KR100576740B1 - Sphingosine precursor, its synthetic method, and sythetic method for sphingosine derivative using the precursor - Google Patents

Abstract

The present invention relates to a sphingosine precursor compound, a method for preparing the same, and a method for preparing a sphingosine derivative using the same. In the present invention, the carbonyl group of the compound [Formula I], which is a sphingosine precursor, is stereoselectively reduced and double-bonded as necessary There is provided a method for producing an optically pure sphingosine derivative represented by [Formula II], further comprising the step of reducing the compound.

[Formula I]

[Formula II]

Wherein X is OH or SH; Y may or may not be present, where present, an acid capable of forming a salt with an amine group provided that R ₄ is hydrogen; Z is a single bond or a double bond; R ₁ is hydrogen or lower alkyl of C ₁ to C ₆ ; R ₂ is a C ₁₀ to C ₂₄ straight or branched chain hydrocarbon; R ₃ is triphenylmethyl or benzyl derivative represented by the following structural formula

Wherein P and Q are each electron withdrawing groups substituted with at least one of P or Q; R ₄ is hydrogen or an ester derivative having the structure

Wherein R ₅ is C ₁ to C ₂₀ substituted or unsubstituted aliphatic hydrocarbon or C ₆ to C ₃₀ substituted or unsubstituted aromatic hydrocarbon

According to the preparation method of the present invention, two different diastereoisomers of three-dimensional and optically pure sphingosine derivatives can be prepared without causing undesirable racemization or epimerization reactions and are optically pure compounds due to the nature of the reaction. There is no need to use column chromatography for separation of metals, so the industrial applicability is very high.

Description

Sphinosine precursor compound, preparation method thereof and preparation method of sphingosine derivative using the same {Sphingosine precursor, its synthetic method, and sythetic method for sphingosine derivative using the precursor}

The present invention relates to a sphingosine precursor, a method for preparing the same, and a method for preparing a sphingosine derivative using the same, and more specifically, using a sphingosine precursor, a synthetic intermediate such as an anticancer agent without side reactions during an undesirable manufacturing process. It relates to a method for preparing an optically pure sphingosine derivative used as.

Natural sphingosine is D (+)-erythro-1,3-dihydroxy-2-aminotrans-4-octadecene Unsaturated aminoalcohol having the structure of [CH ₃ (CH ₂ ) ₁₂ CH = CHCH (OH) CH (NH ₂ ) CH ₂ OH], which is a phospholipid sphingomyelin or glycolipid sere present in the brain, kidney and nervous tissue of an animal It is one of the components constituting the rosid. As one of the sphingosine derivatives, dihydrosphingosine having a reduced double bond of sphingosine is called spinganine.

The sphingosine derivatives can be used as synthetic intermediates such as antibacterial agents, anticancer agents, antibiotics, anti-inflammatory agents, gastric ulcer agents, arteriosclerosis agents, and immunosuppressive agents, and for this, it is important to obtain optically and stericly pure compounds.

Methods for preparing optically pure sphingosine derivatives known in the literature so far include, first, methods using serine as starting material ( J, Org. Chem . 1986, 51, 5320; Helvetica Chimica Acta 1988, 71, 353; Tetrahedron Lett , 1988, 29, 3027; J. Org. Chem . 1990, 55, 1439; J. Org. Chem . 1992, 57, 5469; J. Org. Chem . 1990, 55, 1439; J. Org. Chem . 1992, 57, 5469; J. Org, Chem . 1993, 58, 4309; Synlett 1993, 501; J. Org. Chem . 1998, 63, 3979), and second, methods of using carbohydrates as starting materials ( Tetrahedron 1993, 49 , 6645; Tetrahedron Lett . 1994, 35, 745; Tetrahedron: Asymmetry 1994, 5, 2195; Tetrahedron 1994, 50, 10727; Synthesis 1995, 868; Liebigs Ann . 1995, 33; Tetrahedron: Asymmetry 1996, 7, 897; Tetrahedron Asymmetry 1997, 8, 3237; Synthesis 1997, 33), and third, using a chiral aid as a starting material ( J. Am. Chem. Soc. 1988, 110, 7910; J. Org. Chem . 1994, 59, 3240). ;. Tetrahedron Lett 1996, 37, 4349), Fourth, Way as to material using a chiral compound obtained by using the enzyme or asymmetric epoxidation (Tetrahedron Lett 1981, 22, 4433 ;. Tetrahedron Lett 1983, 24, 5491;... JCS Chem Commun 1991, 820;. J. Org Chem 1994, 59, 7944; J. Org.Chem . 1988, 63, 510).

However, the above methods have the following problems.

The method of using serine as a starting material is not only easy to undergo racemization or epimerization reaction because most of it passes through an aldehyde derivative as an intermediate material, but also due to the lack of stereoselectivity when introducing an organometallic reagent into an aldehyde. It is difficult to obtain pure isomers.

The method of using carbohydrate as a starting material is not only through many reaction steps but also through an unstable aldehyde as an intermediate, and this method is also prone to the above problems. Only isomers of are synthesized.

The use of chiral auxiliaries and the use of chiral compounds through asymmetric epoxidation reactions are difficult to apply to the synthesis of actual sphingosine derivatives due to yield or cost issues. It is also practically difficult to obtain two stereoisomers from one starting material.

An object of the present invention is to provide a novel sphingosine precursor and a method for producing the same.

Another object of the present invention is to use the sphingosine precursor to prepare a novel sphingosine derivative having very high stereoselectivity without causing any undesirable racemization or epimerization reactions that may occur during the synthesis reaction. To provide a way.

In order to achieve the above object, in the present invention, a sphingosine precursor compound represented by the following [Formula I] is provided.

[Formula I]

Wherein X is OH or SH; Y may or may not be present, where present, an acid capable of forming a salt with an amine group provided that R ₄ is hydrogen; Z is a single bond or a double bond; R ₁ is hydrogen or lower alkyl of C ₁ to C ₆ ; R ₂ is a C ₁₀ to C ₂₄ straight or branched chain hydrocarbon; R ₃ is triphenylmethyl or benzyl derivative represented by the following structural formula

(여기서, R₅는 C₁ ~ C₂₀의 치환 또는 비치환된 지방족 탄화수소 또는 C₆ ~ C₃₀의 치환 또는 비치환된 방향족 탄화수소임)Wherein P and Q are each electron withdrawing groups substituted with at least one of P or Q; R ₄ is hydrogen or an ester derivative having the structure

Wherein R ₅ is C ₁ to C ₂₀ substituted or unsubstituted aliphatic hydrocarbon or C ₆ to C ₃₀ substituted or unsubstituted aromatic hydrocarbon

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[화학식Ⅳ]

In order to achieve another object of the present invention, in the present invention, (a) the compound of [Chemical Formula IV] and the compound of Chemical Formula CH ₃ PO (OR ₉ ) _{2 in} the basic conditions to prepare a compound of [Chemical Formula III] Step and (b) a method of producing a compound of formula (Ia), characterized in that it comprises the step of reacting the compound of formula (III) and the formula R ₂ CHO compound in basic conditions and then deprotection (X, Y, R ₁ , R ₂ , R ₃ are as described above, R ₄ is hydrogen and Z is a double bond)
[Formula III]

[Formula IV]

Wherein R ₁ , R ₂ , R ₃ , X, Y are as defined in Formula I, X 'is O or S, R ₇ is a lower alkyl or benzyl group of C ₁ to C ₄ , R ₈ Is a lower alkyl group of C ₁ to C ₄ or — (CH ₂ ) n — (an integer of n = 4 to 6) as a cyclic structure connected to each other, and R ₉ is a lower alkyl group or benzyl group of C ₁ to C ₄ ; And

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The compound produced in step (b), and anhydrous compound ((R ₅ OCO) ₂₀ ) or an acid halide compound (R ₅ OCOR ₁₀ ) further comprising the step of reacting under basic conditions, Ib] Preparation of compounds (X, R ₁ , R ₂ , R ₃ are as described above, R ₄ is the above-mentioned ester derivative which is not hydrogen, Y is absent and Z is a double bond and R ₁₀ is a halogen atom) A method is provided.

Further, in order to achieve another object of the present invention, in the present invention, further comprising the step of performing a stereoselective reduction reaction of the carbonyl group of the compound [Formula I], optionally reducing the double bond, A method for producing an optically pure sphingosine derivative represented by the formula [II] is provided.

[Formula II]

Wherein X, Z, R ₁ , R ₂ , and R ₃ are as defined in Formula I above.

Hereinafter, a method for preparing a sphingosine precursor of the present invention and a method for preparing two different diastereomers of an optically pure sphingosine derivative will be described in detail.

First, the manufacturing process of the sphingosine precursor and the sphingosine derivative of the present invention as a whole is as follows.

The sphingosine precursor [Formula Ia] is prepared by reacting with an aldehyde compound after β-ketophosphonate the compound of Formula IV and then deprotecting under acidic conditions. Ib] is prepared. Optically pure sphingosine derivatives [Formula IIa] and [Formula IIb] are generated as two different diastereomers by stereoselectively reducing the carbonyl groups of the compounds of Formulas Ia and Ib, respectively. This series of manufacturing process is shown in the following [Reaction Scheme 1].

In the above scheme, X means OH or SH, X 'means O or S. Y may be present or non-existent, where present as formic acid, acetic acid, tartaric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, sulfuric acid and Phosphoric acid is included. R ₁ means hydrogen or C ₁ to C ₆ lower alkyl groups, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and phenyl groups. R ₂ means C ₁₀ to C ₂₄ straight or branched chain hydrocarbons. R ₃ means triphenylmethyl or a benzyl derivative represented by the following formula as an amine protecting group.

Here, P and Q are each an electron withdrawing group, and preferably include nitro, methoxy, cyano, chlorine or bromine groups. At least one of P and Q is substituted. Preferred R ₃ is p-methoxybenzyl, 3,4-dimethoxybenzyl, p-nitrobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-chlorobenzyl, among which p-methoxybenzyl Is most preferred. R ₄ is an ester derivative having the formula: a protecting group that is easily removed by a weak acid or weak base.

Here, R ₅ means C ₁ ~ C ₂₀ substituted or unsubstituted aliphatic hydrocarbon or C ₆ ~ C ₃₀ substituted or unsubstituted aromatic hydrocarbon, preferably methyl, ethyl, propyl, butyl, t-butyl , 9-fluorenylmethyl, trichloroethyl, phenylethyl, benzyl, 1-adamantyl, p-methoxybenzyl, and p-nitrobenzyl groups. R ₈ is a lower alkyl group of C ₁ to C ₄ or-(CH ₂ ) n-(an integer of n = 4 to 6) as a cyclic structure connected to each other, preferably methyl, ethyl, propyl, isopropyl,-( CH ₂ ) _4- , (CH ₂ ) _5- , and-(CH ₂ ) _6- . R ₁₀ is a halogen atom such as chlorine, bromine or iodine.

The compound of [Formula II], which is a sphingosine derivative prepared in the above scheme, may have two or three chiral carbons, depending on what the R ₁ group is, so that four or eight stereoisomers are possible. Thus, the present invention includes all possible stereoisomers of the sphingosine derivatives.

With reference to [Scheme 1], a method for producing a sphingosine precursor and a sphingosine derivative will be described for each reaction step.

First, in step (a), the compound of [Formula III], which is a β-ketophosphonate derivative, is prepared by reacting the compound of Formula [IV] with a dialkylmethylphosphonate (CH ₃ PO (OR ₉ ) ₂ ) compound. do.

The compound of formula [IV], the starting material of step (a), is easily synthesized according to the general synthesis method described in the literature. For example, when L-serine or D-serine derivatives are used, the carboxyl group in the serine structure may be prepared by converting the ester into an ester first, and then simultaneously protecting the amine group and the OH group with a protecting group.

As the reaction conditions of step (a), a strong base is usually used under anhydrous conditions. As the strong base, methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium and the like can be used, and an inert solvent is used as the solvent, for example, hexane, toluene, benzene, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane, chloroform, 1,2-dimethoxyethane, ether and the like can be used. The reaction temperature is about -100 ° C to 0 ° C and preferably about -80 ° C to -30 ° C.

Looking at the reactor before step (a), the proton (H ⁺ ) attached to the methyl group carbon of CH ₃ PO (OR ₉ ) ₂ is removed by the strong base to form a carbon anion (cabanion), the reaction is generated, The compound [Chemical Formula III] is produced when carbon anion attacks the carbonyl group carbon of the compound [Chemical Formula IV].

In step (b), a carbonyl group conjugated double bond is introduced by reacting the compound of Formula III with an aldehyde compound (R ₂ CHO) under basic conditions.

The base used in step (b) may be both a strong base and a weak base. For example, methyl lithium, n-butyllithium, sec-butyllithium, t-butyllithium, sodium hydride and the like may be used. Trimethylamine, pyridine, N, N-dimethylaminopyridine, 1,8-diazabicycloundecene (DBU), diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate and the like can be used. Lithium chloride can be used as an additive to speed up the reaction and reduce side reactions. Examples of the reaction solvent include hexane, toluene, benzene, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, dichloromethane, chloroform, 1 , 2-dichloroethane, n-butanol, 2-butanol, ether and the like are used. The reaction temperature is suitably about -20 ° C to 50 ° C.

In step (c), the compound of Formula Ia is produced by simultaneously deprotecting X and N protecting groups of the compound produced in step (b) under acidic conditions. In this case, inorganic acids and organic acids such as dilute hydrochloric acid, dilute sulfuric acid, nitric acid and acetic acid are used as the acid, and the reaction temperature is about -30 ° C to 100 ° C.

In the step (d), by reacting the compound of Formula Ia with anhydrous compound (R ₅ OCO) ₂ O or an acid halide compound (R ₅ OCOR ₁₀ ) under basic conditions, another amine protecting group (R ₄ ) is introduced. The compound of Formula Ib is prepared in which the steric hindrance of the amine group is much larger than that in Formula Ia.

In the reaction conditions of step (d), as the base, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, N, N-dimethylaminopyridine, 1,8-diazabicyclo undecene (DBU), Diisopropylethylamine, potassium carbonate, sodium carbonate and the like can be used. Reaction solvents include water, hexane, toluene, benzene, tetrahydrofuran, dioxane, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, dichloromethane, Chloroform, 1,2-dichloroethane, n-butanol, ether, etc. may be used, or a mixed solvent of water and an organic solvent may be used. It is preferable that reaction temperature is about -20 degreeC-80 degreeC.

Finally, in step (e), the carbonyl groups of the compounds of Formula Ia and Formula Ib are reduced to alcohol groups by stereoselective reduction, respectively, so that two optically pure diastereomers of sphingosine derivatives are each [ Obtained as [Formula IIa] and [Formula IIb].

In the stereoselective reduction reaction of step (e), a reduction reaction with a metal hydride is preferable. Reduction by metal hydride is a reaction suitable for the reduction of ketones, carboxylic acids, esters and amide compounds having a carbonyl group (C = 0). Various hydrogen-metal complexes are used as the reducing agent, for example sodium borohydride (NaBH ₄ ), lithium borohydride (LiBH ₄ ), lithium aluminum hydride (LiAlH ₄ ), potassium borohydride (KBH). ₄ ), L-selectide (LiB (sec-Butyl) ₃ H) diisobutylaluminum hydride ((isobutyl) ₂ AlH), Zinc diborohydride (Zn (BH ₄ ) ₂ ), tetramethylammonium triacetoxyborohydride (Me ₄ NBH (OAc) ₃ ), sodium cyanoborohydride (NaBH ₃ CN), lithium triethylboro Hydride (LiBHEt ₃ ), lithium aluminum triethoxy hydride (LiAlH (OEt) ₃ ), sodium trimethoxyborohydride (NaBH (OMe) ₃ ), and the like. LiAlH ₄ and NaBH ₄ are the most commonly used.

The mechanism of the stereoselective reduction reaction of step (e) is explained according to the steric structures of the compounds of [Formula Ia] and [Formula Ib] as follows.

In the case of the compound of Formula Ib having two amine protecting groups (R ₃ and R ₄ ), since the steric hindrance of the amine side is greater than that of the compound of Formula 3, the amine side when the hydride (H ⁻ ) attacks the carbonyl group Rather, it attacked from the opposite back surface with less steric hindrance, resulting in a compound of formula IIb having a structure of (2S, 3S, 4E) (Felkin-Ahn model). On the other hand, in the case of the compound [Formula Ia], the metal ion of the reducing agent first chelates the carbonyl group with the amine period to form a cyclic complex compound, and then the hydride (H ⁻ ) has a small steric hindrance toward hydrogen. As a result, the compound of formula (IIa) having a structure of (2S, 3R, 4E) is produced. Thus, it is possible to produce optically pure sphingosine derivatives (Cram's cyclic model). For the mechanism of the two stereoselective reduction reactions, reference can be made to the contents described in the literature (JD Morison, Asymmetric Synthesis Volume 2, Chapter 5, Academy Press (1983)).

On the other hand, dihydrosphingosine (sphinganine) derivative can be prepared by reducing the double bond of the compound of [Formula II]. The dihydrophingosine derivative may also be prepared by first reducing the double bond of the compound of Formula Ia or Formula Ib and then reducing the carbonyl group to an alcohol group by the stereoselective reduction reaction described above in the preparation method of Formula II. It may also be prepared. In this case, when the compound of [Formula Ib] is reduced, the R ₄ group must be removed after the reduction.

As the double bond reduction method, a conventional reduction method may be used, but a hydrogenation reaction by catalytic reduction using a noble metal catalyst is most preferable. In this method, since the reduced substance is dissolved in a suitable solvent, a catalyst is added, and hydrogen gas is blown, so the experimental operation is simple and the post-treatment is also very easy. Catalysts used include platinum oxide (PtO ₂ ), palladium / carbon (Pd / C), rhodium (Rh) and Raney Ni.

Hereinafter, a method of preparing a sphingosine precursor and an optically pure sphingosine derivative using L-serine and D-serine as starting materials will be described. For the sake of understanding, a method of preparing two optically pure sphingosine derivatives using L-serine as a starting material is shown in [Scheme 2]. Of course, the scope of the present invention is not limited only to the following examples.

Example 1 Synthesis of (L) -N- (p-methoxybenzyl) serine Methyl Ester (1)

22 ml of methanol was cooled in an ice bath and 5 ml of acetylchloride was added dropwise for 10 minutes. After the addition was completed, the mixture was further stirred for 5 minutes. After the ice bath was removed and stirred for 20 minutes, 2.0 g (19.03 mmol) of L-serine (Aldrich Chemical, L-serine) was added, followed by stirring under reflux for 2 hours. After standing at room temperature for 8 hours, the solvent was distilled under reduced pressure to obtain a white crystalline solid. 40 ml of methanol, 1.92 g (19.03 ml) of trimethylamine, 2.59 g (19.03 ml) of p-anisaldehyde and 1.5 g of magnesium sulfate were added thereto, and the mixture was suspended by stirring at room temperature for 2.5 hours. 20 mL of dichloromethane was added to the suspension, followed by stirring for 10 minutes, and the insoluble material was removed by filtration over celite. The filtrate was cooled using an ice bath and 1.08 g (28.55 mmol) of sodium borohydride was added in three portions over 30 minutes. After stirring for 1 hour at the same temperature, 30 ml of water was added carefully. The pH was adjusted to 1 with 2N hydrochloric acid and then extracted with 30 ml of dichloromethane. The aqueous layer was taken, basified with saturated sodium hydrogen carbonate (NaHCO ₃ ) solution, and extracted with 30 mL of dichloromethane. The organic layer was dried over magnesium sulfate and dried under reduced pressure to obtain 3.9 g (yield 81%) of (L) -N- (p-methoxybenzyl) serine methyl ester.

Melting Point: 49 ℃

[α] _D = -42.08 (c = 1.80, CHCl ₃ )

IR (neat): 3322 (br), 2953, 1733, 1615, 1515, 1555, 1248, 1035 cm ^-1

¹ H-NMR (CDCl ₃ ): 7.27-6.84 (m, 4H), 3.82-3.58 (m, 10H, containing two methyl groups), 3.40 (q, 1H)

Example 2 Synthesis of Methyl N- (p-methoxybenzyl) -N, 0-isopyridene-L-serinate (2)

(L) -N- (p-methoxybenzyl) serine methyl ester (1) 5.88 g (24.57 mmol), 2,2-dimethoxypropane 7.7 g (73.93 mmol), PPTS (Pyridium-p-Toluene Sulfonate) 0.23 The reaction mixture of g and toluene 60ml was stirred under reflux for 2.5 hours, and about 20ml of the solvent was removed by simple distillation. After cooling to about 50 [deg.] C. and adding 3.0 g of 2,2-dimethoxypropane, 15 ml of solvent was simply distilled over 30 minutes. The reaction solution was cooled to room temperature, 0.3 g of triethylamine was added, and then filtered over silica gel. The filtrate was concentrated under reduced pressure, and 0.1 g of triethylamine was added thereto, followed by crystallization with methanol. The crystals were filtered and dried to give 4.6 g (yield 68%) of the title compound.

Melting Point: 80 ℃

[a] _D = -41.97 (c = 1.14, CHCl ₃ )

IR (neat): 2977, 1747, 1513, 1248, 1197cm ^-1

¹ H-NMR (CDCl ₃ ): 7.26-6.79 (m, 4H), 4.12-3.86 (m, 3H), 3.78 (s, 3H, CH ₃ ), 3.65-3.58 (m, 2H), 3.44 (s, 3H, CH ₃ )

Example 3: Synthesis of Compound (3) and (2S, 4E) -2- [N- (p-methoxybenzyl) amino] -3-oxo-4-octadeken-1-ol hydrochloride (4)

0.5 g (4.0 mmol) of dimethylmethylphosphonate (CH ₃ PO (OMe) ₂ ) was added to 20 mL of THF and cooled to -78 ° C. 2.5 ml of butyllithium (n-BuLi) (1.6M) was added dropwise for 5 minutes and stirred at the same temperature for 30 minutes. A solution in which 0.5 g (1.82 mmol) of Compound (2) prepared in Example 2 was dissolved in 5 ml of THF was added dropwise to the cooled solution for 5 minutes. After further stirring for 30 minutes, 10 ml of saturated ammonium chloride solution was carefully added. After adjusting the temperature to room temperature, 50 ml of ethyl acetate and 20 ml of water were added and extracted. The organic layer was taken, washed with water and washed again with brine. Then, after drying with magnesium sulfate, the title compound (3) as an oily substance was quantitatively obtained by distillation of the solvent under reduced pressure. 20 ml of dry THF was added to the obtained residue to dissolve it, and then 0.29 g (1.90 mmol) of DBU, 0.16 g (3.77 mmol) of lithium chloride and 0.81 g (3.81 mmol) of tetradecylaldehyde were added thereto, and then vigorously at room temperature for 4 hours. Stirred. 50 ml of ethyl acetate and 20 ml of water were added to the reaction solution, and extracted. The aqueous layer was further extracted with 20 ml of dichloromethane, and the organic layers were combined and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give slightly brown crystals, which were recrystallized from dichloromethane-acetonitrile to obtain 3.55 g (yield 67%) of the title compound (4) as white crystals.

Melting Point: 124 ℃

[α] _D = -11.30 (c = 0.99, CHCl ₃ )

IR (neat): 2921, 1695, 1628, 1517, 1465, 1254 cm ^-1

¹ H-NMR (CDCl ₃ ): 7.46 (d, 2H), 6.99 (m, 1H), 6.84 (d, 2H), 6.13 (d, 1H0, 4.32-4.22 (m, 4H), 3.98 (q, 1H) ), 3.73 (s, 1H), 3.19 (q, 2H), 1.60-1.15 (m, 24H), 0.86 (t, 3H, CH ₃ )

Example 4 Synthesis of (2S, 3R, 4E) -2- [N- (p-methoxybenzyl) amino] -4-octadeken-1,3-diol (5)

0.32 g (2.32 mmol) of zinc chloride was added to 10 ml of THF, followed by stirring to dissolve completely. 0.17 g (4.49 mmol) of sodium borohydride (NaBH ₄ ) was added thereto, followed by vigorous stirring at room temperature for 3 hours to prepare Zn (BH ₄ ) ₂ . This solution was added dropwise to a solution in which 0.50 g (1.1 mmol) of the starting material compound (4) prepared in Example 3 was dissolved in 30 ml of THF, using a syringe at -78 ° C for 5 minutes. After stirring for 3 hours at the same temperature, 5 ml of water was added carefully. Then, 3.8 ml of concentrated hydrochloric acid was added and stirred at room temperature for 4 hours. The pH was adjusted to 7-8 with saturated sodium hydrogen carbonate solution, and then extracted by adding 50 ml of ethyl acetate and 30 ml of water. The organic layer was taken, washed with water and washed with brine again and dried over magnesium sulfate. Next, the solvent was distilled under reduced pressure to obtain an oily substance, and then crystallized by standing in the air for a while. The crystallized solid was recrystallized with acetonitrile to obtain 0.43 g (yield 91%) of the title compound (5).

Melting Point: 50 ℃

[α] _D = -5.72 (c = 2.30, CHCl ₃ )

IR (neat): 3374 (br), 2919, 1612, 1514, 1469, 1252 cm ^-1

¹ H-NMR (CDCl ₃ ): 7.25-6.83 (q, 4H, ar.), 5.70 (m, 1H, vinyl), 5.41 (q, 1H), 4.19 (t, 1H), 3.78-3.66 (m, 7H), 3.75-2.30 (m, 4H, with OH + NH), 2.02 (q, 2H), 1.55-1.20 (m, 22H), 0.87 (t, 3H, CH ₃ )

Example 5 (2S, 4E) -2- [N- (p-methoxybenzyl) -N- (t-butoxycarbonyl) amino] -3-oxo-4-octadeken-1-ol (6 ) And (2S, 3S, 4E) -2- [N- (p-methoxybenzyl) amino] -4-octadecene-1,3-diol (7)

Using Compound (4) prepared in Example 3 as a starting material, 0.80 g (1.76 mmol) of this compound, 1.20 g (5.5 mmol) of t-butoxycarbonyl anhydride (Boc ₂ O), and 0.39 g of triethylamine ( 3.86 mmol) was added to 15 ml of dioxane and stirred at room temperature for 24 hours. 50 ml of ethyl acetate and 30 ml of water were added and extracted. The organic layer was taken, washed sequentially with water and brine, and dried over magnesium sulfate. The solvent was distilled under reduced pressure to obtain the title compound (6) as a pale yellow oily substance. The next reaction proceeded directly without purification of compound (6). Methanol 30ml was added to dissolve the starting material, the reaction residue, and then cooled using an ice bath. 0.22 g (5.79 mmol) of sodium borohydride was slowly added over 5 minutes and then stirred at the same temperature for 1 hour. 5 ml of water was added to the stirred solution, followed by 8 ml of concentrated hydrochloric acid and 10 ml of THF, followed by stirring at 50 ° C. for 1 hour. The reaction solution was cooled to room temperature, adjusted to a pH of 7 to 8 with saturated sodium bicarbonate solution, and extracted by adding 50 ml of ethyl acetate and 30 ml of water. The organic layer was taken, washed sequentially with water and brine, and dried over magnesium sulfate. Then, the solvent was distilled under reduced pressure to obtain slightly brown crystals, and 0.45 g (yield 61%) of the title compound (7) as white crystals was obtained by recrystallization with n-hexane.

Melting Point: 73 ℃

[α] _D = +14.30 (c = 1.16, CHCl ₃ )

IR (neat): 3600-3150 (br), 2921, 2849, 1515, 1465, 1251cm ^-1

¹ H-NMR (CDCl ₃ ): 7.25-6.83 (m, 4H, ar.), 5.74 (m, 1H, vinyl), 5.41 (m, dd, vinyl), 4.03 (t, 1H), 3.83-3.67 ( m, 7H, including CH ₃ ), 2.61-2.54 (m, 4H, OH + NH), 2.02 (q, 2H, CH ₂ ), 1.45-1.17 (m, 22H), 0.87 (t, 3H, CH ₃ )

Example 6 Synthesis of (2R, 4E) -2- [N- (p-methoxybenzyl) amino] -3-oxo-4-octadeken-1-ol hydrochloride

Using the D-serine as starting material, the title compound was prepared in the same manner as described above in Examples 1, 2 and 3 (yield 70%).

Melting Point: 122 ℃

[α] _D = +11.68 (c = 1.1, CHCl ₃ )

IR (neat): 2921, 1695, 1628, 1517, 1465, 1254 cm ^-1

¹ H-NMR (CDCl ₃ ): 7.46 (d, 2H), 6.99 (m, 1H), 6.84 (d, 2H), 6.13 (d, 1H), 4.32-4.22 (m, 4H), 3.98 (q, 1H), 3.73 (s, 1H), 3.19 (q, 2H), 1.60-1.15 (m, 24H), 0.86 (t, 3H, CH ₃ )

Example 7 Synthesis of (2R, 3S, 4E) -2- [N- (p-methoxybenzyl) amino] -4-octadeken-1,3-diol

Example 1 Compound (2R, 4E) -2- [N- (p-methoxybenzyl) amino] -3-oxo-4-octadeken-1-ol hydrochloride prepared in Example 6 was used as a starting material. The title compound was prepared in the same manner as described above in (2) (yield 87%).

Melting Point: 50 ℃

[α] _D = +5.83 (c = 1.06, CHCl ₃ )

IR (neat): 3374 (br), 2919, 1612, 1514, 1469, 1252 cm ^-1

¹ H-NMR (CDCl ₃ ): 7.25-6.83 (q, 4H, ar.), 5.70 (m, 1H, vinyl), 5.41 (q, 1H), 4.19 (t, 1H), 3.78-3.66 (m, 7H), 3.75-2.30 (m, 4H, with OH + NH), 2.02 (q, 2H), 1.55-1.20 (m, 22H), 0.87 (t, 3H, CH ₃ )

Example 8 Synthesis of (2R, 3R, 4E) -2- [N- (p-methoxybenzyl) amino] -4-octadeken-1,3-diol

Example 1 Compound (2R, 4E) -2- [N- (p-methoxybenzyl) amino] -3-oxo-4-octadeken-1-ol hydrochloride prepared in Example 6 was used as a starting material. The title compound was prepared in the same manner as described above in (5) (yield 60%).

Melting Point: 74 ℃

[α] _D = -14.42 (c = 0.70, CHCl ₃ )

IR (neat): 3600-3150 (br), 2921, 2849, 1515, 1465, 1251cm ^-1

¹ H-NMR (CDCl ₃ ): 7.25-6.83 (m, 4H, ar.), 5.74 (m, 1H, vinyl), 5.41 (m, dd, vinyl), 4.03 (t, 1H), 3.83-3.67 ( m, 7H, including CH ₃ ), 2.61-2.54 (m, 4H, OH + NH), 2.02 (q, 2H, CH ₂ ), 1.45-1.17 (m, 22H), 0.87 (t, 3H, CH ₃ )

 As described above, according to the present invention, two different diastereomers of stereo- and optically pure forms can be prepared without the undesirable racemization or epimerization reaction, which may occur during the manufacturing process, and optically As it is not necessary to use column chromatography for separation of pure products, the industrial applicability is very high.

Claims (5)

Sphingosine precursor compound represented by the following [Formula I]: [Formula I]

Wherein X is OH or SH; Y may or may not be present, where present, an acid capable of forming a salt with an amine group provided that R ₄ is hydrogen; Z is a single bond or a double bond; R ₁ is hydrogen or lower alkyl of C ₁ to C ₆ ; R ₂ is a C ₁₀ to C ₂₄ straight or branched chain hydrocarbon; R ₃ is triphenylmethyl or benzyl derivative represented by the following structural formula

Wherein P and Q are each electron withdrawing groups substituted with at least one of P or Q; R ₄ is hydrogen or an ester derivative having the structure

Wherein R ₅ is C _1-20 alkyl unsubstituted or substituted with halogen, fluorenyl, phenyl, C _1-8 alkoxyphenyl, or nitrophenyl; or C _6-30 aromatic hydrocarbons The precursor compound according to claim 1, wherein R ₃ of the sphingosine precursor is p-methoxybenzyl as an amine protecting group. In the manufacturing method of a compound, (a) preparing a compound of the following Chemical Formula III by reacting the compound of the following Chemical Formula IV with a compound of Chemical Formula CH ₃ PO (OR ₉ ) ₂ under basic conditions; (b) reacting the compound of [Chemical Formula III] with the formula R ₂ CHO compound at basic conditions and then deprotecting. [Formula I]

[Formula III]

[Formula IV]

Wherein R ₁ , R ₂ , R ₃ , X, Y are as defined in claim 1, X 'is O or S, R ₄ is hydrogen, Z is a double bond, and R ₇ is C ₁ -C A lower alkyl group or benzyl group of ₄ , R ₈ is a lower alkyl group of C ₁ to C ₄ or-(CH ₂ ) n-(an integer of n = 4 to 6) as a cyclic structure connected to each other, and R ₉ is C ₁ to C ₄ lower alkyl group or benzyl group. A process for preparing a compound of the formula [I] comprising the step of reacting a compound prepared by the method of claim 3 with an anhydrous compound ((R ₅ OCO) ₂₀ ) or an acid halogen compound (R ₅ OCOR ₁₀ ) under basic conditions : [Formula I]

Wherein R ₁ , R ₂ , R ₃ , and X are as defined in claim 1, Y is absent, Z is a double bond, R ₁₀ is a halogen atom, R ₄ is an ester derivative having the structure

Wherein R ₅ is C _1-20 alkyl unsubstituted or substituted with halogen, fluorenyl, phenyl, C _1-8 alkoxyphenyl, or nitrophenyl; or C _6-30 aromatic hydrocarbons. In the method for preparing an optically pure sphingosine derivative represented by the following [Formula II], the carbonyl group of the compound of [Formula I] according to claim 1 is subjected to stereoselective reduction reaction, and, in some cases, to reduce the double bond. Manufacturing method; [Formula II]

Wherein X, Z, R ₁ , R ₂ and R ₃ are as defined in claim 1.