KR100473802B1 - Method of synthesizing β-amino-α-hydroxy carboxylic acid and its derivatives - Google Patents

Abstract

The present invention is a method for producing a derivative including β-amino-α-hydroxy carboxylic acid and its esters that can be used in antibacterial, anticancer, antibiotic, anti-inflammatory, gastric ulcer, arteriosclerosis and immunosuppressive, hypertension, AIDS, etc. It is about.

Using the process according to the invention, two β-amino-α-hydroxy carboxylic acids can be obtained with high stereoselectivity from one starting material. That is, by changing the type of protecting group of the amino group, the reduction reaction by stereoregulation and the reduction reaction by crosslinking are selectively performed to obtain syn and anti isomers as desired, and the reaction step is easy and the yield is excellent. It is very economical.

Description

Method for synthesizing β-amino-α-hydroxy carboxylic acid and its derivatives

The present invention relates to a method for producing β-amino-α-hydroxy carboxylic acid and derivatives thereof, and more particularly, antibacterial, anticancer, antibiotic, anti-inflammatory, gastric ulcer, arteriosclerosis and immunosuppressant, hypertension, AIDS The present invention relates to a method for producing a derivative including β-amino-α-hydroxy carboxylic acid and esters thereof which can be used.

Methods of preparing optically pure β-amino-α-hydroxy carboxylic acids and derivatives thereof known so far include asymmetric epoxidation reactions ( J. Chem. Soc., Chem. Commun , 1994 , 2767) or asymmetrical hydrides. Method using the Roxy method ( J. Org. Chem . 1994 , 59 , 5104), Method using amino acids ( J. Org. Chem . 1991 , 56 , 6939), Beta lactam method ( J. Org. Chem . 1991 , 56 ., 1681), and methods using asymmetric aldol reactions ( J. Am. Chem. Soc . 1993 , 115 , 1151). However, these methods have difficulty in obtaining pure isomers due to their low optical and stereoselectivity. In addition, there are not only a large number of reaction stages as a whole, but also severe control of reaction conditions such as extreme anhydrous conditions, and use of expensive reaction reagents has limited industrial aspects. In particular, one of the biggest disadvantages is that it is difficult to obtain stereoisomers having different optical activities from one starting material in pure form through reaction reaction.

Accordingly, the technical problem to be solved by the present invention is to solve the above problems and to prepare stereoisomers having different optical activities from one starting material in a pure form, a practical β-amino having a reduced number of reaction steps and a good yield. It is to provide a method for producing -α-hydroxy carboxylic acid and its derivatives.

In order to achieve the technical problem to be achieved by the present invention, the present invention provides a method for producing a β-amino-α-hydroxy carboxylic acid and its derivatives of the formula (1) by oxidation of the compound to provide:

Wherein n is 0 or 1,

R ₁ is hydrogen, a C1-C8 alkyl group, a phenyl group or a benzyl group,

R ₂ is a protecting group of hydrogen or a hydroxy group,

R ₃ is a protecting group of hydrogen or an amine group,

R ₄ is a C1-C20 alkyl group, a C3-C20 cycloalkyl group, a phenyl group or a benzyl group,

R ₅ is hydrogen, a C1-C10 alkyl group or a phenyl group,

X is CH ₃ COO, HCOO, HO ₂ CCH (OH) CH (OH) COO, CH ₃ SO ₃ , CF ₃ CH ₃ COO, CH ₃ C ₆ H ₅ SO ₃ , Cl, HSO ₄ , or H ₂ PO ₄ ego,

* Means chiral carbon.

The compound of Formula 2 may be synthesized by reducing the compound of Formula 4 below:

Wherein R ₃ , R ₄ , and R ₅ are as defined above.

The present invention also provides a method for preparing β-amino-α-hydroxy carboxylic acid of Formula 1 and its derivatives by reduction of a compound of Formula 3:

[Formula 1]

Wherein n is 0 or 1,

R ₁ is hydrogen, a C1-C8 alkyl group, a phenyl group, or a benzyl group,

R ₂ is a protecting group of hydrogen or a hydroxy group,

R ₃ is a protecting group of hydrogen or an amine group,

R ₄ is a C1-C20 alkyl group, a C3-C20 cycloalkyl group, a phenyl group, or a benzyl group,

R ₅ is hydrogen, a C1-C10 alkyl group or a phenyl group,

X is CH ₃ COO, HCOO, HO ₂ CCH (OH) CH (OH) COO, CH ₃ SO ₃ , CF ₃ CH ₃ COO, CH ₃ C ₆ H ₅ SO ₃ , Cl, HSO ₄ , or H ₂ PO ₄ ego,

* Means chiral carbon.

The compound of Formula 3 may be synthesized by oxidizing the compound of Formula 4.

[Formula 4]

Wherein R ₃ , R ₄ , and R ₅ are as defined above in the claims.

The oxidizing step is O ₃ , K ₂ Cr ₂ O ₇ , Na ₂ Cr ₂ O ₇ , KMnO ₄ , NaIO ₄ , Pb (OC (= O) CH ₃ ) ₂ , RuO ₄ , H ₂ O ₂ , RuCl ₃ At least one oxidizing agent selected from the group consisting of: CrO ₃ , (C ₅ H ₅ NH) ₂ Cr ₂ O ₇ (PDC), pyridium chlorochromate (PCC), NaClO ₂ , Hg (OC (= O) CH ₃ ) ₂ It is preferably carried out using.

The reducing step may include NaBH ₄ , LiBH ₄ , LiAlH ₄ , L-selectide, diisopropylaluminum hydride (DIBAL), Zn (BH ₄ ) ₂ , (CH ₃ ) ₄ BH (OC (= 0) CH ₃ ) _3, preferably _{NaBH 3 CN, LiBHEt 3, LiAl} (OC (= O) CH 3) is carried out by using one or more reducing agents selected from the group consisting of _3.

In order to increase the diastereoselectivity in the reduction reaction, a catalyst selected from the group consisting of CeCl ₃ , ZnCl ₂ , NiCl ₂ , and SmCl ₃ is further added.

The alkyl group of C 1 -C 8 is preferably a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and t-butyl.

The protecting group of the hydroxy group is methoxymethyl, methoxythiomethyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, trimethylsilyl, triphenylsilyl, benzyl, p-methoxybenzyl and t-butoxymethyl, tetrahydropyranyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, diphenylmethyl, and triphenylmethyl.

The protecting group of the amine group is acetyl, benzoyl, triphenylmethyl, allyl, di (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, (4-methoxyphenyl) diphenylphenyl, and 9-phenyl It is preferably a group selected from the group consisting of fluororenyl.

The alkyl group of C 1 -C 20 is preferably a group selected from the group consisting of methyl, ethyl, propyl isopropyl butyl, isobutyl, t-butyl, hexyl, and heptyl.

The cycloalkyl group of C 3 -C 20 is preferably a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Β-amino-α-hydroxy carboxylic acid and derivatives thereof synthesized according to the preparation method of the present invention are optically and stericly pure and can be used as synthetic intermediates of pharmaceutical products.

Hereinafter, a method for preparing β-amino-α-hydroxy carboxylic acid and its derivatives according to the present invention will be described in detail.

Β-amino-α-hydroxy carboxylic acid and derivatives thereof according to the present invention are prepared by oxidation, reduction of one compound selected from Formulas 2 to 4:

[Formula 1]

[Formula 3]

[Formula 4]

Wherein n is 0 or 1,

R ₁ is hydrogen, a C1-C8 alkyl group, a phenyl group or a benzyl group,

R ₂ is a protecting group of hydrogen or a hydroxy group,

R ₃ is a protecting group of hydrogen or an amine group,

R ₄ is a C1-C20 alkyl group, a C3-C20 cycloalkyl group, a phenyl group or a benzyl group,

R ₅ is hydrogen, a C1-C10 alkyl group or a phenyl group,

X is CH ₃ COO, HCOO, HO ₂ CCH (OH) CH (OH) COO, CH ₃ SO ₃ , CF ₃ CH ₃ COO, CH ₃ C ₆ H ₅ SO ₃ , Cl, HSO ₄ , or H ₂ PO ₄ ego,

* Means chiral carbon.

This will be described further with reference to Scheme 1, β-amino-α-hydroxy carboxylic acid and its derivatives of Formula 1 are synthesized by the following three methods. The first method is to prepare the compound of formula 2 through the oxidation reaction, ie, step (d). The second method is to prepare a reduction reaction of Formula 3, ie, step (c). The third method is synthesized by redox reaction of Formula 4, i.e., step (c ') and step (d) sequentially or step (d') and step (c) sequentially:

Wherein R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ in the compounds represented by Formulas 1, 2, 3, and 4 are as described above.

Among the three methods, the third method will be described in detail as follows. Step (c ') and step (d) is a step of sequentially reducing the ketone group in the compound of Formula 4, and then converting to carboxylic acid by cleaving the double bond, and (d') and Sequential reaction is a method of obtaining an alpha keto ester obtained by cleaving a double bond in a compound of formula 4, that is, a compound of formula 3, and reducing the ketone group of the compound.

Reaction conditions of the reduction step of (c) and (c ') is NaBH ₄ , LiBH ₄ , LiAlH ₄ , L-selectide, diisopropyl aluminum hydride (DIBAL), Zn (BH ₄ ) ₂ , Me ₄ BH Reducing agents such as (OAc) ₃ , NaBH ₃ CN, LiBHEt ₃ , LiAl (OMe) _3, etc., and the reaction conditions of the oxidation step of (d) and (d ′) are O ₃ , K ₂ Cr ₂ O ₇ , Na ₂ Cr ₂ O ₇ , KMnO ₄ , NaIO ₄ , Pb (OAc) ₂ , RuO ₄ , H ₂ O ₂ , RuCl ₃ , CrO ₃ , (C ₅ H ₅ NH) ₂ Cr ₂ O ₇ (PDC), An oxidizing agent such as pyridium chlorochromate (PCC), NaClO ₂ and Hg (OAc) ₂ is used.

CeCl ₃ , ZnCl ₂ , NiCl ₂ , SmCl ₃ may be used as an additive to increase diastereoselectivity in the reduction reaction. At this time, the reaction solvent is hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ether, ethyl acetate, methanol, ethanol, propanol, butanol, t-butanol and the like can be used, the reaction temperature is preferably 50 ~ 100 degrees.

In the oxidation reaction, the reaction solvent is hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ether, ethyl acetate, water, methanol, Ethanol, propanol, butanol, t-butanol and the like can be used.

In Scheme 1, the compound of Formula 4 is a known compound, and can be prepared by conventional methods in the art. An example of such a production method is shown in Scheme 2. Step (a) and (b) in Scheme 2 is a Horner-Words-Emons reaction, which is a known method for efficiently preparing an enone compound ( Tetrahedron Lett . 1984 , 25 , pp 2183 and Tetrahedron Lett . 1996 , 37 , pp 1077):

Referring to Scheme 2 in more detail, step (a) is a step for preparing the phosphonate intermediate, usually using anhydrous conditions and strong bases. In the reaction, methyl lithium, n-butyllithium, sec-butyllithium, t-butyllithium and lithium diisophylamide (LDA) are used as the strong base, and the solvent is hexane, benzene, toluene, tetrahydrofuran, Dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ether and the like can be used. The reaction temperature is -100 ~ 50 ℃ is possible, preferably -80 ~ 0 ℃. The compound of formula 5 synthesized according to such a method is relatively unstable and should be used immediately after synthesis.

In step (b) of Scheme 2, the compound of Formula 4 may be obtained by reacting a compound of Formula 5 with an aldehyde compound represented by R ₅ CHO under basic conditions. Examples of the base include strong bases such as methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium, sodium hydride and lithium diisophylamide (LDA) or triethylamine, N, N-dimethylaminopyridine, 1, Weak bases, such as 8-diazabicyclo undecene (DBU), diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, can be used. In addition, lithium chloride (LiCl) may be used as an additive to increase the reaction rate. The reaction solvent in step (b) is hexane, benzene, toluene, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, ether, ethyl acetate, methanol, ethanol , Propanol, butanol, t-butanol and the like can be used, and the reaction temperature is preferably -30 to 80 ° C.

Scheme 3 below shows a method for preparing β-amino-α-hydroxy carboxylic acid and its derivatives according to a preferred embodiment of the present invention.

As shown in Scheme 3, the biggest feature of the present invention is that, as described above, two β-amino-α-hydroxy carboxylic acids having optical activity can be obtained with high selectivity from one starting material. In other words, when the enone compound derived from (D) -phenylglycine is reduced, a steric controlled reduction by a steric effect of the amino group proceeds, thereby obtaining a syn compound. In addition, if the enone compound is first removed after ozone decomposition, the protecting group of the amino group is removed, and then reduced, a reduction reaction (chealation controlled reduction) by cross-linking by the amino group proceeds, thereby obtaining an anti compound selectively (Ref. Mengel, A. Reiser, O. Chem. Rev. 1999 , 99 , 1191; Marshall, JA; Garofalo, AW J. Org. Chem . 1993 , 58 , 3675).

Hereinafter, the present invention will be described in more detail with reference to Examples and Examples, which are merely illustrative and do not limit the scope of the present invention.

EXAMPLE

Reference Example 1. (D)- N Method for preparing-(tritylamino) phenylglycine methyl ester

MeOH (200 ml) was cooled in an ice bath and acetylchloride (AcCl) (61 g, 598 mmol) was added dropwise for 20 minutes and stirred for another 5 minutes. The ice bath was removed, stirred for 20 minutes, and then D-phenylglycine (26.0 g, 172 mmol) was added thereto, followed by stirring at reflux for 3 hours. The reaction compound was distilled under reduced pressure to remove most of the solvent, and ethyl acetate (EtOAc, 200 ml) was added thereto, followed by stirring. The solid was filtered and dried to obtain (D) -phenylglycine methyl ester hydrochloride (34 g, 98%).

(D) -phenylglycine methyl ester hydrochloride (10.0 g, 49.6 mmol) and Et ₃ N (11.0 g, 109 mmol) were added to CH ₂ Cl ₂ (150 ml), and the mixture was cooled in an ice bath. Subsequently, PPh ₃ Cl (13.8 g, 49.6 mmol) was added to the reaction compound, and the mixture was stirred at room temperature overnight. After adding water and extracting, the organic layer was dried and distilled under reduced pressure to obtain a foamy solid. The obtained solid was recrystallized with 90% -EtOH determines white (D) - N - (trityl) phenyl glycine methyl ester (19 g, 94%) was obtained.

mp 132-133 ° C .;

[α] _D ²⁵ 153.80 (c 0.92, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.43- 7.05 (m, 20 H), 4.30 (s, 1 H), 3.27 (br s, 1 H), 3.04 (s, 3 H).

Reference Example 2. (L)- N Method for preparing-(tritylamino) phenylalanine methyl ester

Reference Example 1 (D) - N - a (trityl-amino) phenyl glycine methyl ester In the same manner as Synthesis Method (L) - from phenylalanine (8.0 g, 37 mmol) ( L) - N - (D) - N - ( trityl-amino) phenylalanine methyl ester (14.7 g, 94%) was obtained.

mp 90-91 ° C .;

[a] _D ²⁵ +44.63 (c 0.87, CHC1 ₃ );

¹ H NMR (CDCl ₃ ) 7.44-7.17 (m, 20 H), 3.59 (t, J = 6.8 Hz, 1 H), 3.06 (s, 3 H), 2.98 (m, 2 H), 2.67 (br s , 1 H).

Reference Example 3. (L)- N Method for preparing-(tritylamino) leucine methyl ester

Reference Example 1 (D) - N - (trityl-amino) In a similar manner to the phenyl synthesis of glycine methyl ester (L) - leucine from (5.0 g, 38.1 mmol) ( L) - N - ( trityl Amino) leucine methyl ester (12.7 g, 86%) was obtained.

mp 84-85 ° C .;

[α] _D ²⁵ +52.65 (c 0.83, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.55-7.16 (m, 15 H), 3.37 (pseudo t, 1 H), 3.16 (s, 3 H), 2.73 (br s, 1 H), 1.63 (m, 3 H) , 0.91 (dd, J = 7.7, 6.1 Hz, 6H).

Reference Example 4. (1 R, 3 E Method for preparing) -1,4-diphenyl-1- (tritylamino) -but-3-en-2-one

To 100 ml of tetrahydrofuran was added 3.0 g (24.6 mmol) of dimethylmethylphosphonate and cooled to -78 ° C. 15 ml (24.6 mmol) of n-butyllithium (1.6 M) was added dropwise for 10 minutes. N - - (D) obtained in the reference after 10 minutes further stirring at the same temperature for Example 1, a solution obtained by dissolving a (trityl-amino) phenyl glycine methyl ester 2.0g (4.87mmol) in 10ml of tetrahydrofuran in a cooled solution of the above 10 minutes was added dropwise. After stirring for 3 hours at the same temperature, 80 ml of saturated ammonium solution was carefully added, and 100 ml of ethyl acetate was added thereto. The organic layer was taken, washed with water and dried over magnesium sulfate. Separation by silica gel column gave 2.3 g of phosphonate intermediate in the form of syrup.

THF (60 ml) and PhCHO (0.58 g, 5.5 mmol) were added thereto and cooled in an ice bath. 60% NaH (0.22 g, 5.7 mmol) was added in three portions and stirred at room temperature for 16 hours. The reaction solution was poured into iced water and extracted with EtOAc. The organic layer was dried and distilled under reduced pressure to yield a yellow syrup, which solidified when left in the air. 90% recrystallized from -EtOH to afford the title compound as a pale yellow crystal (1 R, 3 E) -1,4- diphenyl-1- (trityl-amino) boot-3-en-2-one (1.9 g, 88%).

mp 95-96 ° C .;

[α] _D ²⁵ 134.6 (c 1.03, CHCl ₃ );

IR (NaCl film) 3027, 1686, 1610, 1449 cm ⁻¹ ;

¹ H NMR (CDCl ₃ ) 7.55-7.12 (m, 21 H, with olefin CH), 2.68 (dd, J = 15.9, 6.2 Hz, 1 H), 4.70 (d, J = 5.6 Hz, 1 H), 4.15 (br s, 1 H).

Reference Example 5. (1 R, 3 E Method for producing) -1-phenyl-1- (tritylamino) -pent-3-en-2one

Note the starting material obtained in Example 1 (D) - N - (trityl) phenyl creates a glycine methyl ester (11.25 mmol) and Reference Example 4 and phosphonate derivatives in the same manner using a condensing to CH ₃ CHO here The title compound ( 1R, 3E ) -1-phenyl-1- (tritylamino) -pent-3-en-one (4.0 g, 85%) was obtained as white crystals.

mp 117-118.5 ° C .;

[α] _D ²⁵ 240.0 (c 1.06, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.46-7.10 (m, 20 H), 6.37 (dt, J = 15.6, 6.9 Hz, 1 H), 5.64 (dd, J = 15.5, 1.4 Hz, 1 H), 4.53 (s , 1 H), 4.05 (br s, 1 H), 1.59 (dd, J = 6.9, 1.6 Hz, 3 H).

Reference Example 6. (4 S ,One E Method for preparing 1,5-diphenyl-4- (tritylamino) -pent-1-en-3one

Note the starting material obtained in Example 2 (L) - N - (trityl) phenyl Allah Min making the methyl ester (2.57 mmol) and Reference Example 4 and phosphonate derivatives in the same manner using the yellow and condensed with PhCHO here The title compound (4S , 1 E ) -1,5-diphenyl-4- (tritylamino) -pent-1-en-3-one (1.09 g, 86%) was obtained as an amorphous solid of.

[α] _D ²⁵ +88.39 (c 0.56, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.48-6.90 (m, 25 H), 6.92 (d, J = 16.0 Hz, 1 H), 6.07 (d, J = 16.0 Hz, 1 H), 3.97 (t, J = 6.6 Hz, 1H), 3.25 (br s, 1H), 2.98 (m, 2H).

Reference Example 7. (4 S ,One E Method for preparing) -6-methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-one

Reference Example 3 The starting material (3.86 mmol) in Reference Example 4 in the same manner as in making the phosphonate derivative afforded the title compound as a crystalline solid with yellow by condensation with PhCHO here (4 S, 1 E) from obtained from the - 6-Methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-one (1.33 g, 75%) was obtained.

mp 103-105 ° C .;

[α] _D ²⁵ +119.17 (c 0.97, CHC1 ₃ );

¹ H NMR (CDCl ₃ ) 7.55-7.05 (m, 21 H), 6.30 (d, J = 16.0 Hz, 1 H), 3.71 (t, J = 6.8 Hz, 1 H), 1.75 (m, 1 H) , 1.54 (t, J = 6.8 Hz, 2H), 0.92 (dd, J = 6.5, 1.6 Hz, 6H).

Reference Example 8. (1 R, 3 E ) -1-amino-1,4-diphenyl-but-3-en-2-one hydrochloride

(1 R, 3 E) -1,4- diphenoxylate butyl-1- (trityl-amino) obtained reference in THF (10 ml) in Example 4-a boot-3-en-2-one (0.61 g, 1.27 mmol) After adding conc-HCl (0.3 ml) was added. After stirring for 1 hour at room temperature, the starting material disappeared by TLC, and Et ₂ O (10 ml) was added thereto. The precipitated solid was filtered off and then washed and dried to the title compound (1 R, 3 E) -1- amino-1,4-phenylene with EtOAc - Boot-3-en-2-one hydrochloride White crystals of ( 0.33 g, 95%).

mp> 188 ° C. (dec.);

[α] _D ²⁵ 61.91 (c 0.97, MeOH);

¹ H NMR (CD ₃ OD) 7.79 (d, J = 16.0, 1 H), 7.55-7.33 (m, 10 H), 6.81 (d, J = 16.0 Hz, 1 H), 5.57 (d, J = 2.5 Hz, 1 H).

Reference Example 9. (1 R, 3 E ) -1-amino-1-phenyl-pent-3-en-2-one hydrochloride

Note in the same manner as in Example 8 obtained in Example 5 (1 R, 3 E) -1-phenyl-1 (trityl-amino) pent-3-ene was prepared from 2-one. (Yield 90%, colorless crystals).

mp> 165 ° C. (dec.);

[a] _D ²⁵ 184.20 (c 1.01, MeOH);

¹ H NMR (CD ₃ OD) 7.48-7.42 (m, 5H), 7.09 (dt, J = 15.6, 6.9 Hz, 1 H), 6.13 (dd, J = 15.6, 1.6 Hz, 1 H), 5.44 ( s, 1 H), 1.80 (dd, J = 6.9, 1.6 Hz, 3 H).

Reference Example 10. (4 S, One E Method for preparing 4-amino-1,5-diphenyl-1-pent-1-en-3-one hydrochloride

Prepared from (4 S, 1 E ) -1,5-diphenyl-4- (tritylamino) -pent-1-en-3-one obtained in Reference Example 6 in the same manner as Reference Example 8 Yield 96%, colorless crystals).

mp> 195 ° C. (dec.);

[α] _D ²⁵ +34.28 (c 0.77, MeOH);

¹ H NMR (CD ₃ OD) 7.70 (d, J = 16.0 Hz, 1 H), 7.59-7.31 (m, 10 H), 6.89 (d, J = 16.0 Hz, 1 H), 4.75 (t, J = 6.9 Hz, 1 H), 3.23 (m, 1 H).

Reference Example 11. (4 S, One E Method of preparing 4-amino-6-methyl-1-phenyl-hept-1-en-3-one hydrochloride

Prepared from ( 4S , 1E ) -6-methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-one obtained in Reference Example 7 in the same manner as Reference Example 8. (Yield 99%, colorless crystals).

mp> 162 ° C. (dec.);

[α] _D ²⁵ +21.98 (c 0.48, MeOH);

¹ H NMR (CD ₃ OD) 7.81 (d, J = 16.0 Hz, 1 H), 7.72-7.41 (m, 5H), 7.05 (d, J = 16.0 Hz, 1 H), 4.44 (dd, J = 9.5, 3.8 Hz, 1 H), 1.80 (m, 2 H), 1.65 (m, 1 H), 1.04 (dd, J = 7.1, 6.0 Hz, 6 H).

Example 1. (1 R ,2 R, 3 E Method for preparing 1,4-diphenyl-1- (tritylamino) -but-3-en-2-ol

(1 R, 3 E ) -1,4-diphenyl-1- (tritylamino) -but-3-en-2-one (57 mg, in CH ₂ Cl ₂ (0.6 ml) obtained in Reference Example 4 0.11 mmol) was added to dissolve it, MeOH (2 ml) was added thereto, and the mixture was cooled in an ice bath. CeCl ₃ · 7H ₂ O (82 mg, 0.22 mmol) was added and stirred for 5 minutes followed by NaBH ₄ (17 mg, 0.45 mmol). After 3 hours at the same temperature, water and EtOAc were added and extracted. The organic layer was dried and dried under reduced pressure to obtain a syrup, and recrystallized with a mixed solvent of CHCl ₃ / MeOH (1/5) to obtain the title compound (1 R , 2 R, 3 E ) -1,4-diphenyl-1- ( Tritylamino) -but-3-en-2-ol Obtained as white crystals (28 mg, 50%).

mp 211-213 ° C;

[α] _D ²⁵ +33.13 (c 1.02, CHCl ₃ );

IR (NaCl film) 3028, 1492, 1448 cm ⁻¹ ;

¹ H NMR (CDCl ₃ ); 7.46-6.96 (m, 25H), 6.31 (d, J = 15.9 Hz, 1 H), 5.85 (dd, J = 15.9, 6.9 Hz, 1 H), 6.90 (d, J = 6.6 Hz, 1 H) , 3.75 (d, J = 6.6 Hz, 1 H).

Example 2. (1 R ,2 R, 3 E Method for preparing) -1-phenyl-1- (tritylamino) -pent-3-en-2-ol

Note obtained in Example 5 (1 R, 3 E) -1-phenyl-1 (trityl-amino) pent-3-ene in the same manner as in Example 1 by using 2-one The title compound of (2 R , 3R, 3E ) -1-phenyl-1- (tritylamino) -pent-3-en-2-ol (75%, colorless crystals) was obtained.

mp 103-104.5 ° C .;

[α] _D ²⁵ 48.52 (c 1.40, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.46-6.96 (m, 20 H), 5.35 (dt, J = 15.3, 6.4 Hz, 1 H), 5.11 (ddd, J = 15.3, 7.6, 1.5 Hz, 1 H), 3.77 (d, J = 6.5 Hz, 1H), 3.39 (t, J = 7.0 Hz, 1H), 2.39 (br, 2H), 1.57 (dd, J = 6.4, 1.0 Hz, 3H).

Example 3 (3 S ,4 S, One E Method for preparing 1,5-diphenyl-4- (tritylamino) -pent-1-en-3-ol

Using the (4S , 1 E ) -1,5-diphenyl-4- (tritylamino) -pent-1-en-3-one obtained in Reference Example 6 in the same manner as in Example 1 compound (3 S, 4 S, 1 E) -1,5- diphenyl-4- (trityl-amino) pent-1-ene to give the 3-ol (74%, solid foam).

[α] _D ²⁵ 90.36 (c 1.37, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.58-6.86 (m, 25 H), 6.53 (dd, J = 16.0, 1.5 Hz, 1 H), 5.94 (dd, J = 16.0, 4.8 Hz, 1 H), 4.02 (m , 1 H), 2.80 (m, 1 H), 2.53 (dd, J = 13.3, 11.6 Hz, 1 H), 2.26 (dd, J = 13.3, 4.2 Hz, 1 H).

Example 4. (4 S, 3 S, One E) Preparation of -6-methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-ol

The title compound described above in the same manner as in Example 1 using (4S, 1E) -6-methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-one obtained in Reference Example 7. ( 4S, 3S, 1 E ) -6-methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-ol (68%, colorless crystals) was obtained.

mp 136-138 ° C .;

[α] _D ²⁵ 85.62 (c 1.35, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.54-7.17 (m, 20 H), 6.64 (dd, J = 15.9, 1.3 Hz, 1 H), 6.16 (dd, J = 15.9, 5.5 Hz, 1 H), 4.11 (m , 1 H), 2.67 (dt, J = 8.8, 3.9 Hz, 1 H), 2.50 (br, 2 H), 1.46 (m, 1 H), 1.26 (m, 1 H), 0.57 (d, J = 6.5 Hz, 3 H), 0.50 (d, J = 6.5 Hz, 3 H).

Example 5 (1 R ,2 S, 3 E Method for preparing 1-amino-1,4-diphenyl-but-3-en-2-ol

Note obtained in Example 8 (1 R, 3 E) -1- amino-1,4-diphenyl-boot-3-en-2-one hydrochloride (0.3 g, 0.9 mmol) was added to a THF (30 ml) 78 Cooled to C. Zn (BH 4) 2 (0.1 M in THF, 1.8 ml, 1.8 mmol) solution was added dropwise by syringe and stirred at the same temperature for 5 hours. 30 ml of water was carefully added to the reaction solution, and the pH was adjusted to 1 with 1N-HCl solution, followed by stirring at room temperature for 2 hours. Washed with n -hexane, the aqueous layer was taken, adjusted to PH 10 with 1N-NaOH solution and extracted three times with CHCl ₃ . After drying over anhydrous Na ₂ SO ₄ , distillation under reduced pressure, and separated by flash chromatography, a white solid was obtained, and recrystallized with Et ₂ O / n -hexane (1/3) to obtain the title compound (0.20 g, 75%). Got it.

mp 95-96 ° C .;

[α] _D ²⁵ 87.38 (c 0.93, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.35-7.21 (m, 10H), 6.62 (d, J = 16.0 Hz, 1 H), 6.04 (dd, J = 16.0, 6.4 Hz, 1 H), 4.41 (t, J = 5.5 Hz, 1 H), 4.08 (d, J = 5.5 Hz, 1 H), 2.10 (br s, 3 H);

FAB MS m / z : 240 (M + l).

Example 6. (1 R ,2 S, 3 E Method for preparing 1-1-amino-1-phenyl-pent-3-en-2-ol hydrochloride

Using ( 1R, 3E ) -1-amino-1-phenyl-pent-3-en-3-one hydrochloride obtained in Reference Example 9 as a starting material using the same method as in Example 5, the title compound ( 1R , 2 S, 3 E ) -1-amino-1-phenyl-pent-3-ene- e -ol hydrochloride (83%, colorless crystals) was obtained.

mp 164.5-165.5 ° C .;

[α] _D ²⁵ +3.40 (c 0.99, MeOH);

¹ H NMR (CD ₃ OD) 7.46-7.37 (m, 5H), 5.80 (m, 1H), 5.22 (ddd, J = 15.3, 7.3, 1.7 Hz, 1H), 4.46 (t, J = 4.9 Hz, 1H), 4.24 (d, J = 4.7 Hz, 1H), 1.63 (dd, J = 6.5, 0.8 Hz, 3H);

FAB MS m / z : 178 (M + 1-HCl).

Example 7. (4 S , 3 R, One E Method for preparing 4-amino-1,5-diphenyl-pent-1-en-3-ol hydrochloride

Using (4 S, 1 E ) -4-amino-1,5-diphenyl-1-pent-1-en-3-one hydrochloride obtained in Reference Example 10 as a starting material using the same method as in Example 5 Compound ( 4S , 3R, 1E ) -4-amino-1,5-diphenyl-pent-1-en-3-ol hydrochloride (78%, colorless crystals) was obtained.

mp 206-207 ° C;

[α] D25 +48.23 (c 0.39, MeOH);

¹ H NMR (CD ₃ OD) 7.44-7.23 (m, 10H), 6.75 (d, J = 15.9 Hz, 1 H), 6.28 (dd, J = 15.9, 6.4 Hz, 1 H), 4.48 (m, 1 H), 3.63 (m, 1 H), 3.03 (dd, J = 14.4, 8.3 Hz, 1 H), 2.87 (dd, J = 14.4, 8.3 Hz, 1 H);

FAB MS m / z : 254 (M + 1-HCl).

Example 8 (3 R ,4 S, One E Method for preparing 4-amino-6-methyl-1-phenyl-hept-1-en-3-ol hydrochloride

( 4S, 1 E ) -4-amino-6-methyl-1-phenyl-hept-1-en-3-one hydrochloride obtained in Reference Example 11, using the same method as in Example 5 as a starting material, the title compound. ( 3R , 4S, 1E ) -4-Amino-6-methyl-1-phenyl-hept-1-en-3-ol hydrochloride (88%, colorless crystals) was obtained.

mp 83-84 ° C .;

[α] _D ²⁵ 3.30 (c 1.24, MeOH);

¹ H NMR (CD ₃ OD) 7.46-7.21 (m, 5H), 6.77 (d, J = 15.9 Hz, 1 H), 6.25 (dd, J = 15.9, 6.3 Hz, 1 H), 4.50 (m, 1 H), 3.40 (m, 1 H), 1.75 (m, 1 H), 1.49 (t, J = 7.3 Hz, 2 H), 0.98 (d, J = 3.3 Hz, 3 H), 0.94 (d, J = 3.3 Hz, 3 H);

FAB MS m / z : 220 (M + 1-HCl).

Example 9. (1 R ,2 R, 3 E Method for preparing 1-amino-1,4-diphenyl-but-3-en-2-ol

Example 1 obtained in the (1 R, 2 R, 3 E) -1,4- diphenyl-1- (trityl-amino) boot-3-en-2-ol (70 mg) with THF (3 ml) And 1N-HCl (1 ml) were added and stirred at room temperature for 30 minutes. Alkaline with saturated NaHCO ₃ solution and extracted with CHCl ₃ . The organic layer was dried and recrystallized with Et ₂ O to give the title compound (1 R , 2 R, 3 E ) -1-amino-1,4-diphenyl-but-3-en-2-ol (48 mg, 70 %) Was obtained as a white solid.

mp 125-126 ° C .;

[α] _D ²⁵ +96.79 (c 1.0, CHCl ₃ );

IR (NaCl film) 3361, 3028, 1448 cm ⁻¹ ;

¹ H NMR (CDCl ₃ ) 7.36-7.19 (m, 10H), 6.57 (dd, J = 15.9, 1.0 Hz, 1H), 6.08 (dd, J = 15.9, 5.5 Hz, 1H), 4.30 (dt , J = 6.7, 1.2 Hz, 1 H), 3.85 (d, J = 6.7 Hz, 1 H), 2.36 (br s, 3 H);

FAB MS m / z : 240 (M + l).

Example 10. (1 R ,2 R ) -1- (benzoylamino) -2- ( t- Method for preparing Butyldimethylsilyloxy) -1,4-diphenyl-but-3-ene

Embodiments obtained in Example 9 (1 R, 2 R, 3 E) -1- amino-1,4-diphenyl-boot-3-en-2-ol (55 mg, 0.23 mmol) and Et3N (21 mg, 0.46 mmol) were added CH ₂ Cl ₂ (5 ml) and cooled to 0 ° C. PhCOCl (48.3 mg, 0.35 mmol) was added and stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure, MeOH (3 ml) and dilute 1N-K ₂ CO ₃ aqueous solution (1 ml) were added, and the O -benzoylated compound was hydrolyzed by stirring for about 0.5 hours at 50 ° C. The mixture was adjusted to PH 2-3 with dilute hydrochloric acid, extracted with EtOAc, and distilled under reduced pressure to obtain a compound protected with N- Bz as a white solid. If necessary, it could be recrystallized from CH ₂ Cl ₂ / n -hexane (10/1), and the following reaction was carried out without purification {mp 178-179 ° C; [α] _D ²⁵ 1.89 (c 1.09, CHCl ₃ )}. To this compound was dissolved dimethylformamide (DMF) (1 ml), imidazole (31 mg, 0.46 mmol), 4-dimethylaminopyridine (DMAP) (catalyst amount) and TBDMSCl (52 mg, 0.35 mmol), respectively, were added at room temperature. Stir for 4 hours. Water and Et ₂ O were added and extracted, and the organic layer was dried and distilled under reduced pressure. Separation by flash chromatography (EtOAc / n -hexane = 1/6, rf = 0.20) and recrystallization from 50% -EtOH to give the title compound (1 R , 2 R ) -1- (benzoylamino) -2- ( t -butyldimethylsilyloxy) -1,4-diphenyl-but-3-ene (93 mg, 88%) was obtained as white crystals.

mp 117-119 ° C;

[α] _D ²⁵ 14.56 (c 0.89, CHCl ₃ );

IR (NaCl film) 2929, 1656, 1484 cm ⁻¹ ;

¹ H NMR (CDCl ₃ ) 7.81-7.22 (m, 15 H), 7.15 (d, J = 8.3 Hz, 1 H, NH), 6.66 (d, J = 15.9 Hz, 1 H), 6.30 (dd, J = 15.9, 5,9 Hz, 1 H), 5.30 (dd, J = 8.3, 1.8 Hz, 1 H), 4.64 (m, 1 H), 0.87 (s, 9 H), -0.11 (s, 3 H ), -0.38 (s, 3H);

FAB MS m / z : 458 (M + l).

Example 11. (2 S , 3 R ) -3-benzoylamino-2- ( t -Butyldimethylsilyloxy) -3-phenylpropionic acid methyl ester

CH2Cl2 (1 R, 2 R) obtained in the Example 10 compound in (15 ml) -1- (benzoylamino) -2- (t-butyldimethylsilyloxy) -1,4-diphenyl-3-en Boot (100 mg, 0.22 mmol) was added and then cooled to 78 ° C. 2.5 M-methanolic NaOH solution (0.5 ml) was added and the reaction was terminated after 2 hours while injecting O ₃ (blue). Water was added, and after extraction, the organic layer was dried and distilled under reduced pressure. Flash chromatography (EtOAc / n - hexane = 1/8, rf = 0.18 ) separated by a colorless syrup of the title compound (2 S, 3 R) -3- benzoylamino -2- (t - butyldimethylsilyl Oxy) -3-phenylpropionic acid methyl ester (71 mg, 77%) was obtained.

[α] _D ²⁵ +45.66 (c 2.10, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.81-7.22 (m, 11H), 5.59 (dd, J = 8.5, 1.7 Hz, 1H), 4.50 (d, J = 1.7 Hz, 1H), 3.74 (s, 3 H), 0.77 (s, 9 H), -0.11 (s, 3 H), -0.34 (s, 3 H).

Example 12. (2 S , 3 R Method for preparing 3-benzoylamino-2-hydroxy-3-phenyl propionic acid methyl ester

The compound obtained in Example 11 in THF (5 ml) (2 S, 3 R) -3-benzoylamino -2- (t - butyldimethylsilyloxy) -3-phenyl-propionic acid methyl ester (37 mg, 0.089 mmol ), Cooled in an ice bath, and tetrabutylammonium fluoride (TBAF) (1.0 M in THF, 0.12 ml, 0.12 mmol) was added thereto. After stirring at the same temperature for 1.5 hours, water and EtOAc were added, and the aqueous layer was adjusted to pH 2-3 with hydrochloric acid and extracted. The organic layer was dried and evaporated under reduced pressure to precipitate a solid, which was recrystallized with a mixed solvent of EtOAc / n -hexane = 1/3. ( 2S , 3R ) -3-benzoylamino-2-hydroxy-3-phenylpropionic acid methyl ester (25 mg, 93%) was obtained as white needle crystals.

mp 181-183 ° C;

[α] _D ²⁵ +47.2 (c 0.35, MeOH);

[α] _D ²⁵ +49.1 (c 1.01, MeOH);

¹ H NMR (CDCl ₃ ) 7.76-7.28 (m, 10H), 7.00 (d, J = 9.0 Hz, 1H), 5.72 (dd, J = 9.0, 1.9 Hz, 1H), 4.61 (d, J = 1.9 Hz, 1 H), 3.82 (s, 3 H), 3.33 (br, 1 H).

Example 13. (2 R , 3 R Method of Preparation) -3-benzoylamino-2-hydroxy-3-phenylpropionic acid methyl ester

Embodiments obtained in Example 5 (1 R, 2 S, 3 E) -1- amino-1,4-diphenyl-boot-3-en-2-ol in the same path for the synthesis of Example 12, starting of the The title compound was prepared.

mp 153-154 ° C;

[α] _D ²⁵ +24.08 (c 0.96, CHC1 ₃ );

¹ H NMR (CDCl ₃ ) 7.82-7.26 (m, 11H, including NH), 5.60 (dd, J = 8.6, 3.6 Hz, 1H), 4.70 (d, J = 3.6 Hz, 1H), 3.72 ( s, 3 H).

¹³ C NMR (CDCl ₃ ) 172.9, 167.4, 137.2, 134.7, 132.4, 129.3, 129.1, 128.2, 127.8, 73.7, 56.2, 53.4.

Example 14 (3 R ) Oxo-3-phenyl-3- (tritylamino) -propionic acid methyl ester

CH ₂ Cl ₂ (30 ml) obtained in compound Reference Example 4 (1 R, 3 E ) -1,4-diphenyl-1- (tritylamino) -but-3-en-2-one (600 mg, 1.25 mmol) was added and then cooled to 78 ° C. 1M-methanolic NaOH solution (6 ml) was added and the reaction was terminated after 3 hours while injecting O ₃ (blue). Water was added and saturated citric acid solution (3 ml) was added and extracted. The organic layer was dried, dried under reduced pressure, and separated by flash chromatography (EtOAc / n -hexane = 1/3, rf = 0.53). After brief standing it solidified and recrystallized with 80% -EtOH to give pale yellow crystals as the title compound ( 3R ) -2-oxo-3-phenyl-3- (tritylamino) -propionic acid methyl ester (408 mg, 75% )

mp 131-132 ° C;

[α] _D ²⁵ -252.59 (c 1.04, CHC1 ₃ );

IR (NaCl film) 1730 (CO) cm ⁻¹ ;

¹ H NMR (CDCl ₃ ) 7.55-7.17 (m, 20H), 5.34 (s, 1H), 3.75 (br, 1H), 3.57 (s, 3H).

Example 15 (3 S Method for preparing 2-oxo-4-phenyl-3- (tritylamino) -butyric acid methyl ester

The same method as Example 14 using (4S , 1E ) -1,5-diphenyl-4- (tritylamino) -pent-1-en-3-one prepared in Reference Example 6 as a starting material. The title compound (78%, light yellow crystals) was obtained.

mp 108-109 ° C .;

[α] D25 +117.01 (c 1.01, CHCl ₃ );

IR (NaCl film) 1729 (CO) cm ⁻¹ ;

¹ H NMR (CDCl ₃ ) 7.35-7.11 (m, 20H), 4.41 (dd, J = 7.1, 5.8 Hz, 1H), 3.60 (s, 3H), 2.95 (dd, J = 13.3, 5.4 Hz , 2 H, NH), 2.71 (dd, J = 13.3, 5.4 Hz, 1 H);

FAB MS m / z : 450 (M + l).

Example 16. (3 S (Method) -5-methyl-2-oxo-3- (tritylamino) -hexanoic acid methyl ester

In the same manner as in Example 14, using (4S, 1E) -6-methyl-1-phenyl-4- (tritylamino) -hept-1-en-3-one prepared in Reference Example 7 as a starting material. The title compound (80%, yellow syrup) was obtained.

[α] _D ²⁵ +77.47 (c 0.52, CHCl ₃ );

IR (NaCl film) 1729 (CO) cm ⁻¹ ;

¹ H NMR (CDCl ₃ ) 7.51-7.13 (m, 15 H), 4.16 (t, J = 6.6 Hz, 1 H), 3.65 (s, 3 H), 2.78 (br, 1H), 1.94 (m, 1 H), 1.40 (t, J = 6.7 Hz, 2H), 0.93 (t, J = 6.7 Hz, 6H);

FAB MS m / z : 416 (M + l).

Example 17. (2 R , 3 R A method for preparing methyl-3-amino-2-hydroxy-3-phenyl-propionic acid methyl ester

Α-keto ester (3R) -2-oxo-3-phenyl-3- (tritylamino) -propionic acid methyl ester (200 mg, 0.46 mmol) obtained in Example 14 was added to MeOH (5 ml) and conc -HCl (0.13 ml, 1.6 mmol) was added. Stir at room temperature for 40 minutes and wash with n-hexane (23 ml). The MeOH layer was taken, distillation under reduced pressure, MeOH (5 ml) was added again, and distillation under reduced pressure. Water and excess HCl contained in the obtained syrup-like product were volatilized for several hours under high vacuum to quantitatively obtain enon hydrochloride having a trityl group deprotected as a white semi solid. MeOH (5 ml) was added to the residue, and the mixture was cooled to 20 ° C and NaBH ₄ (52 mg, 1.38 mmol) was added in three portions. After stirring for 1 hour at the same temperature, water (5 ml) was added and distillation under reduced pressure to remove most of the MeOH. Extraction with CHCl ₃ (415 ml), drying and drying the organic layer under reduced pressure yielded a crystal, which was recrystallized with a mixed solvent of EtOAc / n-hexane (1/3) to obtain the title compound (2R, 3R) -3- as white crystals. Amino-2-hydroxy-3-phenyl-propionic acid methyl ester (66 mg, 73%) was obtained.

mp 84-85 ° C .;

[α] _D ²⁵ +31.27 (c 0.56, CHCl ₃ );

¹ H NMR (CDCl ₃ ) 7.30-7.24 (m, 5H), 4.44 (d, J = 4.1 Hz, 1H), 4.29 (d, J = 4.1 Hz, 1H), 3.63 (s, 3H) , 2.20 (br s, 3 H).

Hydrochloride:

mp 172-174 ° C .;

[α] _D ²⁵ +14.6 (c 0.99, MeOH).

Example 18. (2 S , 3 S A method for preparing methyl-3-amino-2-hydroxy-3-phenyl-butyric acid methyl ester

Using the ( 3S ) -2-oxo-4-phenyl-3- (tritylamino) -butyric acid methyl ester obtained in Example 15 as a starting material, the title compound was obtained in the same manner as in Example 17 (83% , Light yellow amorphous solid).

[α] _D ²⁵ +19.3 (c 1.03, 1N-HCl);

¹ H NMR (CDCl ₃ ) 7.33-7.18 (m, 5H), 4.24 (d, J = 3.7 Hz, 1H), 3.75 (s, 3H), 3.35 (m, 1H), 2.81 (dd, J = 13.6, 4.6 Hz, 1 H), 2.59 (dd, J = 13.6, 9.4 Hz, 1 H), 2.34 (br, 3 H). 129.2, 127.1.

Treatment of this compound with HCl (2S, 3 S) -3-amino-2-hydroxy-3-phenyl-butyric acid can be obtained in the form of the methyl ester hydrochloride (colorless crystals).

Hydrochloride:

mp 147-148.5 ° C .;

[a] _D ²⁵ +13.81 (c 0.70, MeOH).

Example 19. (2 S , 3 S A method for preparing methyl-3-amino-2-hydroxy-3-methyl-hexanoic acid methyl ester

Using the ( 3S ) -5-methyl-2-oxo-3- (tritylamino) -hexanoic acid methyl ester obtained in Example 16 as a starting material, the title compound was obtained in the same manner as in Example 17 (80 %, Colorless crystals).

mp 48-49 ° C. (sublimable in vacuum);

[α] _D ²⁵ +15.06 (c 0.79, CHCl ₃ );

¹ H NMR (CD ₃ OD) 4.16 (d, J = 3.9 Hz, 1H), 3.76 (s, 3H), 4.16 (d, J = 3.9 Hz, 1H), 3.76 (s, 3H), 3.12 (dt, J = 9.3, 4.1 Hz, 1H), 1.60 (m, 1H), 1.34 (m, 1H), 1.18 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H) , 0.89 (d, J = 6.6 Hz, 3H).

Using the process according to the invention, two β-amino-α-hydroxy carboxylic acids with optical activity can be obtained with high stereoselectivity from one starting material. That is, by changing the type of protecting group of the amino group, the reduction reaction by stereoregulation and the reduction reaction by crosslinking are selectively performed to obtain syn and anti isomers as desired, and the reaction step is easy and the yield is excellent. It is very economical.

Claims (12)

A method of preparing β-amino-α-hydroxy carboxylic acid of Formula 1 and its derivatives by oxidation of a compound of Formula 2: <Formula 1> <Formula 2> Wherein n is 0 or 1, R ₁ is hydrogen, a C1-C8 alkyl group, a phenyl group, or a benzyl group, R ₂ is a protecting group of hydrogen or a hydroxy group, R ₃ is a protecting group of hydrogen or an amine group, R ₄ is a C1-C20 alkyl group, a C3-C20 cycloalkyl group, a phenyl group or a benzyl group, R ₅ is hydrogen, a C1-C10 alkyl group or a phenyl group, X is CH ₃ COO, HCOO, HO ₂ CCH (OH) CH (OH) COO, CH ₃ SO ₃ , CF ₃ CH ₃ COO, CH ₃ C ₆ H ₅ SO ₃ , Cl, HSO ₄ , or H ₂ PO ₄ ego, * Means chiral carbon. The method of claim 1, wherein the compound of Formula 2 is synthesized by reducing the compound of Formula 4. <Formula 4> Wherein R ₃ , R ₄ , and R ₅ are as defined in claim 1. To prepare a β-amino-α-hydroxy carboxylic acid and its derivatives of the formula (1) by the reduction of the compound of formula (3): <Formula 1> <Formula 3> Wherein n is 0 or 1, R ₁ is hydrogen, a C1-C8 alkyl group, a phenyl group or a benzyl group, R ₂ is a protecting group of hydrogen or a hydroxy group, R ₃ is a protecting group of hydrogen or an amine group, R ₄ is a C1-C20 alkyl group, a C3-C20 cycloalkyl group, a phenyl group or a benzyl group, R ₅ is hydrogen, a C1-C10 alkyl group or a phenyl group, X is CH ₃ COO, HCOO, HO ₂ CCH (OH) CH (OH) COO, CH ₃ SO ₃ , CF ₃ CH ₃ COO, CH ₃ C ₆ H ₅ SO ₃ , Cl, HSO ₄ , or H ₂ PO ₄ ego, * Means chiral carbon. The method of claim 3, wherein the compound of Formula 3 is synthesized by oxidizing the compound of Formula 4. <Formula 4> Wherein R ₃ , R ₄ , and R ₅ are as defined in claim 3. The method according to claim 1 or 4, wherein the oxidizing step is O ₃ , K ₂ Cr ₂ O ₇ , Na ₂ Cr ₂ O ₇ , KMnO ₄ , NaIO ₄ , Pb (OC (═O) CH ₃ ) ₂ , RuO ₄ , H ₂ O ₂ , RuCl ₃ , CrO ₃ , (C ₅ H ₅ NH) ₂ Cr ₂ O ₇ (PDC), pyridiumchlorochromate (PCC), NaClO ₂ , Hg (OC (= O) CH _{3 2} ) using at least one oxidant selected from the group consisting of. The method of claim 2 or 3, wherein the reducing step is NaBH ₄ , LiBH ₄ , LiAlH ₄ , L-selectide, diisopropylaluminum hydride (DIBAL), Zn (BH ₄ ) ₂ , (CH ₃ ) ₄ BH (OC (= 0) CH ₃ ) ₃ , NaBH ₃ CN, LiBHEt ₃ , LiAl (OC (═O) CH ₃ ) ₃ , wherein the method is carried out using at least one reducing agent selected from the group consisting of: The method according to claim 2 or 3, wherein a catalyst selected from the group consisting of CeCl ₃ , ZnCl ₂ , NiCl ₂ , and SmCl ₃ is further added to increase diastereoselectivity in the reduction reaction. The method according to any one of claims 1 to 4, wherein the C1-C8 alkyl group is a group selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and t-butyl. How to. The protecting group of the hydroxy group according to any one of claims 1 to 4, wherein the protecting group of the hydroxy group is methoxymethyl, methoxythiomethyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl, t-butyldimethylsilyl, trimethyl In the group consisting of silyl, triphenylsilyl, benzyl, p-methoxybenzyl, t-butoxymethyl, tetrahydropyranyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, diphenylmethyl, and triphenylmethyl The selected group. The protecting group of the amine group according to any one of claims 1 to 4, wherein the protecting group of the amine group is acetyl, benzoyl, triphenylmethyl, allyl, di (4-methoxyphenyl) methyl, N-5-dibenzosuberyl, (4 -Methoxyphenyl) diphenylphenyl, and 9-phenylfluororenyl. The method according to any one of claims 1 to 4, wherein the C1-C20 alkyl group is a group selected from the group consisting of methyl, ethyl, propyl isopropyl butyl, isobutyl, t-butyl, hexyl, and heptyl. How to. 5. The method of claim 1, wherein the cycloalkyl group of C 3 -C 20 is a group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 6.