JP2500799B2 - New Intermediates of Optically Active Unsaturated Amino Alcohol Derivatives - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel intermediate for producing ceramide or its homolog, which is an important constituent of ganglioside, which is expected to be developed as a treatment for bokeh and an anticancer drug.

[0002]

BACKGROUND OF THE INVENTION Ganglioside is a general term for glycosphingolipids having sialic acid, and is widely distributed in living tissues of various higher animals. In recent years, it has become clear that the role of ganglioside as a receptor molecule for hormones and bacterial toxins, and that ganglioside expresses neural cell proliferation and differentiation promoting factor activity, etc. Has become. Among them, the hydrophobic ceramide bound to the end of the ganglioside is particularly attracting attention as a factor that controls the reactivity of sugar chains. However, since an excellent chemical synthesis method for ceramide and its homologue has not been established yet, the carbon number of the sphingosine portion, the type of fatty acid, the difference in activity due to cis and trans, etc. have not yet been clarified, The consideration is awaited. Examples of the chemical synthesis method of ceramide and its homologue include ED Rei starting from D-glucose.
St. et al. [J. Org. Chem., 35 , 4127 (1970)], Ogawa et al. [Glycoconjugate J., 1 , 107 (1984)], D-mannose starting material Obayashi et al. Chem.Lett., 1985 ,
1715] and many other methods have been proposed and implemented so far. However, all of these existing methods have a large number of steps and are complicated to operate, and even the method of Ogawa et al.
Two steps (11 steps from protected glucose) are required. Therefore, in the present situation, the appearance of a simpler and more effective production method of ceramide and its homologue, which is an important constituent component of ganglioside and has been attracting attention as a factor controlling the reactivity of sugar chains, has been eagerly awaited.

[0003]

OBJECTS OF THE INVENTION The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an intermediate useful in chemically synthesizing ceramide and its homologues.

[0004]

SUMMARY OF THE INVENTION The present invention provides the formula [a]

Embedded image Wherein, X is -N ₃ group, -NH ₂ group, -NHCOR ⁶ group (R ⁶ represents a saturated or unsaturated alkyl group having 1 to 30 carbon atoms, straight-chain, in either branched R) is cis or trans-(CH ₂ ) _n CH ₃
Represents a substituent represented by (n represents an integer of 0-20),
Y and Y ′ both represent a hydrogen atom, or Y and Y ′ together represent the following formula [b]

Embedded image (R ¹ and R ² both represent a methyl group, or one of them represents a phenyl group and the other represents a hydrogen atom), and a substituted methylidene group may be formed. However, when the Y and Y 'are both hydrogen atoms, X is -N ₃ group. ] It is invention of the trans type or / and cis type compound shown by these.

The synthetic routes of the compounds of the present invention and ceramides and their homologs using the compounds are schematically shown in
It becomes as follows. However, R ¹ , R ² , R ⁶ and n are the same as described above, R ³ represents a hydrogen atom or a —CHO group, and R ⁴
Represents a protecting group such as a mesyl group, a trifluoromesyl group, a tosyl group, and a brosyl group, and R ⁵ represents a —NHCOR ⁶ group (provided that
R ⁶ is the same as above. ) Represents.

[0006]

Embedded image

[Chemical 6]

The protected D-xylose represented by the formula [I ₀ ] is prepared by converting D-xylose into N, N-dimethylformamide (DMF) according to the method described in Carbohydr. Res., 52 , 95 (1976). ) It is easily obtained by reacting with 2,2-dialkoxypropane or dialkoxybenzyl in the presence of a dehydration condensing agent such as p-toluenesulfonic acid in a solvent.
In addition, protected D-galactose represented by the formula [I ₀ ^' ] can also be treated in the same manner as above with 2,2-dialkoxypropene or dialkoxybenzyl in the presence of p-toluenesulfonic acid in DMF solvent. It is easily obtained by reacting with. Further, the protected D-galactose represented by the formula [I ₀ ^' ] is, for example, Aust. J. Chem., 31 , 1371 to 1374 (1978).
It can also be obtained by reacting with isopropenyl methyl ether in the presence of p-toluenesulfonic acid according to the method described in Carbohydr.Res., 93 , 177.
~ 190 (1981), D-galactose can also be obtained by reacting with benzaldehyde in the presence of zinc chloride.

The D-threose derivative represented by the formula [I] is obtained by oxidizing the protected D-xylose represented by the formula [I ₀ ] or the protected D-galactose represented by the formula [I ₀ ^' ] by a method known per se. Can be easily obtained. Examples of the oxidant used in the oxidation step (step A ₀ or step A ₀ ^′ ) include
Usually, sodium periodate, potassium periodate, sodium metaperiodate, potassium metaperiodate, lead tetraacetate and the like can be mentioned, but the invention is not particularly limited thereto. Step A ₀ or compounds obtained by the process A ₀ ^'[I] is usually, and R ³ is a hydrogen atom [I (H)] and R ³ is -CHO group a mixture of [I (F)] However, it is usually used as it is in step A.

Step A is the Witt forming betaine ylide.
It is performed by the ig reaction. That is, D- represented by the formula [I]
A threonose derivative (a mixture of compound [I (H)] and compound [I (F)] may be used) in the presence of alkyllithium, aralkyllithium or aryllithium (eg, butyllithium, phenyllithium, etc.) An onium salt (Wittig reagent) is allowed to act to give an olefin compound represented by the formula [II]. Examples of onium salts of phosphorus irene compounds include methyl triphenylphosphonium chloride, butyl triphenylphosphonium bromide,
Octyl trimethylphosphonium chloride, decyl
Examples include trimethylphosphonium bromide, tetradecyl triphenylphosphonium bromide, hexadecyl triphenylphosphonium bromide, octadecyl trimethylphosphonium bromide, and the like, but are not limited to these, and general formula R ⁷ ₃ PC = R ⁸ (provided that R ⁷ , R ⁸ independently represents an alkyl group or an aryl group.) Any of the hydrogen halide adducts of phosphorus-ylene compounds represented by the formula ( ⁸ ) can be used as the Wittig reagent. Step A is usually carried out as follows. That is, for example, compound [I] (compound [I (H)] and compound [I (F)]
Mixture of 1 to 1.5 mol of Wittig reagent is dissolved in a nitrogen stream in an ether solvent such as tetrahydrofuran (THF), dioxane, diethyl ether or a mixed solvent of these and another nonpolar solvent. To this, 1 to 2 mol of alkyl, aralkyl or aryllithium as a catalyst, for example, phenyllithium, butyllithium, etc. is dissolved in a suitable solvent if necessary and added, and usually 10 to 30
Stir for a minute. Then, this is -30 ℃ or less, preferably -50 ℃
After cooling, 1 mol of compound [I] (a mixture of compound [I (H)] and compound [I (F)] previously dissolved in the same solvent such as THF as described above was added under a nitrogen stream, and -30 20 ~ -40 ~ C
After stirring for -40 minutes, 1-2 mol of phenyllithium is added again and the mixture is stirred at room temperature for 30-60 minutes. After the reaction, post-treatment is performed according to a conventional method, and purification is performed by column chromatography, recrystallization or the like to obtain trans-olefin [IIE] and / or cis-olefin [IIZ].

In step B, compound [II] ([IIE] or /
And [IIZ]) is a step of protecting (modifying) the hydroxyl group of (IIZ)) with a protecting group (modifying group). Examples of the modifier used here include methanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluene. Examples thereof include, but are not limited to, sulfonyl chloride (tosyl chloride), p-bromobenzenesulfonyl chloride (brosyl chloride), and the like. The amount of these modifiers to be used is generally 1 to 1.5 times the mol of the compound [II], and the reaction conditions are, for example, methanesulfonyl chloride and trifluoromethanesulfonic anhydride, the reaction temperature is 0. ℃ or less, preferably -10 ℃ or less, the completion of the reaction is usually confirmed by TLC, etc., the reaction time is usually
Dozens of minutes to several hours are sufficient. As the reaction solvent, a basic solvent such as pyridine, picoline, lutidine, triethylamine or the like is usually preferably used, but a mixed solvent of these and another non-polar solvent is also used if necessary. After completion of the reaction, it is possible to proceed to the next step, that is, step C without isolating the product, which is usually done.
When the compound [IIE] is used as a raw material, the compound [III] obtained is a trans isomer [IIIE], and [IIZ]
It goes without saying that the cis-form [IIIZ] of the compound [III] can be obtained by using

Step C is a step of azidating the compound [III] ([IIIE] or / and [IIIZ]) with an azide. Examples of the azide used here include hydrogen azide HN ₃ And sodium azide, hydrogen azide, lithium azide, copper azide, silver azide, etc. Since azide has poor solubility, it is usually used in a large excess of several times to several tens of times of theory. The reaction is usually carried out in a DMF solvent, but there is no problem if the solvent used in step B remains. The reaction temperature depends on the compound [II
When [I] is mesylate, tosylate, or brosylate, the reaction time is usually 100 to 120 ° C. and the reaction time is several hours to tens of hours, but when compound [III] is trifluoromesylate, it is usually -10 ° C. or lower. The reaction is performed for a few hours to a dozen hours.
After the reaction, the compound is subjected to post-treatment by a conventional method and purified by column chromatography or the like to obtain a trans isomer [IV] of compound [IV].
E] and / or cis isomer [IVZ] is obtained. That is, the compound [II
From [E] to compound [IIIE], to compound [IVE], and from compound [IIZ] to compound [IIIZ], to compound [IV]
Z] are obtained in good yield. In addition, [IVE], [IVZ]
Both also are in X is -N ₃ group in formula [a] of the above, it is and novel compounds to form a substituted methylidene group represented by Y and Y 'Togashiki [b].

Compound [IV] ([IVE] or / and [IV]
Z]) to obtain a ceramide represented by the compound [IX] or a homologue thereof, the route of step D → E → F and step D ′.
There are two routes, → E '→ F', but the difference is whether to remove the protecting group (modifying group) later or first.
There is no essential difference between the two.

Step D in the D → E → F route is a step of reducing compound [IV] ([IVE] or / and [IVZ]) to compound [V], which is used here. Examples of the reducing agent include reducing agents such as sodium borohydride, lithium aluminum hydride, and hydrogen sulfide that do not reduce double bonds. Further, in this step, similar results can be obtained by catalytic reduction in the presence of a Lindlar catalyst, and further by a method using phosphines as a reaction reagent. The amount of the reducing agent used is usually 1 to 10 times the molar equivalent of the theoretical amount, and the reaction conditions vary depending on the reducing agent used and the reducing method and are appropriately selected, for example, sodium borohydride is used as the reducing agent. If it was,
The reaction is carried out by refluxing in an alcohol solvent such as 2-propanol for 10 to 60 hours. After the reaction, the compound is subjected to post-treatment by a conventional method and purified by column chromatography or the like to obtain the trans-form [VE] or / and the cis-form [VZ] of compound [V] in high yield. [VE], [V
Z] is a novel compound in which X in the above formula [a] is a —NH ₂ group, and Y and Y ′ form a substituted methylidene group represented by the formula [b]. is there.

Step E is acylation of compound [V] ([VE] or / and [VZ]) with a fatty acid. The fatty acid used here is a saturated or unsaturated one having 1 to 30 carbon atoms. Fatty acids may be mentioned, and may be linear or branched, and for example, acetic acid, propionic acid, butyric acid, capric acid, lauric acid, myristic acid, palmitic acid, octadecanoic acid (stearic acid), tetracosanoic acid ( Specific examples thereof include lignoceric acid), melissic acid, oleic acid, and linoleic acid, but it goes without saying that they are not limited to these. The amount of the fatty acid used is usually 1 to 1.5 times the molar amount of the compound [V], and the reaction is usually 1,3-dicyclohexylcarbodiimide (DC
C), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (WSC) and the like in the presence of a dehydration condensing agent (usually 1 to 1.5 times the molar amount relative to compound [V]), a suitable reaction Solvents such as dichloromethane, dichloroethane,
Chloroform, dichloromethane-dioxane mixed solvent,
The reaction is carried out by stirring and reacting in a solvent such as a mixed solvent of dichloroethane-dioxane at room temperature to slightly warming for 1 to 10 hours. After the reaction, post-treatment is carried out by a conventional method, and purification by column chromatography, recrystallization, etc. gives a trans isomer [VIE] or / and a cis isomer [VIZ] of compound [VI] in high yield. In addition, both [VIE] and [VIZ]
X in the above formula [a] is a —NHCOR ⁶ group,
Further, Y and Y'are novel compounds in which a substituted methylidene group represented by the formula [b] is formed.

In step F, compound [VI] is obtained by hydrolysis.
([VIE] or / and [VIZ]) is a step of removing a protecting group, and is usually a compound [VI] ([VIE] or / and [VIZ])
Is dissolved in a weak acid such as acetic acid, formic acid, or tetrafluoroboric acid, a low-concentration mineral acid, or a strong aprotic acid, and water is added to the reaction at room temperature or under heating if necessary. Completion of the reaction is confirmed by TLC as in the other steps. The reaction time varies depending on the type of acid used and the reaction temperature, but is usually several minutes to several hours. After completion of the reaction, post-treatment is carried out according to a conventional method, and purification is carried out by column chromatography, recrystallization or the like to obtain the desired ceramide or its homologue in high yield. From [VIE] to [IX] trans body [IXE]
However, it goes without saying that the cis-form [IXZ] of [IX] can be obtained from [VIZ].

Process D'on the D '->E'-> F 'route
Is a step of removing the protective group (modifying group) of the compound [IV] ([IVE] or / and [IVZ]) by hydrolysis, and similar to the step F, the compound [IV] ([IVE] or / and [IV
Z]) is dissolved in a weak acid such as acetic acid, formic acid, or tetrafluoroboric acid or other acids, and water is added at room temperature or under heating if necessary to carry out the reaction. The end of the reaction is TL as in step F.
It may be confirmed by C or the like, but usually several minutes to several hours is sufficient. After completion of the reaction, post-treatment is performed according to a conventional method, and purification is performed by column chromatography, recrystallization or the like to obtain a trans isomer [VIIE] or / and a cis isomer [VIIZ] of compound [VII]. Both [VIIE] and [VIIZ] are novel compounds in which X in the above-mentioned formula [a] is a —N ₃ group and both Y and Y ′ are hydrogen atoms.

Step E'is a reduction step, but the reducing agent used here is exactly the same as that in step D, such as sodium borohydride, lithium aluminum hydride, hydrogen sulfide and the like which does not reduce the double bond. The agent is mentioned as a more preferable one. It is needless to say that similar results can be obtained by catalytic reduction in the presence of a Lindlar catalyst, or by using phosphines as a reaction reagent, as in step D. Amount of reducing agent used, reaction solvent,
The reaction temperature, reaction time, post-treatment, etc. are all in accordance with step D.
The product is purified by column chromatography, recrystallization, etc. to obtain the trans isomer [VIIIE] and / or cis isomer [VIIIZ] of compound [VIII].

Step F'is an acylation step of compound [VIII] ([VIIIE] or / and [VIIIZ]) with a fatty acid. The fatty acid used here is exactly the same as Step E and has 1 carbon atom. To 30 saturated or unsaturated fatty acids, which may be linear or branched, for example,
Acetic acid, propionic acid, butyric acid, capric acid, lauric acid,
Specific examples thereof include, but are not limited to, myristic acid, palmitic acid, octadecanoic acid (stearic acid), tetracosanoic acid (lignoceric acid), melissic acid, oleic acid, and linoleic acid. The amount of fatty acid used, other reaction conditions, post-treatment, etc. are all in step E.
It is enough to do according to that. The product is purified by column chromatography, recrystallization, etc. to obtain the desired ceramide or its homologue. From [VIIIE] to [IX]
It is needless to say that the trans form [IXE] of [IX] and the cis form [IXZ] of [IX] can be obtained from [VIIIZ].

Compound [IV] ([IVE] or / and [IV]
Z]) to the compound [IX] ([IXE] or / and [IXZ])
It is optional to adopt the route of the process D → E → F or the route of the process D ′ → E ′ → F ′ as the route for manufacturing the. No matter which route is used, according to the above-mentioned production method via the novel intermediate of the present invention, D
8 steps from xylose or D-galactose (protection D-
Ceramide or its homologue can be obtained from xylose or protected D-galactose in 7 steps). Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[0020]

EXAMPLES Example 1. (1) 3,5-O-isopropylidene-D-xylofuranose
[I₀] D-xylose 20 g was dissolved in DMF 250 ml and stirred,
Add 40 ml of 2,2-dimethoxypropane and p-to this at 40-45 ° C.
Add 0.3 g of ruene sulfonic acid monohydrate, and at the same temperature for 3 hours
The reaction was carried out with stirring. After the reaction, return to room temperature and use excess heavy carbon.
After adding sodium acid salt and stirring for 15 minutes, the insoluble material was filtered off.
did. The filtrate was concentrated under reduced pressure, and the resulting syrup was treated with silica gel.
Column chromatography [filler: Wakogel C-3
00 (trade name of Wako Pure Chemical Industries, Ltd.), eluent: chloroform
→ Chloroform / methanol (100/1) → Chloroform
Solvent / methanol (50/1)], 3,5-O-isopro
Pyridene-D-xylofuranose [I₀] Syrup 7.8g
Got Yield 31%. [Α]_D ²⁰: + 19.2 ° (C = 0.5, methanol). IR (film): ν 3370 (OH), 840 cm^-1((CH₃)₂C).¹ H-NMR (60MHz, CDCl₃): Δ 1.45 ((CH₃)₂C),
3.5 (OH), 3.8 to 4.4 (m, ring protons), 5.2 (s, J_1,2
 ~ 0Hz, H-1β), 5.67ppm (d, J_1,2 3.8Hz, H-1α). (2) 2,4-O-isopropylidene-D-threose [I
(H)_a] And its formate [I (F)_a] Synthesis of compound [I] obtained in (1)₀] 5g to 250ml of methanol
Dissolve and add 7.4 g of sodium periodate to the chamber.
The reaction was allowed to stir at temperature for 3 hours. After the reaction, insoluble matter was filtered off and filtered.
The syrup obtained by concentrating the liquid under reduced pressure is a silica gel column.
Chromatography [filler: Wakogel C-200 (Wako
Junyaku Kogyo Co., Ltd. product name), eluent: chloroform / methano
(150/1)], 2,4-O-isopropylidene
-D-threose [I (H)_a] And its formate [I (F)_a]
4.2 g of a mixture of (1: 1) was obtained. [Α]_D: -50 ° (C = 0.56, chloroform). IR (film): ν 3700-3100 (OH), 1720 (C = O), 85
0cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 1.49,1.50,1.52,
1.56 (4s, 6H, (CH₃)₂C), 8.06,8.16 (2s, 1H, CHO), 9.5
4ppm (s, 0.5H, CHO). This mixture was subjected to the next reaction without separation and purification. (3) (2R, 3R, 4E) -1,3-O-isopropylidene-4-octa
Decene-1,2,3-triol [II_aE] and (2R, 3R, 4Z) -1,3-
O-isopropylidene-4-octadecene-1,2,3-trio
Le [II_aZ] Synthesis of tetradecyl triphenylphosphonium bromide 1
Dissolve 8.8 g in 100 ml of THF in a nitrogen stream,
Nyllithium 2.0M cyclohexane-ether (70: 3
0) 17.4 ml of the solution was added and stirred at room temperature for 30 minutes. this
Was cooled to -60 ° C and dissolved in 19 ml of THF in advance [I
(H)_a] And [I (F)_a] Gradually add 4.7g of the mixture to -30 ℃
After stirring at room temperature for 30 minutes, phenyllithium 2.0M
Add 24.7 ml of chlorohexane-ether (70:30) solution.
And stirred at room temperature for 40 minutes. Pour the reaction solution into ice water,
After stirring vigorously for 1 hour, the product was extracted with ether.
Was. Obtained by washing the oil layer with water, dehydration and drying with Glauber's salt, and concentration under reduced pressure.
Silica gel column chromatography of syrup
(Filler: Wakogel C-300, Eluent: Chloroform)
And trans olefin [II_aE] 3.3g and Sisore
Fin [II_aZ] 3.1 g was obtained. After that, water each
Recrystallized to give colorless crystals. Compound [II_aE] m.p .: 44.5-45.5 ° C. [Α]_D: -26.4 ° (C = 0.69, chloroform). IR (Nujol): ν 3440 (OH), 1780 to 1580 (-C = C
-) ， 840〜860cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, -CH₂C
H ₃ ), 1.15 ~ 1.5 (22H, -CH₂-), 1.46,1.49 (2s, 6H, (CH
₃)₂C), 2.06 (~ q, 2H, H-6,6 '), 3.36 (~ s, 1H, H-
2), 3.84 (dd, 1H, H-1_ax), 4.07 (dd, 1H, H-1_eq), 4.3
6 (-d, 1H, H-3), 5.60 (m, 1H, J_4,5 15.4, J_{4,6 (6 ')} 1.
5Hz, H-4), 5.80ppm (m, 1H, J_4,5 15.4, J_5,66.6, J_{5,6 '} 
5.9Hz, H-5). Elemental analysis value (C_{twenty one}H₄₀O₃Actual value (%): C 74.25; H 11.78 Calculated value (%): C 74.06; H 11.84 Compound [II_aZ] m.p .: 44.5-45.5 ° C. [Α]_D: -3.2 ° (C = 0.37, chloroform). IR (Nujol): ν 3500 (OH), 1750 to 1580 (-C = C
-) ， 820〜860cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, -CH₂C
H ₃ ), 1.15 ~ 1.5 (22H, -CH₂-), 1.45,1.52 (2s, 6H, (CH
₃)₂C), 2.0 to 2.2 (m, 2H, H-6,6 '), 2.83 (broad s, 1H,
OH), 3.33 (to s, 1H, H-2), 3.84 (dd, 1H, H-1_ax), 4.7
0 (-d, 1H, H-3), 4.09 (dd, 1H, H-1_eq), 5.55 to 5.70pp
m (m, 2H, H-4,5). Elemental analysis value (C_{twenty one}H₄₀O₃Actual value (%): C 73.91; H 11.80 Calculated value (%): C 74.06; H 11.84 (4) (2S, 3R, 4E) -2-azido-1,3-O-isopropylidene-
4-octadecene-1,3-diol [IV_aSynthesis of E] (i) Mesylate [III_aRoute via E] Compound [II_aE] 2 g is dissolved in 12 ml of pyridine, and -20 to-
Add 0.82 ml of methanesulfonyl chloride at 25 ℃ and stir.
I responded. After the reaction, 20 ml of DMF and sodium azide were added to the reaction solution.
After adding 9.6 g of lithium, the mixture was stirred at 110 ° C. overnight. The reaction solution
Syrup obtained by extraction with chloroform and evaporation of the solvent
Silica gel column chromatography (filler: Waco
-Gel C-300, eluent: chloroform)
Compound [IV_aE] of 1.84 g was obtained. Yield 85% ([I
I_aE]). [Α]_D: -35.3 ° (C = 0.567, chloroform). IR (film): ν 3000 to 2800 (CH), 2100 (N₃), 17
50 ~ 1600 (-C = C-), 870cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, -CH₂C
H ₃ ), 1.2 to 1.5 (22H, -CH₂-), 1.41,1.47 (2s, 6H, (C
H₃)₂C), 2.10 (~ q, 2H, J_5,6▲ ＝ ▼ J_6,7 7, J_4.61.5Hz, H
-6), 3.29 (m, 1H, J_{1ax, 2} 10.3, J_2,3 9.5, J_{1eq, 2} 5.5H
z, H-2), 3.62 (dd, 1H, J_gem 11.7, J_{1ax, 2} 10.3Hz, H-
1_ax), 3.92 (dd, 1H, J_{1eq, 2} 5.5Hz, H-1_eq), 4.07 (dd,
1H, J_3,4 7.3Hz, H-3), 5.46 (m, 1H, J_4,5 15.4, J_4,6 1.5
Hz, H-4), 5.91ppm (m, 1H, J_4,5 15.4, J_5,6 ~ 7Hz, H-
Five). Elemental analysis value (C_{twenty one}H₃₉N₃O₂Measured value (%): C 69.24; H 10.68; N 11.52 Calculated value (%): C 69.00; H 10.75; N 11.50 (ii) Trifluoromesylate [III '_aRoute via E]
To compound [II_aE] 2 g of pyridine-dichloromethane
(2: 1) Dissolve in 15 ml and dichloromethane beforehand
1.5 ml of trifluoromethanesulfonic anhydride dissolved in
Was added at -20 to -25 ° C, and the mixture was reacted at the same temperature for 3 hours with stirring.
After the reaction, dichloromethane was distilled off at 15 ° C or below, and
And cooled to -20 ° C, DMF 20ml and sodium azide 7.5
g, and stirred overnight at -20 to -25 ° C. Chloro the reaction solution
Syrup obtained by extracting with solvent and distilling off the solvent
Kagel column chromatography (filler: Wakogel
 C-300, eluent: chloroform)
[IV_aE] of syrup 850 mg was obtained. Yield 40% ([II_aE]
From)). The physical constants and spectral data of this product are (i)
In agreement with the one obtained in. (4) '(2S, 3R, 4Z) -2-azido-1,3-O-isopropylide
4-octadecene-1,3-diol [IV_aSynthesis of Z] [4] Compound [IV_a[II] according to the synthetic method of compound [II
_aZ] from mesylate [III_a82% yield via Z]
And also trifluoromesylate [III '_aZ]
The compound [IV_aZ] syrup was obtained. [Α]_D: -74.7 ° (C = 0.91, chloroform). IR (film): ν 3000 to 2800 (CH), 2100 (N₃), 17
60 ~ 1600 (-C = C-), 870cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, -CH₂C
H ₃ ), 1.2 to 1.5 (22H, -CH₂-), 1.41,1.50 (2s, 6H, (C
H₃)₂C), 2.18 (~ q, 2H, J ~ 7Hz, H-6), 3.33 (m, 1H, J
_{1ax, 2}▲ ＝ ▼ J_2,3 10, J_{1eq, 2} 5.5Hz, H-2), 3.65 (dd, 1
H, J_gem 11.7, J_{1ax, 2} ~ 10Hz, H-1_ax), 3.95 (dd, 1H, J
_{1eq, 2} 5.5Hz, H-1_eq), 4.46 (~ t, 1H, J_2,3▲ ＝ ▼ J_3,4 9
~ 10Hz, H-3), 5.38 (m, 1H, J_3,4 9, J_4,5 10.6, J_4,6 1.5
Hz, H-4), 5.78ppm (m, 1H, J_4,5 10.6, J_{5,6 (6 ')} 7-8Hz,
H-5). Elemental analysis value (C_{twenty one}H₃₉N₃O₂Actual value (%): C 69.32; H 10.58; N 11.49 Calculated value (%): C 69.00; H 10.75; N 11.50 (5) (2S, 3R, 4E) -2-amino-1,3-O -Isopropylidene-
4-octadecene-1,3-diol [V_aSynthesis of E] Compound [IV_aE] 2 g is dissolved in 2-propanol 40 ml,
Add 0.8g of sodium borohydride to this and keep for 30 hours
The mixture was heated to reflux reaction. After the reaction, cool the reaction mixture and
Solvent was added to decompose excess reagent, and the solvent was distilled off to leave the residue.
Ether was added to the residue and the insoluble material was filtered off. The filtrate is concentrated under reduced pressure.
The resulting syrup was subjected to silica gel column chromatography.
Raffy [filler: Wakogel C-200, eluent: chloro
Form / methanol (100/1)]
Compound [V_aE] 1.78 g was obtained. 95% yield. [Α]_D: + 9.7 ° (C = 0.559, chloroform). IR (film): ν 3380,3300 (NH₂), 1760 to 1520 (N
H, -C = C-), 890cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, -CH₂C
H ₃ ), 1.0 to 1.5 (24H, -CH₂-And NH₂), 1.42, 1.49 (2s,
6H, (CH₃)₂C), 2.00 (~ q, 2H, J ~ 7Hz, H-6), 2.69 (m,
1H, J_{1ax, 2} 10.3, J_2,3 9.5, J_{1eq, 2} 5.1Hz, H-2), 3.55
(~ T, 1H, J_gem 11.4, H-1_ax), 3.85 (~ t, 1H, J_3,4 7.7H
z, H-3), 3.87 (dd, 1H, H-1_eq), 5.39 (m, 1H, J_4,5 15.
4, J_{4,6 (6 ')} 1.5Hz, H-4), 5.83ppm (m, 1H, J_4,5 15.4, J
_{5,6 (6 ')} 6.6Hz, H-5). Elemental analysis value (C_{twenty one}H₄₁NO₂Measured value (%): C 74.03; H 12.36; N 4.00 Calculated value (%): C 74.28; H 12.17; N 4.13 (5) '(2S, 3R, 4Z) -2-amino-1,3- O-isopropylidide
4-octadecene-1,3-diol [V_aSynthesis of Z] (5) Compound [V_a2-Propane according to the synthetic method of E]
Compound [IV_aZ] treated with sodium borohydride
And post-treatment in the same manner_aZ] in 93% yield
Was. [Α]_D: + 14.8 ° (C = 0.864, chloroform). IR (film): ν 3380,3300 (NH₂), 1760 to 1560 (N
H, -C = C-), 880cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, -CH₂C
H ₃ ), 1.0 to 1.5 (24H, -CH₂-And NH₂), 1.41,1.52 (2s,
6H, (CH₃)₂C), 2.72 (m, 1H, J_{1ax, 2}▲ ＝ ▼ J_2,39 ~ 10, J
_{1eq, 2} 5.5Hz, H-2), 3.58 (~ t, 1H, J_gem 11.4, J_{1ax, 2} 
~ 10Hz, H-1_ax), 3.89 (dd, 1H, H-1_eq), 4.28 (~ t, 1H,
J_2,3▲ ＝ ▼ J_3,4 9Hz, H-3), 5.33 (m, 1H, J _4,5 10.6, J
_{4,6 (6 ')} 1.5Hz, H-4), 5.76ppm (m, 1H, J_4,5 10.6, J
_{5,6 (6 ')} 7-8Hz, H-5). Elemental analysis value (C_{twenty one}H₄₁NO₂Actual value (%): C 74.14; H 12.20; N 3.98 Calculated value (%): C 74.28; H 12.17; N 4.13 (6) (2S, 3R, 4E) -1,3-O-isopropylidene- 2-octa
Decanamid-4-octadecene-1,3-diol [VI_aE₁]of
Synthetic compound [V_aE] 1 g of dichloromethane-dioxane
(1: 1) Dissolve in 20 ml and add 1.22 g of DCC and
Add 1.26 g of phosphoric acid and stir at room temperature for 5 hours.
Was. After the reaction, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain
Silica gel column chromatography
(Filler: Wakogel C-300, Eluent: Chloroform)
And then crystallize with ethanol to give compound [VI
_aE₁] 1.5 g of crystals were obtained. Yield 84%. m.p .: 67.0-67.5 ℃ [α]_D: -0.5 ° (C = 0.4, chloroform). IR (KBr): ν 3300 (NH), 3000 to 2800 (CH),
1640, 1560 (amide), 870 cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 6H, -CH₂C
H ₃ ), 1.0 to 1.7 (m, 52H, -CH₂-), 1.42,1.49 (2s, 6H, (C
H₃)₂C), 2.03 (~ q, 2H, J 7 ~ 8Hz, -CH = CH-CH ₂ -), 2.12
(M, 2H, -CO-CH ₂ -), 3.64 (dd, 1H, J_gem ~ 11, J_{1ax, 2} 9.
2Hz, H-1_ax), 3.77 to 3.87 (m, 1H, H-2), 3.99 (dd, 1H, J
_{1eq, 2} 5.1Hz, H-1_eq), 4.08 (~ t, 1H, J_2,3 9.5, J_3,4 7.
7Hz, H-3), 5.20 (d, 1H, J 8.4Hz, NH), 5.42 (dd, 1H, J
_4,5 15.4Hz, H-4), 5.75ppm (m, 1H, J_4,5 15.4, J_{5,6 (6 ')}
 ~ 7Hz, H-5). Elemental analysis value (C₃₉H₇₅NO₃Actual value (%): C 77.51; H 12.36; N 2.13 Calculated value (%): C 77.29; H 12.49; N 2.31 (6) '(2S, 3R, 4Z) -1,3-O-isopropylidene -2-Ok
Tadecanamide-4-octadecene-1,3-diol [VI_aZ₁]
Synthesis of (6) Compound [VI_aE₁], The compound [V
_aZ] and stearic acid are reacted in the presence of DCC and post-treatment
The compound [VI_aZ₁] Crystals were obtained with a yield of 87%. m.p .: 74.0-74.5 ° C [α]_D: -9.9 ° (C = 0.485, chloroform). IR (Nujol): ν 3360 (NH), 3000 to 2800 (CH), 1
640,1530 (amide), 880 cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 6H, -CH₂C
H ₃ ), 1.0 to 1.75 (m, 52H, -CH₂-), 1.41,1.52 (2s, 6H,
(CH₃)₂C), 1.90 to 2.25 (m, 4H, -CO-CH ₂ -And-CH = CH-CH ₂
-), 3.71 (dd, 1H, J_gem ~ 11, J_{1ax, 2} 9.2Hz, H-1_ax),
3.8 to 3.96 (m, 1H, H-2), 3.99 (dd, J_{1eq, 2} 1.5Hz, H-
1_eq), 4.50 (~ t, 1H, J_2,3 9.5, J_3,4 8.8Hz, H-3), 5.2
3 (d, 1H, J 8.1Hz, NH), 5.39 (to t, 1H, J_4,5 10.7Hz, J
_{4,6 (6 ')} 1.5Hz, H-4), 5.69ppm (m, 1H, J_4,5 10.7, J_5,6 
7.3Hz, H-5). Elemental analysis value (C₃₉H₇₅NO₃Measured value (%): C 77.36; H 12.44; N 2.22 Calculated value (%): C 77.29; H 12.49; N 2.31

Reference Example 1. (1) (2S, 3R, 4E) -2-octadecanamide-4-octadecene
1,3-diol (N- stearoyl sphingosine; ceramide) [IXE _1] Synthesis Example 1 with the compound obtained [VI _a E _1] 1.2g of acetic acid 60ml
4 ml of water was added thereto, and the mixture was reacted at 45 to 50 ° C for 1 hour. After confirming the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (filler: Wakogel C-200, eluent: chloroform) and then crystallized with ethanol to give compound [IXE ₁ ] 1.06
g was obtained. Yield 95%. mp: 97-98 ° C [α] _D : -4.8 ° (C = 0.5, chloroform). IR (Nujol): ν 3500-3100 (OH, NH), 3000-2800
(CH), 1640,1550 cm ^-1 (amide). ¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD): δ 0.88 (-
t, 6H, -CH ₂ C H ₃ ), 1.0 to 1.4,1.5 to 1.7 (m, 50H + 2H, -CH
_2- ), 2.04 (~ q, 2H, J _5,6 ▲ = ▼ J _6,7 ~ 7Hz, -CH = CH-C H ₂
-), 2.2 (t, 2H, J 7-8Hz, -CO-C H _2- ), 3.64 (m, 1H, H-
1), 3.75 to 3.90 (m, 2H, H-1 ', H-2), 4.19 (to t, 1H, J
_2,3 ~ 5, J _3,4 6.6Hz, H-3), 5.49 (~ dd, 1H, J _{3, 4} , 6.6,
_{J 4,5 15.4Hz, H-4)} , 5.75ppm (m, 1H, J 4,5 15.4, J 5,6 ~
7Hz, H-5). Elemental analysis value (as C ₃₆ H ₇₁ NO ₃ ) Actual value (%): C 76.55; H 12.48; N 2.51 Calculated value (%): C 76.40; H 12.65; N 2.48 (1) '(2S, 3R, 4Z ) -2-Octadecanamide-4-octadecene-1,3-diol (N-stearoyl cis-sphingosine; stereoisomer of ceramide) [IXZ ₁ ] Synthesis according to the synthesis method of compound [IXE ₁ ] of (1) The isopropylidene group of the compound [VI _a Z ₁ ] obtained in Example 1 was removed and post-treatment was carried out in the same manner to quantitatively obtain a crystal of the compound [IXZ ₁ ]. mp: 94-95 ° C. [Α] _D : -7 ° (C = 0.5, chloroform). IR (Nujol): ν 3500-3200 (OH, NH), 3000-2800
(CH), 1640,1550 cm ^-1 (amide). ¹ H-NMR (270 MHz, CDCl ₃ + CD ₃ OD): δ 0.88 (-
t, 6H, -CH ₂ C H ₃ ), 1.0 to 1.4,1.5 to 1.7 (m, 50H + 2H, -CH
_2- ), 1.95 to 2.30 (m, 4H, -CH = CH-C H ₂ -and -CO-C H _2- ),
3.6 to 3.9 (m, 3H, H-1, H-1 'and H-2), 4.52 (dd, 1H, J _2,3
5.1, J _3,4 8 ~ 9Hz, H-3), 5.43 (~ t, 1H, J _4,5 ~ 11Hz, H
-4), 5.75ppm (m, 1H, J _4,5 ~ 11, J _{5,6 (6 ')} ~ 7Hz, H-
Five). Elemental analysis value (as C ₃₆ H ₇₁ NO ₃ ) Actual value (%): C 76.24; H 12.53; N 2.36 Calculated value (%): C 76.40; H 12.65; N 2.48

Example 2. (2S, 3R, 4E) -1,3-O-isopropylidene-2-tetracosana
Mido-4-octadecene-1,3-diol [VI_aE₂] Was synthesized according to (1) to (5) of Example 1 [V_aE]
The compound [VI] described in (6) of Example 1 was used._aE₁]
The compound [V_aE] and tetracosanoic acid DC
The reaction was carried out in the presence of C, and similarly post-treatment was carried out to give the compound [VI
_aE₂] Crystals were obtained with a yield of 93%. m.p .: 61.5-62.0 ℃ [α]_D: -0.4 ° (C = 0.507, chloroform-methanone
Le (50/1)). IR (Nujol): ν 3310 (NH), 3000 to 2800 (CH), 1
640,1550 (amide), 870cm^-1((CH₃)₂C).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 6H, -CH₂C
H ₃ ), 1.0 to 1.7 (m, 64H, -CH₂-), 1.42,1.49 (2s, 6H, (C
H₃)₂C), 1.9 to 2.2 (m, 4H, -CO-CH ₂ -And-CH = CH-CH
₂ -), 3.65 (dd, 1H, J_gem ~ 11, J_{1ax, 2} 9.2Hz, H-1_ax),
3.75 to 3.90 (m, 1H, H-2), 3.99 (dd, 1H, J_{1eq, 2} 5.1Hz, H
-1_eq), 4.08 (~ t, 1H, J_2,3 9.5, J_3,4 7.7Hz, H-3), 5.
20 (d, 1H, J 8.4Hz, NH), 5.42 (dd, 1H, J_4,5 15.4Hz, H-
4), 5.75ppm (m, 1H, J_4,5 15.4, J_{5,6 (6 ')} 6.6Hz, H-
Five). Elemental analysis value (C₄₅H₈₇NO₃Measured value (%): C 78.06; H 12.84; N 1.98 Calculated value (%): C 78.31; H 12.71; N 2.03

Reference Example 2. (2S, 3R, 4E) -2-Tetracosanamid-4-octadecene-1,3-
Diol (N-Lignocelloyl sphingosine; Cerami
De) [IXE₂] Synthesis of [IXE] described in (1) of Reference Example 1₁]]
The compound [VI obtained in Example 2_aE₂] Of isopropylidide
The ceramide [IXE₂]of
Crystals were obtained quantitatively. m.p .: 92-94 ℃ [α]_D: -1.5 ° (C = 1.165, chloroform / methanone
Le (50/1)). IR (Nujol): ν 3500-3100 (OH, NH), 3000-2800
(CH), 1640,1550cm^-1(Amide).¹ H-NMR (270MHz, CDCl₃+ CD₃OD): δ 0.89 (~
t, 6H, -CH₂CH ₃ ), 1.0 to 1.4, 1.45 to 1.70 (m, 62H + 2H, -CH₂
-), 2.04 (~ q, 2H, J_5,6▲ ＝ ▼ J_6,7 ~ 7Hz, -CH = CH-CH
₂ -), 2.21 (t, 1H, J 7 ~ 8Hz, -CO-CH ₂ -), 3.65 (dd, 1H,
J_gem ~ 11, J_1,2 3-4Hz, H-1), 3.81 (dd, 1H, J_gem ~ 1
1, J_1,2 4.8Hz, H-1 '), 3.8 to 3.9 (m, 1H, H-2), 4.14
(~ T, 1H, J 6 ~ 7Hz, H-3), 5.48 (~ dd, 1H, J_3,4 7, J_4,5
 15.4Hz, H-4), 5.73ppm (m, 1H, J_4,5 15.4, J_{5,6 (6 ')} 7H
z, H-5). Elemental analysis value (C₄₂H₈₃NO₃Measured value (%): C 77.85; H 12.76; N 2.08 Calculated value (%): C 77.57; H 12.87; N 2.15

Example 3. (1) Synthesis of (2S, 3R, 4E) -2-azido-4-octadecene-1,3-diol [VIIE] The compound [IV synthesized according to (1) to (4) of Example 1
2 g of _a E] was dissolved in 40 ml of acetic acid, 2.4 ml of water was added, and the mixture was reacted at 45 to 50 ° C. for 1 hour. After confirming the end of the reaction,
The reaction solution was concentrated under reduced pressure, and the residue was subjected to column chromatography [filler: Wakogel C-200, eluent: chloroform /
After purification with methanol (400/1)], ether-n-
Crystallization with hexane yielded crystals of compound [VIIE] quantitatively. mp: 50.5 to 51.5 ° C [α] _D : -33.5 ° (C = 0.441, chloroform). IR (film): ν 3700-3100 (OH), 3000-2800 (C
H), 2100 cm ^-1 (N ₃ ). ¹ H-NMR (90 MHz, CDCl ₃ ): δ 0.88 (∼t, 3H, -CH ₂
C H _3- ), 1.1 to 1.5 (m, 22H, -CH _2- ), 2.06 (m, 2H, H-
6), 2.48 (broad s, 2H, OH), 3.48 (~ q, 1H, J 5 ~ 6Hz,
H-2), 3.78 (~ d, 2H, J 5 ~ 6Hz, H-1), 4.22 (~ t, 1H, J
~ 6Hz, H-3), 5.49 (m, J _3,4 6.5, J _4.5 15.4, J _4,6 1.5H
z, H-4), 5.82ppm (m, J _4,5 15.4, J _{5,6 (6 ')} ~ 6Hz, H-
Five). Elemental analysis value (as C ₁₈ H ₃₅ N ₃ O ₂ ) Actual value (%): C 66.17; H 11.00; N 12.83 Calculated value (%): C 66.42; H 10.84; N 12.91 (1) '(2S, 3R , 4Z) -2-Azido-4-octadecene-1,3-diol [VIIZ] Synthesis of compound [IV] synthesized according to (1), (2), (3) and (4) ′ of Example 1 _a Z] and [1] [VIIE]
The isopropylidene group of [IV _a Z] was removed and post-treatment was carried out in the same manner according to the synthetic method of 1. to quantitatively obtain a crystal of compound [VIIZ]. mp: 42.5-43.0 ° C. [α] _D : -53.1 ° (C = 0.557, chloroform). IR (film): ν 3700-3100 (OH), 3000-2800 (C
H), 2100 cm ^-1 (N ₃ ). ¹ H-NMR (90 MHz, CDCl ₃ ): δ 0.88 (∼t, 3H, -CH ₂
C H _3- ), 1.1 to 1.5 (m, 22H, -CH _2- ), 2.11 (m, 2H, H-
6), 2.27 (broad s, 2H, OH), 3.49 (~ q, 1H, J 5 ~ 6Hz,
H-2), 3.79 (~ d, 2H, J 5-6Hz, H-1), 4.58 (dd, 1H, J
_{2,3 ~6, J 3,4 ~8Hz, H} -3), 5.45 (m, 1H, J 3,4 ~8, J 4.5
11, J _4,6 ~ 1Hz, H-4), 5.67ppm (m, 1H, J _4,5 11, J _5,6 ~
7Hz, H-5). Elemental analysis value (as C ₁₈ H ₃₅ N ₃ O ₂ ) Actual value (%): C 66.25; H 10.77; N 13.12 Calculated value (%): C 66.42; H 10.84; N 12.91

Reference Example 3. (1) Synthesis of (2S, 3R, 4E) -2-amino-4-octadecene-1,3-diol (sphingosine) [VIIIE] From the compound [IV _a E] described in (5) of Example 1, V _a E]
According to the method for synthesizing the compound of Example 3, the compound [VII] obtained in (1) of Example 3
[E] was heated to reflux with excess sodium borohydride in 2-propanol, and the resulting product was subjected to silica gel column chromatography [filler: Wakogel C-200, eluent: dichloromethane / methanol (20/1)]. After purification by crystallization with ether-petroleum ether, crystals of sphingosine [VIIIE] were obtained in 95% yield. mp: 81.5-82.5 ° C IR (film): ν 3600-3050 (OH, NH ₂ ), 3000-2800
(CH), 1760 to 1500 cm ^-1 (NH, -C = C-), Complete disappearance of absorption peak (2100 cm ^-1 ) based on N ₃ . ¹ H-NMR (270 MHz, CDCl ₃ ): δ 5.43 (m, 1H, J _3,4
6.6, J _4,5 15.4, J _4,6 1.5Hz, H-4), 5.75ppm (m, 1H, J _4,5
15.4, J _5,6 ~ 7Hz, H-5). (1) Synthesis of '(2S, 3R, 4Z) -2-amino-4-octadecene-1,3-diol (cis-sphingosine) [VIIIZ] Synthesis of compound [VIIIE] from compound [VIIE] of (1) According to the method, the azido group of [VIIZ] obtained in (1) ′ of Example 3 was reduced to an amino group, the product was similarly purified, and then crystallized with ethyl acetate to give a crystal of cis-sphingosine [VIIIZ]. Was obtained in 94% yield. mp: 72~73 ℃ IR (film) : ν 3600~3000 (OH, NH 2), 3000~2800
Complete disappearance of absorption peak (2100 cm ^-1 ) based on (CH), 1750 to 1500 cm ^-1 (NH, -C = C-), N ₃ . ¹ H-NMR (270 MHz, CDCl ₃ ): δ 0.88 (t, 3H, -CH ₂ C
H ₃ ), 1.00 to 1.43 (m, 24H, -CH _2- ), 1.9 to 2.2 (m, 2H, H-
6,6 '), 2.84 (broad m, 1H, H-2), 2.90-3.25 (broad
m, 4H, NH, OH), 3.5-3.8 (broad m, 2H, H-1,1 '), 4.41
(M, 1H, H-2), 5.43 (~ t, 1H, J _3,4 9 ~ 10, J _4,5 10.6Hz,
H-4), 5.60ppm (m, 1H, J _5,6 10.6, J _6,7 7.3Hz, H-5). (2) (2S, 3R, 4E) -2-octadecanamide-4-octadecene
Synthesis of 1,3-diol (N-stearoyl sphingosine; ceramide) [IXE ₁ ] 1 g of [VIIIE] obtained in (1) was dissolved in 20 ml of dichloromethane-dioxane (1: 1), and stearic acid 1.
28 g and DCC 1.24 g were added, and the mixture was reacted with stirring at room temperature for 5 hours. After the reaction, insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, and the syrup obtained was purified by silica gel column chromatography (filler: Wakogel C-200, eluent: chloroform) and crystallized with ethanol to give ceramide. [IX
E ₁ ] was obtained with a yield of 90%. The physical constants and spectral data of the obtained ceramide [IXE ₁ ] were the same as those obtained in (1) of Reference Example 1. (2) '(2S, 3R, 4Z) -2-Octadecanamide-4-octadecene-1,3-diol (N-stearoyl cis-sphingosine; stereoisomer of ceramide) [IXZ ₁ ] Synthesis of (2) The compound [VIII] obtained in (1) ′ in the presence of DCC according to the method for synthesizing the compound [IXE ₁ ] from [VIIIE]
Z] and stearic acid are reacted and post-treated in the same manner to produce N-
91 crystals of stearoyl cis-sphingosine [IXZ ₁ ]
% Yield. The physical constants and spectrum data of the obtained N-stearoyl cis-sphingosine [IXZ ₁ ] were the same as those obtained in (1) ′ of Reference Example 1.

Reference Example 4. (1) 4,6-O-benzylidene-D-galactopyranose [I
₀ ^'] D-galactose 7.2 g was suspended in DMF 100 ml,
Dimethoxybenzyl 14 ml and p-toluenesulfonic acid 170
After adding mg, the mixture was reacted with stirring at 35 to 40 ° C for 2 hours. reaction
After neutralizing by adding a large excess of sodium hydrogen carbonate,
The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to remove the residue.
Silica gel column chromatograph dissolved in loroform
E [filler: Wakogel C-200, eluent: chloroform
System / methanol (100/1) → chloroform / methanoe
(50/1) → chloroform / methanol (20/1)]
, 4,6-O-benzylidene-D-galactose [I₀ ^']
Of syrup was obtained with a yield of 80%. The syrup obtained is
It is a mixture of α, β-anomers, and one of the
Crystals precipitated as crystals, but the mixture was used as is in the next step.
I used it. Compound [I₀ ^'] Physical constant of the crystal m.p .: 180-182 ℃ [α]_D: + 126.5 ° (C = 0.51, methanol). Elemental analysis value (C₁₃H₁₆O₆As measured) (%): C 58.41; H 6.13 Calculated value (%): C 58.20; H 6.01 (2) 2,4-O-benzylidene-D-threose [I (H)_b] And
And its formate [I (F)_b] Synthesis of compound [I] obtained in (1)₀ ^'] 4 g to 200 ml of methanol
Dissolve and add 8.3g of sodium metaperiodate to it
And stirred at room temperature for 3 hours. After the reaction, insoluble matter was filtered off,
The residue obtained by distilling off the solvent is purified by silica gel column chromatography.
Topography [Filler: Wakogel C-200, Eluent: KU
Loloform / methanol (150/1)], 2,4-
O-benzylidene-D-threose [I (H)_b] And its Holme
Body [I (F)_b] 3.1 g of a mixture (about 1: 1) was obtained.
This mixture was subjected to the next reaction without separation and purification. (3) (2R, 3R, 4E) -1,3-O-benzylidene-4-octadecese
N-1,2,3-triol [II _1bE] and (2R, 3R, 4Z) -1,3-O-
Benzylidene-4-octadecene-1,2,3-triol [II_1b
Z] Synthesis of the compound [I] obtained in (2) according to (3) of Example 1.
(H)_b] And [I (F)_b] 4.4 g of a mixture of
In the presence of tetradecyl triphenylphosphonium
Reaction with lomid and post-treatment as in Example 1 (3)
Trans olefin [II_1bE] 4.5g and Sisov
In [II_1bZ] 0.9 g was obtained. Compound [II_1bE] m.p .: 53.5-54.5 ° C. [Α]_D: -0.6 ° (C = 0.506, chloroform). IR (Nujol): ν 3600 (free OH), 3450 (hydrogen bond)
OH), 3100 to 3000 (benzene ring CH), 1760 to 1660 (-C
H = CH-), 780 ~ 680cm^-1(Benzene ring).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, C
H₃), 1.1 to 1.5 (m, 22H, -CH₂-), 2.08 (~ q, 2H, H-6,
6 '), 2.66 (broad s, 1H, OH), 3.53 (-s, 1H, H-2),
4.08 (dd, 1H, J_gem 12, J_{1eq, 2} 1 ~ 1.5Hz, H-1_eq), 4.25
(Dd, 1H, J_{1ax, 2} 1.8Hz, H-1_ax), 4.41 (d, 1H, J_3,4 6.2H
z, H-3), 5.62 (s, 1H, φ-CH =), 5.66 (m, 1H, J_4,5 15.
8, J_3,4 6.2Hz, H-4), 5.88 (m, 1H, J_4,5 15.8, J_5,6 ~ 7H
z, H-5), 7.3 ~ 7.6ppm (m, 5H, phenyl). Elemental analysis value (C_{twenty five}H₄₀O₃Actual value (%): C 77.43; H 10.26 Calculated value (%): C 77.27; H 10.38 Compound [II_1bZ] Syrup. [Α]_D: + 30.5 ° (C = 0.485, chloroform). IR (film): ν 3600 (free OH), 3450 (hydrogen bond)
OH), 3100 to 3000 (benzene ring CH), 1760 to 1560 (-CH =
CH-), 780-680 cm^-1(Benzene ring).¹ H-NMR (270MHz, CDCl₃): Δ 0.88 (t, 3H, C
H₃), 1.0 to 1.5 (m, 22H, -CH₂-), 2.00 to 2.25 (m, 2H, H-
6,6 '), 2.75 (broad s, 1H, OH), 3.49 (~ s, 1H, H-
2), 4.12 (dd, 1H, J_gem 12, J_{1eq, 2} 1.0 to 1.5Hz, H-
1_eq), 4.25 (dd, 1H, J_gem 12, J_{1ax, 2} 1.8Hz, H-1_ax),
4.73 (d, 1H, J_3,4 5.1Hz, H-3), 5.66 (s, 1H, φ-CH =),
5.5 to 5.8 (m, 2H, H-4,5), 7.3 to 7.6ppm (m, 5H, pheny
l). Elemental analysis value (C_{twenty five}H₄₀O₃Measured value (%): C 77.68; H 10.52 Calculated value (%): C 77.27; H 10.38

Reference Example 5. (1) (2R, 3R, 4E) -1,3-O-benzylidene-4-eicosene-
1,2,3-triol [II _2b E] and (2R, 3R, 4Z) -1,3 -O- benzylidene-4-eicosene 1,2,3-triol [II _{2 b} Z]
In the presence of phenyllithium, 4.4 g of a mixture of the compounds [I (H) _b ] and [I (F) _b ] obtained in (2) of Reference Example 4 was used using hexadecyltriphenylphosphonium bromide as the Wittig reagent. Then, this was reacted with and post-treated in the same manner as in (3) of Reference Example 4 to obtain 4.9 g of trans isomer [II _2b E] and 1.0 g of cis isomer [II _2b Z]. Compound [II _2b E] mp: 63.0-63.5 ° C. [Α] _D : -1.9 ° (C = 0.537, chloroform). Elemental analysis (as C ₂₇ H ₄₄ O ₃₎ Found (%): C 77.76; H 10.62 Calculated (%): C 77.83; H 10.65 Compound _{[II 2b Z] mp: 47~48} ℃. [Α] _D : + 42.3 ° (C = 0.40, chloroform). Elemental analysis value (as C ₂₇ H ₄₄ O ₃ ) Actual value (%): C 78.05; H 10.78 Calculated value (%): C 77.83; H 10.65

Example 4. (1) (2R, 3R, 4E) -1,3-O-isopropylidene-4-eicosene-1,2,3-triol [II _2a E] and (2R, 3R, 4Z) -1,3-
Synthesis of O-isopropylidene-4-eicosene-1,2,3-triol [II _2a Z] 18.8 g of hexadecyl triphenylphosphonium bromide was substituted for 18.8 g of tetradecyl triphenylphosphonium bromide in (3) of Example 1. The compound [II _2a E] was prepared in the same manner as in (3) of Example 1 except for the above.
3.5 g and compound [II _2a Z] 3.3 g were obtained. Compound [II _2a E] mp: 50-51 ° C. [Α] _D : -24.9 ° (C = 0.527, chloroform). Compound [II _2a Z] mp: 50-51 ° C. [Α] _D : -3.0 ° (C = 0.534, chloroform). (2) Synthesis of (2S, 3R, 4E) -1,3-O-isopropylidene-2-O-mesyl-4-eicosene-1,2,3-triol [III _2a E] Obtained by (1) (4) of Example 1 using the compound [II _2a E]
Compound [III _2a E] was synthesized and isolated according to the method (i). [Α] _D : -34 ° (C = 0.788, chloroform). (2) Synthesis of '(2S, 3R, 4Z) -1,3-O-isopropylidene-2-O-mesyl-4-eicosene-1,2,3-triol [III _2a Z] Obtained by (1) (4) of Example 1 using the compound [II _2a Z]
Compound [III _2a Z] was synthesized and isolated according to the method (i). [Α] _D : -38.4 ° (C = 0.544, chloroform). (3) (2S, 3R, 4E) -2-azido-1,3-O-isopropylidene-
Synthesis of 4-eicosene-1,3-diol [IV _2a E] Using the compound [III _2a E] obtained in (2) and following the method of (i) in (4) of Example 1 _2a E] was synthesized. [Α] _D : -39.4 ° (C = 0.50, chloroform). (3) Synthesis of '(2S, 3R, 4Z) -2-azido-1,3-O-isopropylidene-4-eicosene-1,3-diol [IV _2a Z] (2)' Compound obtained in [ ₂ ] III _2a Z] was used to synthesize the compound [IV _2a Z] according to the method of (i) in (4) of Example 1. [Α] _D : -77.7 ° (C = 0.48, chloroform). (4) (2S, 3R, 4E) -2-Amino-1,3-O-isopropylidene-
Synthesis of 4-eicosene-1,3-diol [V _2a E] Using the compound [IV _2a E] obtained in (3) and following the method of Example 1 (5), a compound [V _2a E] was obtained. It was [Α] _D : + 7.5 ° (C = 0.644, chloroform). (4) 'Synthesis of (2S, 3R, 4Z) -2-amino-1,3-O-isopropylidene-4-eicosene-1,3-diol [V _2a Z] (3)' IV _2a Z] was used to obtain the compound [V _2a Z] according to the method of (5) ′ of Example 1. [Α] _D : + 23.1 ° (C = 0.407, chloroform). (5) Synthesis of (2S, 3R, 4E) -1,3-O-isopropylidene-2-octadecanamide-4-eicosene-1,3-diol [VI _2a E] The compound obtained in (4) [V _2a E] and (6) of Example 1
Compound [VI _2a E] was obtained according to the method described in 1. mp: 71-72 ° C. [Α] _D : + 0.46 ° (C = 0.652, chloroform). (5) Synthesis of '(2S, 3R, 4Z) -1,3-O-isopropylidene-2-octadecanamide-4-eicosene-1,3-diol [VI _2a Z] (4)' Compound obtained in [ V _2a Z] was obtained according to the method of (6) ′ in Example 1 to obtain the compound [VI _2a Z]. mp: 79.5-80.5 ° C. [Α] _D : -9.8 ° (C = 0.531, chloroform).

[0029]

INDUSTRIAL APPLICABILITY As described above, the present invention is useful for synthesizing ceramide or its homolog, which is an important constituent of the glycosphingolipid ganglioside, which is expected to be developed as a treatment for bokeh and an anticancer drug. The present invention provides a novel compound as an intermediate, and according to the method for producing ceramide or a homologue thereof via the novel intermediate of the present invention, the number of steps is D-
Eight steps from xylose or D-galactose (7 steps from protected xylose or galactose), which is much shorter than the conventional method [eg, the existing method has the smallest number of steps (D- From glucose 1
2 steps compared to 2 steps, 11 steps from protected D-glucose)
Is. ], It has a remarkable effect in that it is extremely advantageous in synthesis, and it is a great contribution to the art.

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Claims (1)

(57) [Claims] 1. The formula [a]: Wherein, X is -N ₃ group, -NH ₂ group, -NHCOR ⁶ group (R ⁶ represents a saturated or unsaturated alkyl group having 1 to 30 carbon atoms, straight-chain, in either branched R) is cis or trans-(CH ₂ ) _n CH ₃
Represents a substituent represented by (n represents an integer of 0-20),
Y and Y ′ both represent a hydrogen atom, or Y and Y ′ together represent the following formula [b] (R ¹ and R ² both represent a methyl group, or one of them represents a phenyl group and the other represents a hydrogen atom), and a substituted methylidene group may be formed. However, when the Y and Y 'are both hydrogen atoms, X is -N ₃ group. ] The trans-type and / or cis-type compound shown by these.