, antitumor, cancer metastasis and nerve cell growth.

  2-decanoylamino-3-morpholino-1-phenyl-1-propanol (hereinafter abbreviated as PDMP) represented by the following formula, which is a 2-acylamino alcohol derivative.

は糖脂質の生合成制御活性を有するが、その活性は４種類存在する立体異性体間で大きく異なる。そのため、光学活性な異性体の分離はデカノイルアミノアセトフェノンをマンニッヒ反応でモルホリンと縮合させた後、水素化ホウ素ナトリウムで還元してＰＤＭＰを４種類の立体異性体の混合物として得た後、結晶化法によりジアステレオマーを分割し、さらに、ラセミ体を結晶化法にて光学分割することにより行われている（非特許文献１及び２）。
J. Lipid. Res., 28, 565-571,1987 Advancesin Lipid Research, 26, 183-213, 1993

Has biolipid biosynthesis control activity, but its activity varies greatly among the four stereoisomers. Therefore, optically active isomers were separated by condensing decanoylaminoacetophenone with morpholine by Mannich reaction, and then reducing with sodium borohydride to obtain PDMP as a mixture of four stereoisomers, followed by crystallization. The diastereomer is divided by the method, and the racemate is optically resolved by the crystallization method (Non-patent Documents 1 and 2).
J. Lipid. Res., 28, 565-571,1987 Advancesin Lipid Research, 26, 183-213, 1993

  An object of the present invention is to provide a method for efficiently obtaining PDMP having a plurality of asymmetric centers from chiral compounds and an optically active compound thereof, and requires a particularly complicated optical resolution step. It provides a stereoselective synthesis method that does not.

  The inventors of the present invention have conducted research to develop a more convenient and general stereoselective production method of PDMP and its analogs. As a result, the present inventors have two asymmetric centers in the molecule, and peptide synthesis Synthesis consisting of a reaction that proceeds with steric retention using N-protected-2-aminopropanediol, which is protected at low cost by a urethane-type protecting group as a reagent for use, as the main starting material and asymmetric source By establishing a route, it was found that all four stereoisomers of PDMP or its analogs could be synthesized stereoselectively, and the present invention was completed.

  That is, the gist of the present invention is as follows.

General formula (1)
[Chemical 1]
Y—CH ₂ —C * H (NHP ¹ ) —C * H (OH) —R ¹ (1)
(In the formula, * represents an asymmetric carbon, and P ¹ is substituted with a benzyloxycarbonyl group, a fluorenyl group or a methylsulfonyl group which may be substituted with a nitro, halogen, lower alkoxy, lower alkoxyphenylazo or phenylazo group. Represents an amino protecting group or an alkyl group selected from an alkoxycarbonyl group containing a linear, branched or cyclic alkyl group and a benzenesulfonyl group, and R ¹ represents an alkyl group, a cycloalkyl group or an aryl group. , Y is a methanesulfonyl group, trihalogenoalkyl methanesulfonyl group, p- toluenesulfonyl group, a benzenesulfonyl group, and p- bromo represents a leaving group selected from a benzenesulfonyl group. aminopropanol derivative represented by), R ² H (wherein, R ² is represented by the following formula (I) ~ (VI) A group.) In reacted with an amine represented the general formula (2)
[Chemical 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 described above) are synthesized, P ¹ is eliminated from the compound, and the general formula (3)
[Chemical 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), and then R ¹¹ COOH (wherein R ¹¹ is an alkyl having 3 to 18 carbon atoms optionally having a hydroxyl group). A carboxylic acid or a reactive derivative thereof represented by the general formula (4)
[Chemical formula 4]
R ² —CH ₂ —C * H (NHCOR ¹¹ ) —C * H (OH) —R ¹ (4)
(Wherein R ¹ , R ² and R ¹¹ have the same meanings as described above).

〔式中、Ｒ³及びＲ⁴は、同一又は異なり、水素原子、低級アルキル基、低級アルケニル基、ヒドロキシ低級アルキル基、低級アルコキシアルキル基、アミノ低級アルキル基、シクロアルキル基、ヒドロキシシクロアルキル基、アラルキル基又は低級アルキル基が置換されていてもよいピペラジノ基を表し（但し、Ｒ ³ 及びＲ ⁴ は、同時に水素原子であることはない。）、Ｒ⁵は水素原子、ヒドロキシ基、低級アルキル基、低級アルコキシ基、ヒドロキシ低級アルキル基、カルボキシル基、低級アルコキシカルボニル基、アラルキル基、ピペリジノ基、アシルオキシ基、アミノ基及びアミノ低級アルキル基から選ばれる１又は２以上の同一又は異なる置換基を表し、Ｒ⁶は水素原子又はＲ⁵と同一の１又は２以上の同一又は異なる置換基を表し、Ｒ⁷は酸素で中断されていてもよい低級アルキレン基を表し、Ｒ⁸及びＲ⁹は同一又は異なり、水素原子、低級アルキル基又はヒドロキシ低級アルキル基を表すか、或いはＲ⁸とＲ⁹はそれらが結合している窒素原子と共に低級アルキル基が置換していてもよいピペリジノ基又はモルホリノ基を表し、ｍは２〜６の整数を表し、ｐは２又は３を表し、Ｘは下記式(VII)又は(VIII)を表す。

[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 (wherein R ³ and R ⁴ are not simultaneously a hydrogen atom) , R ⁵ is a hydrogen atom, a hydroxy group or a lower alkyl group; Represents one or two or more identical or different substituents selected from 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, R ⁶ represents a hydrogen atom or R ⁵ the same one or more identical or different substituents, ⁷ represents an optionally substituted lower alkylene group which may be interrupted by oxygen, R ⁸ and R ⁹ are the same or different, a hydrogen atom, or a lower alkyl group or a hydroxy lower alkyl group, or R ⁸ and R ⁹ are those A piperidino group or a morpholino group that may be substituted with a lower alkyl group together with the nitrogen atom bonded thereto, m represents an integer of 2 to 6, p represents 2 or 3, and X represents the following formula (VII) Or (VIII).

（式中、Ｒ¹⁰は水素原子、低級アルキル基、アシル基、低級アルコキシカルボニル基又はピリジル基を表す）〕。

(Wherein R ¹⁰ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxycarbonyl group or a pyridyl group)].

  According to the method of the present invention, using an N-protected-2-aminopropanol derivative as a raw material, PDMP having a plurality of asymmetric centers and an optically active substance of the analog thereof can be efficiently used without particularly complicated optical resolution. Can be synthesized. That is, since the four stereoisomers of the PDMP analog can be synthesized stereoselectively, the method of the present invention is extremely useful.

Hereinafter, the present invention will be described in detail.
PDMP and its analogs, which are found as glycolipid biosynthesis regulators, are other interesting compounds having physiological effects such as antiviral, antitumor, cancer metastasis suppression and nerve cell growth promoting action. These are structurally based on 2-aminoalcohol and have at least two asymmetric carbons in the molecule, but the four stereoisomers resulting therefrom have different actions, so PDMP and its analogs In order to study the correlation 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, the present invention uses, as a main starting material, a 2-aminopropanediol derivative having two asymmetric carbon atoms in the molecule and having an amino group protected by a urethane-type protecting group, and thus, four types of PDMP analogs. This is based on the novel findings shown below.
1) Use a chiral compound having two asymmetric carbon atoms in the molecule as a starting material. 2) Introduce a leaving group (such as a mesyl group) into only the primary hydroxyl group from the primary and secondary hydroxyl groups. After doing so, the substitution of the mesyl group with a primary or secondary amine, 3) the stereoselective synthesis of PDMP was made possible by constituting all the reaction steps with steric retention.

Hereinafter, the present invention will be described according to the synthesis route shown in FIG. In the present invention, “lower” means having 1 to 6 carbon atoms. In the method of the present invention, an 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, but is 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, a benzyloxycarbonyl group which may be substituted with a nitro, halogen, lower alkoxy, lower alkoxyphenylazo or phenylazo group, or fluorenyl or methylsulfonyl. An amino-protecting group such as an alkoxycarbonyl group containing a linear, branched or cyclic alkyl group having 1 to 15 carbon atoms which may be substituted with a group, specifically a benzyloxycarbonyl group or a substituted benzyl group. Oxycarbonyl groups such as p-nitrobenzyloxycarbonyl group, p-bromobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group and the like; alkoxycarbonyl groups such as t-butoxycal It represents an amino protecting group such other benzenesulfonyl group; sulfonyl group, cyclopentyloxy group, octyloxy carbonyl group or a substituted alkoxycarbonyl group, such as 9-fluorenylmethoxycarbonyl group, methylsulfonyl ethoxycarbonyl group.

  Y represents a leaving group, specifically, a leaving group selected from methanesulfonyl (mesyl), trihalogenomethanesulfonyl such as trifluoromethanesulfonyl, p-toluenesulfonyl, benzenesulfonyl, and p-bromobenzenesulfonyl group. To express.

The aminopropanol derivative is obtained by cooling the optically active N-protected-2-aminopropanediol represented by (Compound a) in FIG. 1 in a solvent such as pyridine or an anhydrous solvent such as dichloromethane in the presence of pyridine. It can be produced by methanesulfonylation (mesylation) of only the primary hydroxyl group of the diol by treating with methanesulfonyl chloride (Ms-Cl) at room temperature, for example (step 1). After isolation of this product, in some cases without isolation, the product is treated with an amine of the formula R ² H in an organic solvent such as ethyl alcohol or N, N-dimethylformamide as a starting material. It can lead to the compound shown in 2) (step 2).

This amine is represented by R ² H, wherein R ² represents the above formulas (I) to (VI), and in the formulas (I) to (VI), the cycloalkyl group or hydroxycycloalkyl group has 3 carbon atoms. -8, and the carbon number of the aralkyl group is 6-20. R ² is preferably a morpholino group; a lower alkylamino group; a morpholino lower alkyl 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 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 group.
In the compound represented by the general formula (1), R ¹ is preferably phenyl, dimethoxyphenyl, or dihydroxyphenyl, and the amine represented by R ² H is preferably morpholine .

In Step 3, the alkyl group or amino-protecting group protecting the amino group is removed by a conventional method such as catalytic reduction, acid treatment, base treatment, etc., and the resulting compound is represented by the general formula (3). Next, the produced amino group is acylated with a carboxylic acid represented by the formula R ¹¹ COOH or a reactive derivative thereof, for example, an acid halide or an acid anhydride of carboxylic acid, thereby showing the target general formula (4). (Step 4). In this formula, R ¹¹ represents an alkyl group or alkenyl group having 3 to 18 carbon atoms, and may have a hydroxyl group at the 2- or 3-position thereof. 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 reacted with a carboxylic acid having 8 to 16 carbon atoms (R ¹¹ COOH) and a condensing agent usually used in an amide bond reaction to obtain the target general formula (4). It can also lead to the 2-acylaminoalcohol derivative shown (step 4). Specifically, as carboxylic acid, octanoic acid, 2-hydroxyoctanoic acid, decanoic acid, 2-hydroxydecanoic acid, dodecanoic acid, 2-hydroxydodecanoic acid, myristic acid, 2-hydroxymyristic acid, palmitic acid, 2-hydroxy Fatty acids such as palmitic acid and hydroxy-substituted fatty acids are used, and as the condensing agent, known ones such as dicyclohexylcarbodiimide and water-soluble carbodiimide are used. Specific examples of the water-soluble carbodiimide include 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDC).

In a preferred embodiment of the amino alcohol derivative represented by the general formula (1) and the general formula (2) in the above production process, in the general formula (1) and the general formula (2), R ¹ is an alkyl group, a cycloalkyl group, Or a phenyl group which may be substituted with 1 to 3 identical or different substituents selected from lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl and nitro, and P ¹ is nitro, halogen, lower alkoxy, Selected from benzyloxycarbonyl group optionally substituted by lower alkoxyphenylazo or phenylazo group and alkoxycarbonyl group including linear, branched or cyclic alkyl group optionally substituted by fluorenyl or methylsulfonyl group An amino protecting group or an alkyl group having 3 to 18 carbon atoms R ² is an amino alcohol derivative having the same definition as in claim 1.

In another preferred embodiment, in general formulas (1) and (2), R ¹ is an alkyl group having 6 to 15 carbon atoms, a cyclohexyl group, or a phenyl group, P ¹ is a benzyloxycarbonyl group, t An amino protecting group or decyl group selected from a butoxycarbonyl group and an octyloxycarbonyl group, wherein R ² is a morpholino group; a lower alkylamino group; a morpholino lower alkylamino group; a cycloalkyl optionally substituted by a hydroxy group Pyrrolidino group optionally substituted with hydroxy group or hydroxy lower alkyl group; piperazino group optionally substituted with lower alkyl group; bis (hydroxy lower alkyl) amino group; and hydroxy group or hydroxy lower alkyl group Selected from piperidino groups optionally substituted with An amino alcohol derivative which consists in an amino group.

In a further preferred embodiment, 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. N-methylpiperazino group, bis (hydroxyethyl) amino group, or hydroxycyclohexylamino group, and the steric configuration thereof is (1S, 2S), or an amino alcohol derivative represented by general formula (2), or R ¹ Is a phenyl group, 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 the configuration thereof is (1R, 2R) An amino alcohol derivative.

In a preferred embodiment of the amino alcohol derivative represented by the general formula (3) obtained in the production process, in the general formula (3), R ¹ is an alkyl group having 6 to 15 carbon atoms, 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 optionally substituted with a hydroxy group; a pyrrolidino group optionally substituted with a hydroxy group or a hydroxy lower alkyl group; An amino group comprising a piperazino group optionally substituted with a lower alkyl group; a bis (hydroxy lower alkyl) amino group; and an amino group selected from a hydroxy group or a piperidino group optionally substituted with a hydroxy lower alkyl group It is an alcohol derivative.

  In the method of the present invention, the product may be isolated in each step of the production process. However, in some cases, the product is isolated using an optically active diol which is a raw material of the general formula (1) as a starting material. Instead, the stepwise reaction as described above can be carried out gradually to lead to the target 2-acylaminoalcohol derivative represented by the general formula (4).

  As a method for synthesizing N-protected-2-aminopropanediols, which are starting materials of the amino alcohol derivative of the general formula (1), which is the starting material of the present invention, a method of reducing aminoketones (J. Org. Chem. 54, 1866 (1989)), N- (diphenylmethylene) amino acid ester treated with diisobutylaluminum hydride followed by Grignard reagent (J. Org. Chem., 57, 5469 (1992)), N-protection -Method of reacting aminoaldehyde or N-protected amino acid acid chloride with organometallic reagent (J. Am. Chem. Soc., 95, 4098 (1973)), Asymmetric aldol reaction of 2-oxazolidinone and aldehyde ( J. Am. Chem. Soc., 108, 6757 (1986)) (Evans method), chiral imidazolidinone and asymmetric aldol reaction of oxazolidinone and aldehyde (Helv. Chem. Acta, 70, 237 (1987)), etc. It has been known. On the other hand, as a method for synthesizing N-protected-α-amino ketones as raw materials for N-protected-2-aminopropanediols, an N-protected-α-amino acid is used as a starting material and an amino acid carboxyl group is converted into an acid chloride. After conversion, a method of reacting benzene with Friedel-Crafts (J. Am. Chem. Soc., 103, 6157 (1981)), treating the carboxyl group of the amino acid with an alkyl lithium reagent to form a lithium salt, and then Grignard A method of reacting with a reagent is known (J. Org. Chem., 54, 1866 (1989)).

  EXAMPLES Next, although an Example demonstrates this invention still in detail, this invention is not limited to a following example, unless the summary is exceeded. In the following examples, MeOH, 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) was dissolved in pyridine (350 ml), and methanesulfonyl chloride (5.6 ml, 72.3 mmol) was added dropwise over 5 minutes on ice. After stirring for 30 minutes on an ice bath, the mixture was stirred overnight at room temperature. After confirming that the reaction was completed by TLC (chloroform: methanol = 20: 1), the solvent was distilled off, ethyl acetate (500 ml) was added, 1N HCl (250 ml × 3), saturated brine ( 250 ml) and dried over sodium sulfate, and the solvent was distilled off. The precipitated crystals were washed with ethyl acetate: hexane = 1: 1 to obtain the title material (25.3 g, yield 95.0%) as white crystals.
TLC Rf 0.55 (CHCl ₃ : MeOH = 20: 1), 0.83 (AcOEt), 0.62 (Hexane: AcOEt = 1: 2)
¹ H-NMR (CDCl ₃ ) δ: 7.35-7.26 (10H, m, aromatic), 5.30 (1H, d, J = 7.81Hz, NH), 5.02 (2H, s, CH ₂ -O-CO), 4.99 (1H, d, J = 3.91Hz, 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) was dissolved in methylene chloride (150 ml), pyridine (12.1 ml, 149.6 mmol) was added, and then methanesulfonyl chloride (4. 5 ml, 58.1 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, hexane: ethyl acetate = 1: 1), water (100 ml) and chloroform (50 ml) were added, and the organic layer was 1N-hydrochloric acid. , Washed sequentially with 100 ml each of water, saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate and filtered. The solvent was distilled off, hexane: ethyl acetate = 2: 1 (100 ml) was added, and the mixture was left overnight. The precipitated crystals were collected by filtration and washed with hexane: ethyl acetate = 2: 1 to give the title compound (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 mmol) was dissolved in ethanol (50 ml), morpholine (9.8 ml, 112.6 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. for 3 days. After confirming the completion of the reaction by TLC (chloroform: methanol = 20: 1, hexane: ethyl acetate = 1: 2, ethyl acetate), the solvent was distilled off, water (50 ml), ethyl acetate (150 ml) ), 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 obtain the title material (3.61 g, yield 38.1%) as a colorless oil.
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 mmol) was dissolved in N, N-dimethylformamide (6 ml), and morpholine (1.11 g, 12.8 mmol) was added at room temperature. Stir for hours. After confirming that the reaction was almost complete by TLC (chloroform: methanol = 20: 1, hexane: ethyl acetate = 1: 2, ethyl acetate), saturated sodium hydrogen carbonate solution (70 ml), ethyl acetate (100 ml) The organic layer was washed successively with 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 obtain the title material (507.5 mg, yield 43.0%) as a colorless oil.

Example 5 Synthesis of (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-Benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (438.8 mg, 1.19 mmol) was dissolved in methanol (10 ml), 10% palladium carbon (126.5 mg, 10.0 mol%) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. After confirming that the reaction was completed by TLC (chloroform: methanol = 9: 1 and 7: 3), palladium carbon was removed by filtration. The filtrate was concentrated to give the title material (275.6 mg, yield 98.5%) as a colorless oil.
TLC Rf 0.48,0.24 (CHCl ₃ : MeOH = 7: 3) (tailing), 0.68 (CHCl ₃ : MeOH: aqNH ₃ = 4: 1: trace)
¹ H-NMR (CD ₃ OD) δ: 7.36-7.26 (5H, m, aromatic), 4.47 (1H, d, J = 6.60Hz, H-1), 3.65 (4H, m, (CH ₂ ) ₂ O ), 3.21-3.14 (1H, m, H-2), 2.51-2.43, 2.32-2.24, 2.11-2.05 (6H, m, (CH ₂ ) ₃ N)

Example 6 Synthesis of (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-Benzyloxycarbonylamino-3-morpholino-1-phenyl-1-propanol (3.82 g, 10.3 mmol) was dissolved in methanol (10 ml), ammonium formate (2.6 g, 41.3 mmol), 10% palladium on carbon (888.5 mg, 8.09 mol%) was added, and at room temperature overnight. Stir. After confirming that the reaction was completed by TLC (chloroform: methanol = 9: 1 and 7: 3), palladium carbon was removed by filtration. The filtrate was concentrated to give the title material (2.34 g, yield 99.0%) as a colorless oil.

Example 7 Synthesis of (1S, 2S) -2-decanoylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol ( 1.33 g, 4.0 mmol) was dissolved in methanol (4 ml), and decanoyl chloride (0.82 ml, 4.0 mmol) was added under ice-cooling in the presence of triethylamine (668.0 μl, 4.8 mmol). . After 30 minutes, TLC (ethyl acetate, chloroform: methanol = 20: 1, chloroform: methanol = 7: 3) confirmed that the reaction was almost complete, then added methanol (30 ml) and left for 90 minutes. . The reaction solution was concentrated under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water (20 ml) and saturated brine (20 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an oil (853.5 mg). The obtained oil was purified by silica gel column chromatography (ethyl acetate) to obtain the title material (930.5 mg, yield 59.6%) as a colorless oil.
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 (1H, d, J = 7.26Hz, NH), 4.95 (1H, d, J = 3.63Hz, H-1) , 4.28 (1H, m, H-2), 3.72 (4H, m, (CH ₂ ) ₂ O), 2.63-2.44 (6H, m, (CH2) 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) was dissolved in tetrahydrofuran (4 ml), decanoic anhydride (109.2 mg, 0.334 mmol) was added under ice-cooling in the presence of triethylamine (80.0 μl, 0.575 mmol), Stir for one day at room temperature. After confirming that the reaction was almost completed by TLC (ethyl acetate, chloroform: methanol = 20: 1, chloroform: methanol = 7: 3), ethyl acetate (30 ml) and saturated sodium bicarbonate solution (20 ml) were added. The organic layer was washed with water (20 ml) and saturated brine (20 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an oil (130.8 mg). The obtained oil was purified by silica gel column chromatography (ethyl acetate) to obtain the title material (37.2 mg, yield 40.5%) as a colorless oil.

Example 9 Synthesis of (1S, 2S) -2-decanoylamino-3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-Benzyloxycarbonylamino-1-phenyl-1,3-propane Diol-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. . After confirming that the reaction was almost completed by TLC (n-hexane: 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 washed with saturated sodium hydrogen carbonate solution (50 ml), water (50 ml × 2) and saturated brine (50 ml), and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oil (13.7 g). Methanol (50 ml) and 10% palladium carbon (2.3 g, 8.6 mol%) were added to the oil, and the mixture was vigorously stirred overnight under a hydrogen atmosphere. 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 give an oil (9.33 g). This oil was dissolved in methanol (25 ml), triethylamine (4.2 ml, 30 mmol) was added, and decanoyl chloride (5.15 ml, 25 mmol) was added dropwise under ice cooling. After 30 minutes, TLC (ethyl acetate, chloroform: methanol = 20: 1, chloroform: methanol = 7: 3) confirmed that the reaction was almost complete, then added methanol (20 ml) and allowed to stand 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 was washed with water (40 ml × 3) and saturated brine (40 ml), dried over sodium sulfate, and concentrated under reduced pressure to give an oil (9.73 g). The obtained oil was purified by silica gel column chromatography (ethyl acetate) to obtain the title material (4.35 g, yield 44.6%) as a colorless oil.

Example 10 (1S, 2S, 2 ′S) -2- (2′-hydroxydecanoylamino) -3-morpholino-1-phenyl-1-propanol and (1S, 2S, 2′R) -2- ( Synthesis of 2′-hydroxydecanoylamino) -3-morpholino-1-phenyl-1-propanol (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol (141.5 mg, 0. 600 mmol) was dissolved in methylene chloride (6 ml), 2-hydroxydecanoic acid (100 mg, 0.531 mmol) and N-hydroxysuccinimide (150.8 mg, 1.131 mmol) were added, and the mixture was stirred at room temperature for 15 minutes. Add 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (134.0 mg, 0.699 mmol) on the bath It was stirred overnight. After confirming that the reaction was almost completed by TLC (ethyl acetate, chloroform: methanol = 20: 1), ethyl acetate (30 ml) was added, and the organic layer was mixed with 5% citric acid aqueous solution (15 ml), saturated bicarbonate. The mixture was washed successively with sodium solution (15 ml) and water (15 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, chloroform: methanol = 20: 1) to give 15.6 mg of (1S, 2S, 2 ′S) isomer of the title substance ((1S, 2S, 2 ′S)) (1S , 2S, 2′R) was obtained. The absolute configuration of the title compound was identified by performing synthesis in the same manner using (2R) -2-hydroxydecanoic acid as a raw material.

(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 (1H, 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 )), 1.31-1.20 (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, 126.0, 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 (CDCl3) δ: 7.37-7.25 (5H, m, aromatic), 6.88 (1H, 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, 126.0, 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 mmol) was dissolved in ethanol, N-methylpiperazine (1.92 g, 19.2 mmol) was added, and the mixture was stirred at 40 ° C. for 3 days. After completion of the reaction, the solvent was distilled off under reduced pressure, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off. Next, the extract was dissolved in methanol, 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, and 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, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off. Next, the extract was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to obtain the title material (10.0 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.25 (5H, m, aromatic), 5.91 (1H, d, J = 7.3 Hz, NH), 4.95 (1H, d, J = 3.4 Hz, 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 (1H, 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 N-methyl according to the method of Example 11 A similar synthesis was performed using (2S) -2-hydroxymethylpyrrolidine instead of piperazine to obtain the title material (89.6 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.35 to 7.23 (5H, m, aromatic), 6.13 (1H, d, J = 6.3 Hz, NH), 4.99 (1H, d, J = 3.4 Hz, 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), 1.80-1.73 (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, 125.7, 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 Synthesis of (1S, 2S) -2-decanoylamino-3- (3-hydroxypyrrolidino) -1-phenyl-1-propanol According to the method of Example 11, instead of N-methylpiperazine, Synthesis was carried out in the same manner using 3-hydroxypyrrolidine to obtain the title material as a colorless oil (a mixture of diastereomers in a ratio of 1: 1, 88.3 mg).
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, 127.5, 127.4, 125.9, 75.3, 75.1, 71.1, 71.0, 63.7, 57.6, 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. Synthesis gave the title material (92.2 mg) as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.23 (5H, m, aromatic), 5.91 (1H, d, J = 7.8 Hz, NH), 5.05 (1H, d, J = 3.4 Hz, 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—CH 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, 125.9, 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 Synthesis of (1S, 2S) -2-decanoylamino-3- (3-hydroxymethylpiperidino) -1-phenyl-1-propanol According to the method of Example 11, instead of N-methylpiperazine And 3-hydroxymethylpiperidine was similarly synthesized to give the title material (a mixture of diastereomer ratio 1: 1, 246.5 mg) as a colorless oil.
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 (0.5H, d, J = 3.4Hz, H-1), 4.94 (0.5H, d, J = 3.4Hz, H-1), 4.33-4.26 (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 (1H, 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, using cyclohexylamine instead of N-methylpiperazine, Synthesis was carried out in the same manner to obtain the title material (40.6 mg) as a colorless oil.
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, 125.5, 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, instead of N-methylpiperazine, Synthesis was performed in the same manner using 4-hydroxycyclohexylamine to obtain the title material (12.0 mg) as a colorless oil.
¹ H-NMR (CDCl 3) δ: 7.4-7.2 (5 H, m, aromatic), 6.36 (1 H, d, J = 6.8 Hz, NH), 5.13 (1 H, d, J = 2.0 Hz, 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 = 6.8 Hz, CH ₃ )

Example 18 Synthesis of (1S, 2S) -2-decanoylamino-3- (2- (N-morpholino) ethylamino-1-phenyl-1-propanol N-methyl according to the method of Example 11 2- (N-morpholino) ethylamine was used instead of piperazine in the same manner to obtain the title material (91.7 mg) as a colorless oil.
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 (2H, 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 Synthesis of (1S, 2S) -2- (2-hydroxy-n-octanoylamino) -3-morpholino-1-phenyl-1-propanol N-methylpiperazine according to the method of Example 11 Instead of, morpholine was used and the synthesis proceeded in the same way to obtain (1S, 2S) -2-amino-3-morpholino-1-phenyl-1-propanol. This compound (99.2 mg, 0.42 mmol) was dissolved in methylene chloride, and 2-hydroxy-n-octanoic acid (80.0 mg, 0.50 mmol), N-hydroxysuccinimide (102.1 mg, 0) was dissolved at room temperature. Then, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (118.1 mg, 0.62 mmol) was added under ice cooling, 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% aqueous citric acid solution, saturated sodium hydrogen carbonate solution and water, dried over sodium sulfate, filtered, and the solvent was distilled off. The reaction residue was purified by silica gel column chromatography (ethyl acetate) to give the title material (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), 3.74,3.73,3.72 (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 (OH) 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, 126.0, 75.3, 72.0, 66.9, 60.0, 54.5, 51.1, 34.9, 31.6, 29.0, 24.7, 22.5, 14.0
{The 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), 3.74,3.73,3.72 (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 (OH) 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, 126.0, 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 Synthesis of (1R, 2S) -2-decanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol According to the method of Example 11, (1S, 2S) Instead of 2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester, (1R, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3 -Propanediol-3-methanesulfonyl ester was used, and 4-hydroxypiperidine was used in place of N-methylpiperazine, and synthesis was carried out in the same manner to obtain the title substance (204.2 mg) as a white solid. .
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 (4H, 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 Synthesis of (1S, 2R) -2-decanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol According to the method of Example 20, (1R, 2S) Instead of 2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester, (1S, 2R) -2-benzyloxycarbonylamino-1-phenyl-1,3 Synthesis was carried out in the same manner using -propanediol-3-methanesulfonyl ester to obtain the title substance (160.5 mg) as a colorless oil.
1 H-NMR (CDCl 3) δ: consistent with the data of Example 20.

Example 22 Synthesis of (1R, 2R) -2-decanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol According to the method of Example 20, (1R, 2S) Instead of 2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-methanesulfonyl ester, (1R, 2R) -2-benzyloxycarbonylamino-1-phenyl-1,3 Synthesis was carried out in the same manner using -propanediol-3-methanesulfonyl ester to obtain the title material (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, 126.4, 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 Synthesis of (1R, 2S) -2-decanoylamino-3-diethylamino-1-phenyl-1-propanol According to the method of Example 11, (1S, 2S) -2-benzyloxycarbonylamino Instead of -1-phenyl-1,3-propanediol-3-methanesulfonyl ester, (1R, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3 Using methanesulfonyl ester, using diethylamine instead of N-methylpiperazine, the same synthesis was performed to obtain the title substance (L-erythro form).
TLC Rf 0.59 (CHCl ₃ : MeOH: AcOH = 9: 1: 1), 0.32 (CHCl ₃ : MeOH: 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, CH2N (CH ₂ ) ₂ ), 2.04 (2H, m, COCH 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 Synthesis of (1S, 2R) -2-decanoylamino-3-diethylamino-1-phenyl-1-propanol According to the method of Example 11, (1S, 2S) -2-benzyloxycarbonylamino Instead of -1-phenyl-1,3-propanediol-3-methanesulfonyl ester, (1S, 2R) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3 Using methanesulfonyl ester, using diethylamine instead of N-methylpiperazine, the same synthesis was performed to obtain the title substance (D-erythro form).
_{^{1 H-NMR (CDCl 3)}} δ: consistent with data of Example 23.

Example 25 Synthesis of (1R, 2S) -2-hexanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol According to the method of Example 20, instead of decanoyl chloride The title compound (250.5 mg) was obtained as a white solid by synthesizing in the same manner using hexanoyl chloride.
¹ H-NMR (CDCl ₃ ) 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 ₂ ), 1.67-1.57 (4H, m, H-3'B, COCH ₂ C H ₂ ), 1.24 (4H, brs, (C H ₂ ) ₂ CH ₃ ), 0.88 (3H, t, CH ₃ )

Example 26 Synthesis of (1R, 2S) -2-octanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol According to the method of Example 20, instead of decanoyl chloride The title compound (230.2 mg) was obtained in the same manner as above using octanoyl chloride.
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 (4H, 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 Synthesis of (1R, 2S) -2-dodecanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol According to the method of Example 20, instead of decanoyl chloride The same synthesis was performed using dodecanoyl chloride as a white solid 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 (4H, 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 28-30
The following stereoisomers were synthesized in the same manner as in Examples 25 to 27. Yield is as follows.
Example 28: (1S, 2R) -2-hexanoylamino-3- (4-hydroxypiperidino) -1-phenyl-1-propanol; 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 mmol) was dissolved in DMF (8 ml), pyrrolidine (1.14 g, 16.03 mmol) was added, and the mixture was stirred at 40-50 ° C. for 18 hours. Ethyl (100 ml) was added, and the organic layer was washed successively with saturated sodium hydrogen carbonate solution (70 ml), water (70 ml) and saturated brine (70 ml) and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title material (1.21 g, yield 85.5%) as a colorless oil.
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, 128.2, 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 mmol) was dissolved in DMF (6 ml), cyclopentylamine (1.09 g, 12.8 mmol) was added, and the mixture was stirred at 40-50 ° C for 32 hours. Further, cyclopentylamine (0.51 g, 5.99 mmol) was added, and the mixture was stirred overnight at 40 to 50 ° C. After confirming that the reaction was almost completed by TLC (ethyl acetate), ethyl acetate (100 ml) was added, and the organic layer was saturated sodium bicarbonate solution (70 ml), water (70 ml), saturated brine (70 ml). After sequentially washing with, dried over sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title material (534.4 mg, yield 45.7%) as a colorless oil.
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 = 2.93,12.21 Hz, 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 (CDCl3) δ: 160.7, 141.0, 136.4, 128.4, 128.2, 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 mmol) was dissolved in DMF (6 ml), piperidine (1.09 g, 12.8 mmol) was added, and the mixture was stirred at 40-50 ° C. for 24 hours. After confirming that the reaction was almost complete by TLC (ethyl acetate, chloroform: methanol = 20: 1), ethyl acetate (100 ml) was added, and the organic layer was saturated sodium bicarbonate solution (70 ml), water (70 ml). ), 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 (ethyl acetate) to obtain the title material (795.4 mg, yield 68.0%) as a colorless oil.
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, 128.3, 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 mmol) was dissolved in DMF (6 ml), cyclohexylamine (1.29 g, 13.0 mmol) was added, and the mixture was stirred at 40-50 ° C for 2 days. Further, cyclohexylamine (0.62 g, 6.25 mmol) was added, and the mixture was stirred overnight at 40 to 50 ° C. After confirming that the reaction was almost complete by TLC (ethyl acetate, chloroform: methanol = 20: 1), ethyl acetate (100 ml) was added, and the organic layer was saturated sodium bicarbonate solution (70 ml), water (70 ml). ), Successively with saturated saline (70 ml), dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to obtain the title material (750.0 mg, yield 61.5%) as a colorless oil.
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, dd, J = 2.44,12.69Hz, H-3B), 2.44 (1H, m, H-2 '), 1.95-1.86, 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, 128.2, 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 According to the method of Example 1, (1S, 2S) -2-t-butoxycarbonylamino- After mesylating 1-phenyl-1,3-propanediol, morpholine substitution was performed according to the method of Example 3. As a result, the title material was obtained in a yield of 63% as a colorless oil.
TLC Rf 0.36 (CHCl ₃ : MeOH = 20: 1)
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (5H, m, aromatic), 4.98 (1H, 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-decanoylamino-3-morpholino-1- starting from (1S, 2S) -2-t-butoxycarbonylamino-3-morpholino-1-phenyl-1-propanol Synthesis of phenyl-1-propanol (1S, 2S) -2-t-butoxycarbonylamino-3-morpholino-1-phenyl-1-propanol (49.9 mg, 0.149 mmol) was dissolved in methylene chloride (1 ml). Under ice cooling, trifluoroacetic acid (1 ml) was added and stirred. After 30 minutes, it was confirmed by TLC (chloroform: methanol = 9: 1) that the reaction was complete, ether (3 ml) 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 material (48.8 mg, yield 82.2%) as a colorless oil.

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 mmol) was dissolved in ethanol (40 ml), sodium iodide (712.8 mg, 4.75 mmol), N-methylpiperazine (1.92 g). , 19.2 mmol) and 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 successively with 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 (chloroform: methanol = 20: 1) to obtain the title material (242.2 mg, yield 13.2%) as a colorless oil.
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, 128.3, 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-hydroxymethylpyrrolidine ( (323.3 mg, 3.20 mmol) was dissolved in ethanol (12 ml), and (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3-propanediol-3-p-bromobenzenesulfonyl ester (782 mg) was dissolved. , 1.50 mmol) in methylene chloride (3 ml). After stirring at 45 ° C. for 2 days and confirming the reaction status by TLC (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 ( Purification with ethyl acetate: 2-propanol = 7: 3) gave the title material (79.5 mg, yield 13.8%) as a colorless oil.
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, 128.3, 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 mmol) was dissolved in ethanol (20 ml), 3-hydroxypyrrolidine (1.19 g, 13.68 mmol) was added, and the mixture was heated at 45 ° C. Stir 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). This gave the title material (527.1 mg, yield 20.8%) as a colorless oil.
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, derived from one diastereomer), 5.20 (0.3H, d, NH, derived from the other diastereomer), 5.00 (3H, s, H-1, CH2-O-CO), 4.34 (0.7H, m, H-3 ', derived from one diastereomer), 4.28 ( 0.3H, m, H-3 ', derived 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, 128.8, 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 mmol) was dissolved in DMF (6 ml), pyrrolidine (0.91 g, 12.8 mmol) was added, and the mixture was stirred at 40 ° C. for 24 hours. 100 ml) was added, and the organic layer was washed successively with saturated sodium hydrogen carbonate solution (70 ml), water (70 ml) and saturated brine (70 ml) and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title material (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: Consistent with the data shown in Example 31.
¹³ C-NMR (CDCl ₃ ) δ: The same data as shown in Example 31.

Example 41 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3- (3-hydroxymethylpiperidino) -1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino- 1-Phenyl-1,3-propanediol-3-methanesulfonyl ester (2.43 g, 6.41 mmol) is dissolved in ethanol (20 ml) and 3-hydroxymethylpiperidine (1.47 g, 12.78 mmol) is added, Stir 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 = 20: 1, ethyl acetate: methanol = 20: 1). The title material (293.3 mg, 11.5%) was obtained as a colorless oil.
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 , Derived from one diastereomer), 4.986 (0.5H, d, J = 8.30Hz, H-1, derived from the other diastereomer), 4.15-4.09 (1H, m, H-2), 3.56-3.45 (2H, m, CH2-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, 128.5, 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-benzyloxycarbonylamino-1 -Phenyl-1,3-propanediol-3-methanesulfonyl ester (273.6 mg, 0.722 mmol) was dissolved in ethanol (3 ml), sodium iodide (119.2 mg, 0.795 mmol), 4-hydroxypiperidine ( 171.5 mg, 1.70 mmol) was added, and the mixture was stirred at room temperature for 4 days. After confirming the reaction status by TLC (chloroform: methanol = 9: 1), 4-hydroxypiperidine (157.0 mg, 1.55 mmol) was added, 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 obtain the title material (112.6 mg, yield 40.6%) as a colorless oil.
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, 2.48, 2.32 (6H, m, (CH2) 3N), 1.89 (2H, m, H-3'A, H-5'A), 1.64-1.56 (2H, m, H-3'B, H-5'B)
¹³ C-NMR (CDCl ₃ ) δ: 156.1, 140.7, 136.4, 128.5, 128.3, 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-benzyloxycarbonylamino-1 -Phenyl-1,3-propanediol-3-methanesulfonyl ester (270.0 mg, 0.712 mmol) was dissolved in ethanol (3 ml), 4-hydroxypiperidine (287.8 mg, 2.85 mmol) was added, For 2 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 = 20: 1) to give the title substance (170 0.9 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-benzyloxycarbonylamino-1 -Phenyl-1,3-propanediol-3-methanesulfonyl ester (273.6 mg, 0.722 mmol) was dissolved in ethanol (3 ml), 4-hydroxypiperidine (291.7 mg, 2.89 mmol) was added, and 45 ° C. For 2 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 = 20: 1) to give the title material (184 as a colorless oil). .3 mg, 66.5% yield).
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-benzyloxycarbonylamino-1 -Phenyl-1,3-propanediol-3-methanesulfonyl ester (295.6 mg, 0.780 mmol) was dissolved in ethanol (3 ml), 4-hydroxypiperidine (315.1 mg, 3.12 mmol) was added, and 45 ° C. For 2 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 = 20: 1) to give the title material (179, colorless oil). 0.7 mg, yield 60.0%).
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, 2.48, 2.32 (6H, m, (CH ₂ ) ₃ N), 1.89 ( 2H, m, H-3'A, H-5'A), 1.64-1.56 (2H, m, H-3'B, H-5'B)
¹³ C-NMR (CDCl ₃ ) δ: 156.1, 140.7, 136.4, 128.5, 128.3, 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 Synthesis of (1S, 2S) -2-benzyloxycarbonylamino-3-diethanolamino-1-phenyl-1-propanol (1S, 2S) -2-benzyloxycarbonylamino-1-phenyl-1,3 -Propanediol-3-methanesulfonyl ester (1.50 g, 3.96 mmol) was dissolved in ethanol (30 ml), diethanolamine (1.69 g, 16.1 mmol) was added, and the mixture was stirred at 45 ° C. for 5 days. After confirming the reaction state 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) to give the title material (81 0.1 mg, yield 5.3%).
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, CH2-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, 128.3, 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 mmol) was dissolved in N, N-dimethylformamide (6 ml), and trans-4-aminocyclohexanol (1.47 g, 12.76 mmol) was dissolved. ) And 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 saturated sodium bicarbonate solution (70 ml), water (70 ml), saturated brine (70 ml). After sequential washing, the organic layer was 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) to obtain the title substance (571.5 mg, yield 45.0%) as white crystals.
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, 128.3, 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) was dissolved in methanol (10 ml), triethylamine (0.518 ml, 3.723 mmol) was added at room temperature, and then chloroformic acid n-octyl ester (0. (625 ml, 3.192 mmol) was added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, methanol (5 ml) was added and stirred for 20 minutes. Then, the solvent was distilled off under reduced pressure, ethyl acetate (100 ml) was added, and the organic layer was washed successively with saturated sodium hydrogen carbonate solution, water and saturated saline 70 ml each. The organic layer was dried over sodium sulfate and filtered, and the solvent was distilled off under reduced pressure. The resulting crude product was purified on a silica gel column (elution solvent; hexane: ethyl acetate = 1: 2) to obtain the title material (814.5 mg, yield 78.1%) as a colorless oil.
TLC Rf 0.21 (Hexane: AcOEt = 1: 2), 0.32 (CHCl ₃ : MeOH = 20: 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, COOCH 2),} 3.73 (4H, m, (CH 2) 2 O), 2.66-2.45 (6H, m, CH 2 N (CH 2) 2), 1.54 (2H, m, COOCH 2 C H ₂ ), 1.27 (10H, m, (C H ₂ ) ₅ CH ₃ ), 0.88 (3H, t, CH ₂ C H ₃ )
¹³ C-NMR (CDCl ₃ ) δ: 156.5, 140.7, 128.3, 127.6, 126.2, 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) was dissolved in methanol (5 ml), triethylamine (0.186 ml, 1.337 mmol) was added at room temperature, and then chloroformic acid n-octyl ester (0. 240 ml, 1.226 mmol) was added and stirred at room temperature. After 90 minutes, triethylamine (0.186 ml, 1.337 mmol) and chloroformic acid n-octyl ester (0.240 ml, 1.226 mmol) were added, and the mixture was 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 washed successively with saturated sodium hydrogen carbonate solution, water and saturated saline 70 ml each, dried over sodium sulfate, filtered, The solvent was removed under reduced pressure. The resulting crude product was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 20: 1) to obtain the title material (99.5 mg, yield 23.8%) as a colorless oil.
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 = 2.93 Hz, H-1), 4.9 (1H, d, NH), 4.04 (1H, m, H-2), 3.96 (2H, m, COOCH ₂ ), 2.92.2.68 (6H, m, CH ₂ N (CH ₂ ) ₂ ), 1.80 (4H, 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, 126.1, 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 ( 181.8 mg, 0.486 mmol) was dissolved in methylene chloride (5 ml), lithium aluminum hydride (153.0 mg, 4.032 mmol) was added at room temperature, and the mixture was refluxed at 35-40 ° C. for 2.5 hours. After adding 1N hydrochloric acid (15 ml) above and stirring for 30 minutes, saturated sodium hydrogen carbonate solution (70 ml) and chloroform (100 ml) were added, and the organic layer was washed sequentially with 70 ml of water and saturated saline respectively. After drying over sodium, the mixture was filtered and 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), and the title material (121.2 mg, yield 69.) was obtained as a colorless oil. 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, 0.958 mmol) was dissolved in a methylene chloride: methanol mixture (2: 1, 5 ml), and morpholine (0.25 ml, 2.88 mmol) was added at room temperature. Stir at ° C. After 20 hours, morpholine (0.083 ml, 0.958 mmol) was added, and the mixture was further stirred at 40 ° C. for 2 days. After confirming the completion of the reaction by TLC (hexane: ethyl acetate = 1: 2), the solvent was distilled off 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 filtered. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain the title material (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 (2H, 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 (11H, m)
¹³ C-NMR (CDCl ₃ ) δ: 155.8, 136.4, 128.5, 128.2, 128.0, 127.9, 79.6, 67.0, 66.8, 66.3, 60.9, 54.2, 47.9, 40.6, 29.5, 27.1, 26.4, 26.0, 25.8

Example 52 Synthesis of (1S, 2S) -2-decanoylamino-3-morpholino-1-cyclohexyl-1-propanol (1S, 2S) -2-Benzyloxycarbonylamino-3-morpholino-1-cyclohexyl-1 -Propanol (62.9 mg, 0.167 mmol) was dissolved in methanol (2 ml), 10% palladium carbon (17.5 mg, 9.83 mol%) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. 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 oily substance (45 0.0 mg) was obtained. This oil was dissolved in methanol (1 ml), triethylamine (34.8 μl, 0.250 mmol) was added, and decanoyl chloride (41.0 μl, 0.200 mmol) was added dropwise under ice cooling. After 2 hours, it was confirmed by TLC (ethyl acetate, ethyl acetate: methanol = 20: 1) that the reaction was complete, methanol (5 ml) was added, and the mixture was allowed to stand for 20 minutes. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: methanol = 40: 1) to obtain the title material (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, 26.1, 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-methane The sulfonyl ester (514.4 mg, 1.003 mmol) was dissolved in a methylene chloride: methanol mixture (2: 1, 5 ml), morpholine (348 μl, 4.00 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. Three days later, morpholine (100 μl, 1.15 mmol) was added, and the mixture was further stirred at 40 ° C. for 3 days. The reaction solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and chloroform (30 ml) The organic layer was extracted, dried over sodium sulfate and filtered. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 3) to obtain the title material (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 (2H, m, CH ₂ O-CO), 4.99 (1H, br, NH), 4.46-4.11 (1H, m , H-4A), 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 CH 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-octadecanol (59 .2 mg, 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 on carbon was removed by filtration, and the filtrate was concentrated to obtain white crystals (39.7 mg). The white crystals (39.7 mg, 0.107 mmol) were dissolved in a methylene chloride: methanol mixture (1: 1, 2 ml), triethylamine (39.0 μl, 0.280 mmol) was added, and decanoyl chloride ( 48.0 μl, 0.234 mmol) was added dropwise. After stirring at room temperature for 20 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 40: 1) to give the title material (13.9 mg, yield 22.6%) as a colorless oil. )
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 (6H, 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, 29.3, 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-tridecandiol-1-methanesulfonyl The ester (556.2 mg, 1.256 mmol) was dissolved in a tetrahydrofuran: ethanol mixture (1: 1, 4 ml), morpholine (330 μl, 3.79 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. Three days later, morpholine (165 μl, 1.90 mmol) was added, and the mixture was further stirred for 3 days at 40 ° C., then the reaction solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and chloroform (30 ml × 3) was added. The organic layer was extracted, dried over sodium sulfate and filtered. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to obtain the title material (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 (2H, m, CH ₂ O-CO), 4.95 (1H, br, NH), 4.47-4.16 (1H, m , H-4A), 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 (25.0 mg, 57 .6 μmol) was dissolved in methanol (1 ml), 10% palladium carbon (16.5 mg, 26.9 mol%) was added, and the mixture was stirred under a hydrogen atmosphere. After 2 hours, palladium on carbon was removed by filtration, and the filtrate was concentrated to obtain white crystals (18.4 mg). This white crystal (17.3 mg, 57.6 μmol) was dissolved in methanol (0.5 ml), triethylamine (20.0 μl, 0.143 mmol) was added, and decanoyl chloride (24.0 μl, 0.03 mmol) was added under ice cooling. 117 mmol) was added dropwise. After 1 hour, methanol was added and the mixture was allowed to stand for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (10.4 mg, yield 39.8) as a colorless oil. %).
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, 1.41, 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, 29.3, 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), morpholine (480 μl, 5.51 mmol) was added at room temperature, and the mixture was stirred at 40 ° C. Two days later, morpholine (160 μl, 1.84 mmol) was added, and the mixture was further stirred at 40 ° C. for 2 days. Then, the reaction solvent was distilled off under reduced pressure, saturated sodium hydrogen carbonate solution (20 ml) was added, and chloroform (30 ml × 3 The organic layer was dried over sodium sulfate and filtered. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 2) to obtain the title material (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), 10% palladium carbon (36.8 mg, 19.2 mol%) was added, and the mixture was stirred under a hydrogen atmosphere. After 15 hours, palladium on carbon was removed by filtration, and the filtrate was concentrated to give a colorless oil (55.9 mg). This colorless oil (43.9 mg, 0.180 mmol) was dissolved in methanol (1 ml), triethylamine (37.6 μl, 0.270 mmol) was added, and decanoyl chloride (48.0 μl, 0.234 mmol) was added under ice cooling. ) Was added dropwise. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol = 20: 1) to give the title material (6.0 mg, yield 8.4%) as a colorless oil. )
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 (6H, m, (CH ₂ ) ₃ N), 2.19 (2H, m, CO-CH ₂ ), 1.62, 1.41, 1.29, 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, 25.7, 22.6, 14.1

It is the schematic which shows the synthetic route of this invention method.

Claims (4)

General formula (1)
[Chemical 1]
Y—CH ₂ —C * H (NHP ¹ ) —C * H (OH) —R ¹ (1)
(In the formula, * represents an asymmetric carbon, and P ¹ is substituted with a benzyloxycarbonyl group, a fluorenyl group or a methylsulfonyl group which may be substituted with a nitro, halogen, lower alkoxy, lower alkoxyphenylazo or phenylazo group. Represents an amino protecting group or an alkyl group selected from an alkoxycarbonyl group containing a linear, branched or cyclic alkyl group and a benzenesulfonyl group, and R ¹ represents an alkyl group, a cycloalkyl group or an aryl group. , Y is a methanesulfonyl group, trihalogenoalkyl methanesulfonyl group, p- toluenesulfonyl group, a benzenesulfonyl group, and p- bromo represents a leaving group selected from a benzenesulfonyl group. aminopropanol derivative represented by), R ² H (wherein, R ² is represented by the following formula (I) ~ (VI) A group.) In reacted with an amine represented the general formula (2)
[Chemical 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 described above) are synthesized, P ¹ is eliminated from the compound, and the general formula (3)
[Chemical 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), and then R ¹¹ COOH (wherein R ¹¹ is an alkyl having 3 to 18 carbon atoms optionally having a hydroxyl group). A carboxylic acid or a reactive derivative thereof represented by the general formula (4)
[Chemical formula 4]
R ² —CH ₂ —C * H (NHCOR ¹¹ ) —C * H (OH) —R ¹ (4)
(Wherein R ¹ , R ² and R ¹¹ have the same meanings as described above).

[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 (wherein R ³ and R ⁴ are not simultaneously a hydrogen atom) , R ⁵ is a hydrogen atom, a hydroxy group or a lower alkyl group; Represents one or two or more identical or different substituents selected from 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, R ⁶ represents a hydrogen atom or R ⁵ the same one or more identical or different substituents, ⁷ represents an optionally substituted lower alkylene group which may be interrupted by oxygen, R ⁸ and R ⁹ are the same or different, a hydrogen atom, or a lower alkyl group or a hydroxy lower alkyl group, or R ⁸ and R ⁹ are those A piperidino group or a morpholino group that may be substituted with a lower alkyl group together with the nitrogen atom bonded thereto, m represents an integer of 2 to 6, p represents 2 or 3, and X represents the following formula (VII) Or (VIII).

(Wherein R ¹⁰ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxycarbonyl group or a pyridyl group)]. 2. The production method according to claim 1, wherein R ^{1 of the} compound represented by the general formula (1) is the same or different 1 selected from alkyl group, cycloalkyl group, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl and nitro. A benzyloxycarbonyl group, fluorenyl or methyl, which is a phenyl group optionally substituted with 3 substituents, and P ¹ may be substituted with a nitro, halogen, lower alkoxy, lower alkoxyphenylazo or phenylazo group 2- an amino protecting group selected from an alkoxycarbonyl group containing a linear, branched or cyclic alkyl group which may be substituted with a sulfonyl group, or an alkyl group having 3 to 18 carbon atoms, A method for producing an acylamino alcohol derivative. 2. 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. A method for producing a derivative. The manufacturing method of claim 1, R ¹ is an alkyl group having from 6 to 15 carbon atoms of the compound represented by the general formula (1), a cyclohexyl group or a phenyl group, an amine represented by R ² H is a lower alkyl amine; Morpholino lower alkylamine; Cycloalkylamine optionally substituted with hydroxy group; Pyrrolidine optionally substituted with hydroxy group or hydroxy lower alkyl group; Piperazine optionally substituted with lower alkyl group; Bis (hydroxy lower Alkyl) amine; and piperidine which may be substituted with a hydroxy group or a hydroxy lower alkyl group.

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