JPS62207247A - Novel production of optically active unsaturated amino-alcohol derivative and novel intermediate - Google Patents

Abstract

PURPOSE:To shorten a process and readily and effectively obtain a compound useful as a synthetic intermediate for gangliosides useful for treating dotage or as an anticancer agent, by obtaining a sphingosine derivative from a D- threose derivative and acylating the resultant derivative. CONSTITUTION:A D-threose derivative expressed by formula I (R<1> and R<2> are both methyl or either one is phenyl and the other is H; R<3> is H or CHO) is reacted with an onium salt of a phosphorus irene compound to give an olefinic compound and the protecting group is then removed to afford a compound expressed by formula II (R<4> is protecting group, e.g. mesyl tosyl, etc.; n is 0-20), which is reacted with an azide compound, reduced and further acylated to provide a compound expressed by formula III [R<5> is NHCOR<6> (R<6> is 1-30C alkyl)]. The resultant compound is then deprotected by hydrolysis and reduced to give a compound expressed by formula IV, which is further acylated with a fatty acid to afford the aimed substance expressed by formula V.

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a new method for producing ceramide or its homolog, which is an important component of gangliosides, which is expected to be developed as a treatment for blurred vision or as an anticancer drug. [Background of the invention] Ganglioside is a general term for glycosphingolipids containing sialic acid. It is widely distributed in the living tissues of various higher animals. In recent years, it has become clear that gangliosides play a role as a receptor molecule for hormones and bacterial toxins, and that gangliosides express growth and differentiation-promoting factor activity in nervous system cells. It has become. Among these, hydrophobic ceramides attached to the terminals of gangliosides have attracted particular attention as factors that control the reactivity of sugar chains. However, as an excellent chemical synthesis method for ceramide and its homologs has not yet been established, the number of carbon atoms in the sphingosine moiety, the type of fatty acid, and the difference in activity between cis and trans groups have not yet been clarified. That consideration is awaited. Chemical synthesis methods for ceramide and its homologs include 1, for example, E, D, Re using D-glucose as a starting material.
Methods such as 1st [7, Org, Chew,, 35
゜412? (197G)1. Ogawa et al.'s method (Glyc
oconjugateJ, L, 107 (+98
4)1. The method of Ohbachi et al. using D-mannose as a starting material [Chew, Lstt, 1985°1715
Many methods have been proposed so far, including 1.
It has been implemented. However, all of these existing methods have a large number of steps and are complicated to operate, and even the method by Ogawa et al.
(11 steps from protected glucose). Therefore, there is a need for a simpler and more effective method for producing ceramide and its homologs, which are important constituents of gangliosides and are attracting attention as factors that control the reactivity of their sugar chains. [Object of the Invention] The present invention was made in view of the above-mentioned current situation, and an object of the present invention is to provide a simpler and more effective chemical synthesis method for ceramide and its homologues. [Summary of the Invention] The present invention. (1) Formula [I] (However, R1 and R2 both represent a methyl group, or
One represents a phenyl group and the other represents a hydrogen atom, and R
3 is a D-threose derivative represented by a hydrogen group (representing a child or -Cd5 group) in the presence of an alkyl, aralkyl or aryllithium, and is reacted with an onium salt of a phosphorylene compound to obtain the formula [II] (where n represents an integer from 0 to 2G, Hl and R2 are the same as above, and the hydroxyl group thereof is a mesyl group or a trifluoromesyl group. Protected with a protecting group such as tosyl group or procyl group. 2 [ml (However, R4 represents a protecting group such as mesyl group, trifluoromesyl group, tosyl group, procyl group, etc., and R1, R2 and n are the same as above). The compound is reacted with a compound to form an azide compound represented by the formula [■1 (where R1, R2 and n are the same as above), and then this is reduced to form the formula
[V] Protected sphingosine or its homologue represented by R" (wherein R", R2 and n are the same as above) and further acylated with a fatty acid to form the formula [1 [where R5 is -NHCOR]
' group (wherein, R6 represents a saturated or unsaturated alkyl group having 1 to 30 carbon atoms, and may be either linear or monobranched), and R1, R2 and n are the same as above. , ] After preparing a protected ceramide or its analogue, the protective group is removed by hydrolysis to obtain a ceramide or its analogue, or (n) an azide of the formula [■l By hydrolyzing the compound with acid, the protecting group is removed and the formula

A compound represented by [■l H (where n is the same as above)] is further reduced to produce sphingosine or its compound represented by the formula [1 ÷0・OH (where n is the same as above)]. Production of a ceramide or a homologue thereof represented by the formula [IK], V OH (where R% and n are the same as above), which is made into a homologue and then acylated with a fatty acid to produce a ceramide or a homologue thereof. Law. (2) Formula [11% Formula% (However, R1 and R2 both represent a methyl group, or
One represents a phenyl group and the other represents a hydrogen atom, and R
2 represents a hydrogen atom or -C)10 group, Formula 1 [111 (However, n represents an integer of O to 20, and R' and R'' are the same as above.) A method for producing an olefin compound represented by the formula [11] (3) (However, RL and B2 both represent a methyl group. or one represents a phenyl group and the other represents a hydrogen atom, and
n represents an integer of θ to 20
Protected with a protecting group such as a tosyl group or a procyl group, one formula [ml (where R4 represents a protecting group such as a mesyl group, a trifluoromesyl group, a tosyl group, a procyl group, etc., and R1, B2 and n are the same as above) , ) and then reacting it with an azide [ff3 (where R1, R2
and n is the same as above). (4) Formula (where Rt and Rz both represent a methyl group, or
One is a phenyl group and the other is a hydrogen atom, and R7 is water; [represents a child or a protecting group such as a mesyl group, trifluoromesyl group, tosyl group, or procyl group, and n represents an integer from O to 20.) A trans-type and/or cis-type compound represented by (Formula 51 [However, R1 and R2 both represent a methyl group, or
One represents a phenyl group, the other represents a hydrogen atom, and R6 is -
N, group, -N82 group, -1t)IcOR' group (However, R6 represents a saturated or unsaturated alkyl group having 1 to 30 carbon atoms, and may be linear or branched.) and n represents an integer of 0 to 20. (6) This is an invention of a trans-type and/or cis-type compound represented by the formula (where n represents an integer of O to 20). For example, the synthesis route of the production method of the present invention can be diagrammed as shown below. However, R1-R@ and n are the same as above. (R': Furkyl group) (■Mi1 Protected D-galactose +111 [m
l2 [■. ] The protected D-xylose represented by, for example, Carboh7dr, Res, 52.95
(197B), D-xylose was prepared in N,N-dimethylformamide (DMF) solvent in the presence of a dehydration condensation agent such as P-1 luenesulfonic acid, 2.
It can be easily obtained by reacting with 2-dialkoxypropane or dialkoxybenzyl. Also, the formula [1'
Similarly, the retained iD-galactose shown in 1 can be easily obtained by reacting D-galactose with 2,2-dialkoxypropane or dialkoxybenzyl in a DMF solvent in the presence of p-toluenesulfonic acid. can get. In addition, the protected D-galactose represented by the formula [1] is 1, for example, Au5t, J. Chem,, 31.1371-1374 (197
It can also be obtained by reacting with impropenyl methyl ether in the presence of p-toluenesulfonic acid according to the method described in 8).
, Res. According to the method described in I, 177-111G (1981). It can also be obtained by reacting D-galactose with benzaldehyde in the presence of zinc chloride. The D-threose derivative represented by the formula [I] is the above-mentioned D-threose derivative represented by the formula [I].
It can be easily obtained by oxidizing the 3ffD-xylose represented by the formula [T] or the 2(H)-galactose represented by the formula [I'1] by a method known per se. The brewing process (
The oxidizing agent used in step 〇 or step ≦) is 1
Common examples include sodium periodate, potassium periodate, sodium metaperiodate, potassium metaperiodate, lead tetraacetate, but are not particularly limited to these. The compound obtained by step A0 or step ≦ [II is usually a R2 hydrogen atom theal compound [1(H)]
A mixture of compounds [1(F)] having a CHO group is usually used as is in Step A according to the present invention. Step A according to the present invention includes Wi forming betaine ylide.
It is carried out by ttig reaction. That is, the D-threose derivative represented by the formula [II (a mixture of compound [I(H)] and compound (I(F)) can be used), alkyllithium, aralkyllithium or aryllithium (for example, butyllithium, phenyllithium) etc.) in the presence of an onium salt of a phosphoylene compound (Wittig reagent).
An olefin compound represented by formula [17] is used. Examples of onium salts of phosphorylene compounds include methyl triphenylphosphonium chloride, butyl triphenylphosphonium bromide, octyl trimethylphosphonium chloride, decyl trimethylphosphonium bromide, tetradecyl triphenylphosphonium bromide, hexadecyl triphenylphosphonium bromide, and octadecyl trimethylphosphonium bromide.
Examples include, but are not limited to, bromide, etc., and the general formula R3P-CR' (however, R, R'
each independently represents an alkyl group or an aryl group)
The hydrogen halide adduct of the phosphorylene compound shown is
Both can be used as Wittig reagents. Process A
is usually carried out as follows. That is, 1. For example, 1.5 to 3 mol of Witti per 1 mol of compound [E] (mixture of compound [I()) and compound [1(F)])
g reagent in a nitrogen stream, tetrahydrofuran (THF),
Dissolved in an ether solvent such as dioxane, diethyl ether, or a mixed solvent of these and other non-polar solvents, in which 1 to 2 moles of alkyl, aralkyl or aryllithium such as phenyllithium, butyllithium, etc. are added as a catalyst. If necessary, dissolve it in a suitable solvent and add it. 1 Stir for 10 to 30 minutes at room temperature. Next, cool it to -30°C or below, preferably -50°C or below, and add it in advance to the same TH as above.
Compound [11 (compound [1(H)
] and Compound [1 (mixture of F month) 1 mol was added under a nitrogen stream, and after stirring at -30°C to -40°C for 20 to 40 minutes, 1 to 2 mol of phenyllithium was added again and the mixture was stirred at room temperature for 30 to 40 minutes. After the reaction was stirred for 60 minutes, post-treatment was performed according to a conventional method, and the product was purified by column chromatography, recrystallization, etc. Trans olefin [■El or C/ and 1/.cis olefin [1121] are obtained. All of these are new compounds. Step B according to the present invention includes protecting the hydroxyl group of the compound [■] ([IIE] or/and [112]) with a protecting group (modifying group),
a (modification) step, examples of modifiers used here include methanesulfonyl chloride and trifluoromethanesulfonic anhydride. P-toluenesulfonyl chloride (tosyl chloride),
Examples include, but are not limited to, P-bromobenzenesulfonyl chloride (prosyl chloride), etc. The amount of these modifiers used is usually 1 to 1.5 times the mole of compound [11]. For example, when methanesulfonyl chloride or trifluoromethanesulfonic anhydride is used, the reaction temperature is 0°C or lower, preferably -10°C or lower, and the completion of the reaction is usually confirmed by TLC or the like. However, the reaction time is usually sufficient from several tens of minutes to several hours.As the reaction solvent, basic solvents such as pyridine, picoline, lutidine, and triethylamine are usually preferably used, but these and other solvents may be used as necessary. A mixed solvent with a non-polar solvent is also used. After the reaction is completed, the product cannot be released and the reaction can proceed directly to the next step, ie, step 1. This is usually the case. In addition, when compound [II E] is used as a raw material, the obtained compound [m]it57. C body [mE]tel! J, [1
12] For e1. ', it goes without saying that the cis isomer [II[Z] of compound [I[II] is obtained. Step C according to the present invention involves compound [m] ([E] or/
and [IIrZ]) with an azide. Examples of the azide used here include hydrogen azide HN, sodium azide in which hydrogen has been replaced with a metal, potassium azide, and azide. Examples include lithium oxide, copper azide, silver azide, and the like. Since azide has poor solubility, the 0 reaction is usually carried out in a DMF solvent, where it is used in large excess (several to several tens of times the theoretical amount), but even if the solvent used in step B remains, there is no problem. When the compound is mesylate, tosylate, or propatool, the reaction temperature is usually 100 to 120°C and the reaction time is several hours to over ten hours, but when the compound [ml] is trifluoromesylate, After the reaction, which is usually carried out at -10°C or below for several hours to over ten hours, post-treatment is carried out by a conventional method, and the trans form [1'VE] of compound [rV] is purified by column chromatography or the like.
and the ns body [■Z] are obtained. That is, from compound [■E], compound [1'VE] is produced via compound [mE], and from compound [112], compound [1'VE] is produced via compound [mZ].
'i+Z] can be obtained in good yield. [mE]. [mZ], [rV El , and [rV Zl are all new compounds. Compound [■l ([IVE] or/and [r17Z])
In order to obtain the ceramide represented by the compound [IX] or its homolog from
There are two routes: →E'→F°, but the difference is whether the protecting group (modifying group) is removed later or first.
There is no essential difference between the two. The process in the D-E→F route is the compound [■1([
ffEl or/and [ffZl) is reduced to form the compound [
In the step VI, examples of the reducing agent used here include reducing agents that do not reduce double bonds, such as sodium borohydride, lithium aluminum hydride, and hydrogen sulfide. Further, in this step, similar results can be obtained by catalytic reduction in the presence of a Lindlar catalyst or 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 reduction method and are selected as appropriate. For example, sodium borohydride is used as the reducing agent. 1 usually, 2
- After the 0 reaction is carried out by refluxing in an alcoholic solvent such as propatool for 10 to 60 hours, post-treatment is carried out by a conventional method and purified by column chromatography etc. to obtain the compound [trans form of VI [Vrl or / and cis isomer [VZ] e6 obtained in high yield, 't6.
Both EVEN and [VZ] are new compounds. Step Elf, compound [VI ([Vrl or/and [V
Z]) (7) Acylation with fatty acids. The fatty acids used here include saturated or unsaturated fatty acids having 1 to 30 carbon atoms, and may be linear or branched. , for example acetic acid, propionic acid. Acetic acid, capric acid, lauric acid, myristic acid, valmitic acid, octadecanoic acid (stearin m). Tetracosanoic acid (lignocerin i%+), melisic acid. Specific examples include oleic acid and linoleic acid, but it goes without saying that the fatty acid is not limited to these.The amount of fatty acid used is usually 1 to 1.5 times the mole of the compound [Vl]. The reaction usually involves 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-
In the presence of a dehydration condensing agent such as 3-(3°-dimethylaminopropyl)carbodiimide (WSC) (usually used in a molar range of 1 to 1.5 times the compound [VI]), a suitable reaction solvent 1, for example, is added. 1 in a solvent such as dichloromethane, dichloroethane, chloroform, dichloromethane-dioxane mixed solvent, dichloroethane-dioxane mixed solvent, etc. at room temperature or with slight heating.
After the 0 reaction, which is carried out by stirring the reaction for ~10 hours, post-treatment is carried out by a conventional method, and purification by column chromatography, recrystallization, etc. yields the trans form [VI El or/and cis form IZl of compound [1]. Obtained in high yield. [VIIj, [vIZImo[IIIj~[Vrl,
Like [1121 to [VZ]], it is a new compound. Step F is a step in which the protecting group of the compound [Vrl ([■E] or/and ['ilI 21) is removed by hydrolysis.
Dissolve Zl) in a weak acid such as acetic acid, oxidation, or boron tetrafluoride, a low concentration wet acid, or a strong aprotic acid, and add water to the solution at room temperature or with heating if necessary to initiate a reaction. 0
The completion of the reaction is confirmed by TLC as in other steps, but
The reaction time varies depending on the type of acid used and the reaction temperature, but is usually about several minutes to several hours.After the reaction is completed, post-treatment is carried out according to a conventional method. Purified by column chromatography, recrystallization, etc.
The desired ceramide or its homolog can be obtained in high yield. From [■E] is the trans isomer of [IX] [IXE
l,t. [From ffZl, [IX]nosis [
■It goes without saying that Zl can be obtained respectively. The step in the D°→E→F route is to form the compound [ffl ([rVE] or/and [ff
This is a step to remove the protective Jl group (SrIi group) from the compound [rV] ([ffEl or /
and [rlrZ]) in a weak acid such as acetic acid, formic acid, tetrafluoroboric acid, or other acids, and add wood at room temperature or with heating if necessary to complete the zero reaction. 8F
It can be confirmed by TLC etc. in the same manner as above, but usually several minutes to several hours is sufficient.01After the reaction is completed, post-treatment is carried out according to a conventional method, and the compound is purified by column chromatography, recrystallization, etc. Obtain the trans isomer of l (■E1 or/and the cis isomer [WZ]. [■E1. [■
Both Zl are new compounds. Step E is a reduction step, and the reducing agent used here is exactly the same as in the step, such as sodium borohydride, lithium aluminum hydride, hydrogen sulfide, etc.
More preferred are reducing agents that do not reduce bonds. It goes without saying that similar results can be obtained by catalytic reduction in the presence of a Lindlar catalyst, as well as by a method using phosphines as a reaction reagent, as well as by the amount of reducing agent used and the reaction solvent. , reaction temperature, reaction time, post-treatment, etc. are all in accordance with the process. The product is purified by column chromatography, recrystallization, etc., and the compound [■]
The trans isomer [[El or/and the cis isomer [NZ] are obtained. Step F't* is an acylation step of compound [9111 ([[El or/and [Vl[Zl)] with a fatty acid. There are 30 saturated or unsaturated fatty acids, which may be linear or branched, e.g.
Acetic acid, propionic acid, acetic acid, capric acid. Lauric acid, myristic acid, palmitic acid, octadecanoic acid (stearic acid), tetracosane (lignoceric acid), melisic acid, oleic acid. Specific examples include, but are not limited to, linol ugliness, etc. The amount of fatty acid used, other reaction conditions, post-treatment, etc. may all be carried out in accordance with Step E. The product is purified by column chromatography, recrystallization, etc. to obtain the desired ceramide or its homolog. [VIE] Kaf':s L* [IK] Throat 5
y square body [IXEl>? , [912] is [IX]
It goes without saying that the cis isomer [[Zl can be obtained respectively. Compound [ffl ([ffEl or/and [rlrZ]
) Kara compound [IX] ([IXEl or/and [
IX 21) as the production through route and process D-E-F
It is optional whether to adopt the route , or the route D° → E° → F′. Regardless of which route is used, according to the production method of the present invention, ceramide or its homologues can be produced from D-xylose or D-galactose in 8 steps (7 steps from protected D-xylose or protected D-galactose). You can get a body. The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited in any way by these Examples. [Examples] Example 1 (1) 3.5-0-impropylidene-D-xylofuranose [■. ] Synthesis - Dissolve 20 g of xylose in 250 DMF,
H? Below, add 50 ml of 2,2-dimethoxypropane and 0 ml of p-)luenesulfonic acid monohydrate to this at 40-45°C.
．． After 3 g of the mixture was added and reacted with stirring at the same temperature for 3 hours, the mixture was returned to room temperature, excess 1rE sodium carbonate was added, and the mixture was stirred for 15 minutes, and then insoluble materials were removed. The furnace liquid was concentrated under reduced pressure, and the resulting syrup was subjected to silica gel column chromatography [filling material: Wakogel C-300 (trade name of Wako Tsumugi Pharmaceutical Co., Ltd.), eluent: chloroform and roloform/
methanol (100/l) → chloroform/methanol (50/1)] to obtain 3,5-O-impropylidene-D-xylose ol(7) syrup 7.8 g
I got it. Yield 31%. (5) i knee 5.5° (C-0,5, methanol). IR (film): v 3370 (OH), 8
40C11(((:H3)2C).”H-NMR(80MHz, CD0h): δ
1.45 ((CHshC). 3.5 (OH), 3.8-4.4 (m,
ring protons). 5.2 (s, JH, 2~OHz, H-1β),
5.87 ppm (d.Jl, 23.8Hz, H-1α). (2) 2,4-0-impropylidene-〇-threose [1()I)al and its formate [t(F)al
5 g of compound [1o] obtained in synthesis (1) was dissolved in 250 d of methanol, and sodium periodate was added to it.
7.4 g was added and the reaction was stirred at room temperature for 3 hours. After the reaction, one insoluble matter was removed and the furnace solution was concentrated under reduced pressure. Wako Tsumugi Pharmaceutical Co., Ltd. (trade name), eluent: chloroform/meth/-ol (150/1) to obtain 2.4-0-impropylidene-D-threose [
1(H),] and its formate [1(F)al] (approximately 1:1) was obtained. cciD knee 50@(c-o, 5s, chloroform). IR (film) Niji 3700-3100 (OH
), 1720 (C=0). 850CII ((CH3)2C). iH-NMR (270MHz, CDCQ3): a
1.49.1.50゜1.52.1.58 (4S
, OH, ((CHshC), 8.0B, 8.1
8 (2s, IH, CHO), ! 1.
54ppm (s, 0.5H, CHO). This mixture was subjected to the next reaction without separation and purification. (31(2R,3R,4E)-1,3-0-impropylidene-4-octadecene-1,2,3-)liol [
11aSynthesis of El and (2R,3R,4Z)-1,3-0-impropylidene-4-octadecene-1,2,3-triol[II &Zl Tetradecyl triphenylphosphonium bromide
18.8 g was dissolved in 100 d of THF in a nitrogen stream, and 17.4 of a 2.0 M solution of phenyllithium in cyclohexane-ether (To: 3G) was added thereto. Stirred at room temperature for 30 minutes. This was cooled to -60°C. [1(H)al previously dissolved in TI(F19ml)
Gradually add 4.7 g of a mixture of [1(F)al and -
After stirring at 30°C for 30 minutes, a 24.7- solution of phenyllithium in 2.0M cyclohexane-ether (TO:30) was added again, and the reaction mixture was stirred at room temperature for 40 minutes, and poured into ice water. After stirring vigorously for an hour, the product was extracted with ether. The oil layer was washed with water, dehydrated and dried with Glauber's salt, concentrated under reduced pressure, and the resulting syrup was subjected to silica gel column chromatography (filling material: Fuco-gel C-300,
Eluent: chloroform) and transolefin [
IIaE] 3.3g and cis-olefin [11aZ]
3.1 g was obtained. Thereafter, each was recrystallized from hydroalcohol to obtain colorless crystals. Compound [■aE1 m, p,: 44.5-45.5°C. [dD: -28,4' (C-0,89, chloroform). I R (Nujol):y 3400 (OH
), 1780-1580 (-CIIC-), 84
0-860c ((CHI)2G). ” H-N M FL (270MHz, CDO2
z): δ0.8B (t, 3 H. -CH2C), 1.15~1.5 (22B,
-11:82-), 1.4B. 1.413 (2s, 6H, (C)!z)2G)
, 2. O8 (~Q, 2H. H-8,8'), 3.38 (~s, lH,
H-2), 3.84 (dd. l H, H-1ax), 4.07 (dd, L H
, H-1eq), 4.38(~d, IH
, H-3), 5.60 (m, IH, J4,515
．． 4. J4. @(6・) 1.5Hz, H-
4), 5.80ppm (m. IH, J4.S 15.4.J5., 8.JJs
, @・5. lHz. H-5). Elemental analysis value (as C2+HaoOs) Actual value (X)
: C74,25; H11,78 calculated value ($) :
C74,08; H11,84 compound [IIaZ] ts, p: 44.5-45.5°C. rciD: -3,2' (C-0,37, riex 口*Am). I R (Nujol):y, 35 (10
(OH), 1750-1580 (-C-C-),
820-860 cm-' ((GHz)zC). 50-NMR (270MHz, CDCf1s):
8G, 88(t, 3H., -CH2C)h), 1.15-1.5 (22)
1. -CH2-), 1.45°1.52 (2s,
6H, (Oh)2G), 2.0~2.2(m, 2
H. H-8,8'), 2.83(broad s, LH
, OH), 3.33 (~s, I H, H-2)
, 3.84 (dd, IH, H-1Bg). 4.70 (~d, IH, H-3), 4.09 (dd, I
H, H-1eq). 5.55-5.70 ppm (m, 2H, H-4,5
). Elemental analysis value (as C2184003) Actual value ($)
: C73,91, H11,80 calculated value ($) : C
74,0B, H11,84(41(2S, 3R,
4E) -2-azido-1,3-0-inpropylidene-
Synthesis of 4-octadecene-1,3-diol [rV aE] (i) Route compound via mesylate [maEl [■ aE1 2g is dissolved in pyridine 12m, -2
Methanesulfonyl chloride 0.82mg at 0 to -25℃
After the 0 reaction, add DMF 2 to the reaction solution and stir the reaction.
Add 0ml and sodium azide a, eg, and heat to 110℃
The 0 reaction solution was stirred overnight at ] 1.84 g of syrup was obtained. Yield 85% (from [IIaE]). D knee 35.3° (C-0,587, chloroform)
. IR (film): y 3000-2800
(CH), 2100 (Nz). 1750-1800 (-C-C-), 870cm (
(C:Hz)2G)-'H-NMR (270MHz
, CD023): 8 0.88 (t, 3 H. CH2CH, 1.2-1.5 (22H, -C:H2-
), 1.41. 1.47 (2s, 6H, (
CH3)2G), 2.10 (~Q, 2H, Js,
5=Je,t7. J4,6 1.5H2,H-
8), 3.29 (m, IH. Jlax, 2 10.3. J2,2 9.5.
Jleq, 2 5.5Hz, H-2),
3.82 (dd, IH, Jgem 11.7. Jl
ax, 210.3Hz, H-1Bw), 3.9
2 (dd, LH, Jleq, 2 5.5Hz,
H-1eq), 4.07(dd, IH, J3.
4 7.3H2, H-3), 5.48(m, IH, Ja
, s 15.4. J4. a 1.5Hz, H-
4), 5.91ppm (m, IH, J4,5
15.4. J5. , B ~7Hz, H-5). Elemental analysis value (as C2□H,, N, O□) Actual measurement value (
$):C89,24;)I 10.88;N 11
．． 52 calculated value C%): C811, OO, HlG, 75.
N 11.50 (■) Trifluoromesylate [m
'aE] 2 g of the route compound [rlaE] was dissolved in 15 d of pyridine-dichloromethane (2:1), and 1 d of trifluoromethanesulfonic anhydride previously dissolved in dichloromethane was added to the solution.
．． After the reaction, dichloromethane was distilled off at below 15°C, and then cooled again to -20°C and DMF 2
Add G@l and 7.5g of sodium azide, -20~
The reaction solution stirred overnight at -25°C was extracted with chloroform, and the syrup obtained by distilling off the solvent was purified by silica gel column chromatography (filling material: Wakogel C-300, eluent: chloroform), and the compound [ rVaE]
850 g of syrup was obtained. Yield 40% (

[From [■aE]), the physical constant of this thing,
The spectral data were consistent with that obtained with lil. (4)'(2S, 3R, 4Z)-2-7 Zito 1.3
-0- i'/propylidene-4-octadecene-1,
Synthesis of 3-diol [W aZ] Compound G4) [■ According to the synthesis method of aE1, compound [
II aZ] via mesylate [m aZ] with a yield of 82%, and trifluoromesylate [m
'aZ] with a yield of 50%, respectively, the compounds [rVa
Z] syrup was obtained. Knee 74.7° (C-0JI, chloroform)
. IR (film): y 3000-2800 (
OH), 2100013). 1780-1800 (-C-C-), 8700m+
-' ((CH3)2G) -”H-N M R(
270MHz, CDCl! z): δ0.8B(t
, 3H. -C)! 2CH3), 1.2-1.5 (22)1.
-(:H2-), 1.4+, 1.50(2s
, 6H, (CH3)2G), 2.18 (~q,
2H, J ~7Hz, H-8), 3.33 (
m, IH, J(ax, 2=J2,3 10°Jieq,
2 5.5Hz, H-2), 3.85 (dd,
I H, Jge+*11.7. Jlax, 2 ~ 1
OHz, H-1Bm), 3.95 (dd, IH. Jll!q+2 5.5Hz, H-1eq), 4.
48 (~t, lH, J2.3:J3,4 9~
1 GHz, H-3), 5.38 (m, 1)1. J
3.4pm 9, Ja, s 10.8, J4. s 1.5H
z, H-4), s, to the square. IH, J4, 5 10.8. J5. srs'1 7~
8Hz, H-s). Elemental analysis value (as C2, H!5Nso2) Actual value C%
): C89, 32, HIo, 58. N 11. t9 calculated value ($): C813, OQ; HIO, 75, N 1
1.50(51(2S, 3R,4E)-2-7 minnow 1.3-0-inpropylidene-4-year-old tadecene-1
, 3-diol [V aE] Synthesis compound [W aE] 2g is 2-propa/-k
Dissolve in 40ml and add sodium borohydride 0
．． After the reaction, the reaction solution was cooled, acetone was added to decompose the excess reagent, the solvent was distilled off, and ether was added to the residual solution to remove insoluble matter. I passed away. The furnace solution was concentrated under reduced pressure, and the resulting syrup was subjected to silica gel column chromatography [filling material: Wakogel C-200, eluent: chloroform/methanol (
100/I)] to obtain the compound [V aE]
1.78 g was obtained. Yield 35%. View 9.7@ (C-0,559, chloroform). IRDil■): ν 3380. 3300(N)I
t), 1780-1520 (NH, -CIIC-)
, 890cm ((C1,)2G) -'H-
NMR (270MHz, CDα,):
δ 0.88 (t. 3 H, -111:H, CH,), 1.0 to 1.5 (
24H, -CH2- and IH2). 1.42. 1.411 (2s, 6H, (CH
I) 2G), 2.00 (~q. 2H, J ~7Hz, H-8), 2J9 (m, IH
, Jlax, 2L0.3. Jz, 3 El, 5
．． Jleq, 2 5.1) 1z, H-2)
, 3.55 (~L, LH, Jls
s 11.4. H-1am), 3.85(
~t, L H, Jz, a 7.7Hz, H
-3), 3.87 (dd, LH. H-111CI), 5.39 (m, IH, J4
, S 15.4. Ja 16 Is・) 1.51
1z, H-4), 5.83ppm (m, IH,
J4. s 15.4゜J5, s (Is) 6
．． 8) 1z, H-5) *Elemental analysis value (C2□)+4
．． As NO2) Actual value ($): C74,03:H12
,38;N 4.00 calculation i1i(X):C74,2
8;H12,17;N 4.13(51'(2S,
3R,4Z)-2-amino-1,3-0-inpropylidene-4-tadecene-1,3-diol [V a
According to the synthesis method for compound [VaE] in (5), compound [rVaZ] was treated with sodium borohydride in 2-propanol, and the same post-treatment was performed to synthesize compound [VaZ] into 9
Obtained with a yield of 3%. @D: +14.8° (C-0,884, chloroform). I R (fif): y 3380.3300 (
IH2), 1780-1580 (NH, -C=C-)
, 880c ((C)Is)2G) -Direct H-NMR (270MHz, CDO22)
: δ 0.88 (t. 3H, -0820M3), 1.0~1.5 (24
H, -CH2- and IH2), 1.41.1.52
(2s, 6H, (II:Hz)zC), 2.72
(m, IH, JtaLz!J2oss~to, J
1eq+25.5Hz, H-2), 3.58 (~
t, I H* JgB@ 11-4 * Jt a
x-2~1OHz, H-law), 3.8
9 (dd, L H, H-1 eq). 4.28 (~t+ L Hz Jlss""Jls
s 9Hz, H-3). 5.33 (m, L H, Jans 1G-8, J
a, s (@・> 1.5H2°H-4), 5.
78ppm (m, IH, Ja, 5 10.8.
Js+s+@')7-8Hz, H-5). Elemental analysis value (as C21H4□NO□) Actual value ($
): C74,14; I (12,20iN 3.9g calculated value ($): C74,28; H12, l?, N 4.
13 (61(2S, 3R, '4-1,3-0-impropylidene-2-octadecanamide-4-tadecene-1,3-diol [maEtl synthesis compound [V aE] Ig in dichloromethane-dioxa 7 (1:1) dissolved in 20aj and added DCCl to this.
, 22 g and 1.28 g of stearic acid were added, and the reaction was stirred at room temperature for 5 hours. After the reaction, insoluble matter was removed, and 7
The syrup obtained by concentrating the solution under reduced pressure was subjected to silica gel column chromatography (filling material: Fuco-gel C-300).
, eluent dichloroform) and crystallized with ethanol to obtain 1.5 g of crystals of the compound [■aEtl]. Yield 84%. ■, p,: 87.0-87.5°C Viewing: -0-5° (C-0,4, chloroform)
. I R (KBr) 2y 3300 (NH)
, 3000-2800 (CI). 1840, 1560(aside), 870CI
I ((CHI)2G) e'H-NMR(2
70MHz, CDα3): 6 0.88 (t. 6 H, -CH2Ch), 1.0'1.7 (m,
52H, -CH2-). 1.42. 1.49 (2s, 6H, (CH2
) 2G), 2.03 (~q. 2H, J 7-8) 12. -CH-CH-C)! j-
), 2.12 (m. 2 H, -Go-C) I, -), 3.84 (dd, LH
, J~11°-gezen Jtax, 2 9.2Hz, H-1ax), 3.
77 ~3.8? (m, IH. H-2), 3. +J8 (dd, I H, Jll
! 'L2 5. IHz, H-1eq)+4.08
(~t, I H, Jz, s 8.5. J,
, 47.7Hz, H-3), 5.20 (d, I
H, J 8.4Hz, NH), 5.42 (dd. I H, J,, 5 15.4Hz, H-4),
5.75ppm (m, IH. J4+S ts, t, Js, scs・)
~7Hz, H-5). Elemental analysis value (aS) H, NO2) Actual measurement value (X)
:C7? , 51; H12, 38; N 2.13 Calculated value ($): c 7? , 27. H12,4+1;N2
．． 31(8)'(2S, 3R,4Z)-1,3-0-
Synthesis of isopropylidene-2-octadecanamide-4-octadecene-1,3-diol [vIaZtl According to the synthesis method of compound ['1lIaE,] in (6), compound [V aZ] and stearic acid were mixed in the presence of DCC. After reaction and post-treatment, crystals of compound ['ff1aZ1] were obtained in a yield of 87%. m, p,: 74.0-74.5°C. D Knee 8.9 @ (C-0,485, chloroform). I R (Nujol): y 3380 (N)l
), 3000-2800(C)I), 1f14
0.1530(aside), 880CII ((
CH3)2G). 'H-NMR (270MHz, CDα3):
δ 0.88(t, 6H, -CH2CH, 1.
O~1.75 (m, 52H, -CH2-). 1.4+, 1.52(2s, 6H, (CH
z)2G), 1.90-2.25(m, 4H,
-Go-CH2- and -ctt-cu-cu, -). 3.71 (dd, LH, Jge, ~11. Jl
ax, 2 9.2Hz, H-1ax), 3.8~3
．． 98 (m, I H, H-2), 3.99 (dd
. J1eq+2 1.5Hz, H-1eq),
4.50 (~t, IH, J2 .29.5
．． h, 4 8.8H2,H-3), 5.23(d,
IH, J 8. IHz, NH), 5.39 (~
t, l H, J4. S Lo, 7 H2゜J4
, s(s+) 1.5Hz, H-4),
5.89 ppm (m, IH, J4.S10.7.
J5, 67.3Hz, H-5). Elemental analysis value (as 039Ht 5NCh) Actual measurement value (
1):C7? , 38;H12,44;N 2.22 Calculated value m:c 77.29:H12,49:N 2.
31(7)(2S, 3R,4E)-2-octadecanamide-4-old tadecene-1,3-diol (N-stearoylsphingosine:ceramide) [IXEtl
Synthetic compound [m aE1] 1.2g of acetic acid 80
Dissolve m. 4 d of water was added to this, and the reaction was carried out for 1 hour at 45-50'0. After confirming the completion of the reaction, the 1 reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (filling material: Wako Gel C-200, eluent: :chloroform) and then crystallized with ethanol to obtain the compound []XE,]
1.08g was obtained. Yield 95%. Peng, p: 97-88°C [tfflDnee a, a″″ (C proverb 0.5. Chloroform). IR (Nujol): y 3500-310
0 (OH, NH). 3000-2800 (OH), 1840. 155
0cm-Tora amide) *'H-N M R (27
0MHz, CDα, +00300): δG,
f18 (~t, 6H, -CH2GHz), 1
．． 0~1.4.1.5~1.7 (m, 50H*2)1
．． -CH2-), 2.04 (~q, 2H, 1%, @=
J6,7~7Hz, -OH<H-CH2-), 2.
2(t, 2H, J7~8 Hz, -〇〇-C!!j
-), 3.84 (m, L H, H-1). 3.75-3.90 (m, 2H, H-1', H-2)
, 4.111 (~t, IH+ J2 +1 ~5.
J3. , 8.8Hz, H-3), 5.49
(~dd. I H, J,, 4 B, [i, J4.s 1
5.4Hz, H-4), 5.75pp-(m,
IH, J4. , 15.4. J,,6 #7H2,
) I-5). Elemental analysis value (as CzsHy□No) Actual measurement value (X
):C78,55;)I 12.48;N 2.5
1 Calculated value ($): C78,40; H12,85:N
2.48(7)'(2S, 3R,4Z)-2-octadecanamide-4-octadecene-1,3-diol (N
-stearoylcis-sphingosine; stereoisomer of ceramide) [Compound of synthesis (7) of IXZtl [According to the synthesis method of IXEtl, the compound [
The inpropylidene group of [maZt] was removed and similarly post-treated to quantitatively obtain crystals of compound [IXZtl. ■, P: 94-35°C. View 0 Knee 7° (C dew 0.5. Chloroform). IR (Nujol): y 3500
~3200 (OH, NH). 3000-2800(C)I), 1840. 15
50cm-' (aside). 'H-NMR (270MHz, CDα4 +
CD, On): δ0.88 (~t, 6H
, -CHzCH3), 1.0-1.4, 1.5-1.7
(m, 50H+2H, -CH2-), 1.85-2.
30 (m, 4 H. -CH-0H-C1,- and -Go-C)j2-),
3.8-3.9 (m. 3 H,) I-1, 1 (-1' and H-2), 4.5
2 (dd, l H. h +2 5.1 + J214 a ~91
2 e H-3) + 5-43 (~t +I H,
J4 +S ”' 11Hz t H-4) +
5.75ppm (m, I H*Ja, s
~IL JS+@(1') ~7Hz, H-5). Elemental analysis value CCs5Ht□NO,) Actual measurement value (X
): C7B, 24. H12,53, N 2.3B calculated value m:c 78.40; H12,85; N 2.4
B Example 2 (1) Synthesis of (2S, 3R, 4E)-1,3-0-isopropylidene-2-tetracosanamide-4-octadecene-1,3-diol [VlaE2] [VaE] synthesized according to 1) to (5)
The compound described in Example 1 (6) [VTaEl
According to the synthesis method of 1, compound [V aE] and tetracosanoic acid are reacted in the presence of DCC, followed by similar post-treatment,
Crystals of compound [VTaE21] were obtained with a yield of θ3%. 11.9. : 8m5~62.0℃. [aaD knee (1,4° (C-0,507, chloroform-meth/-ol (50/l)). IR (Nujol): y 331G (NH),
3000-280Q (CH). 1840, 1550(aside), 870cm
((CHI)2G) -'H-N M R (270M)
lz, C[lα,) = δ G, 88 (t. -GO-OHj- and -〇) I-C1 (-CI-),
3. f15(dd, l1(,J,,. ~11.Jlax, 2 9.2Hz, H-1ax)
, 3.75-3.10 (m, IH, H-2)
, 3.99(dd, L H, J1eq+25.1H
z, H-1eq), 4.08 (~t, I H, 42
, 39, 5, Jl, 47.7Hz, H-3), 5.
20 (d, IH, J 8.4Hz, NH). 5.42 (dd, L H, Ja, @ 15.4H
z, H-4), 5.75 ppm (m, L H,
J4+s 15.4. J5. @<ec) B, 8H
z, H-5). Elemental analysis value (as Cm5HatNOs) Actual value (Tsumugi): C78.0B, H12.84; N 1. ! 38 Calculated value (X): C7B, 31. H12,71;N2.
03+21(2S, 3R,4E)-2-tetracosanamide-4-year-old tadecene-1,3-diol (N-lignoceroyl sphingosine; ceramide) [IXE
2] Synthesis Example 1 (Compound [IXE+]
According to the synthesis method, the impropylidene group of the compound [vIaE2] obtained in (1) was removed and the same post-treatment was performed to quantitatively obtain crystals of ceramide [IX E2 ]. m, p,: 92~l+4"c. Viewing knee 1.5° (C-1,185, chloroform/
methanol (50/l)). IR (Nujol): y 3500-310
0 (DH, NH). 3QOO~280Q(C)! ), 1840.
1550 cm-' (amtde). 'H-NMR(270MHz, C[)α, -c
o, on): δ 0,83(t,6)1, -CH2C)
Ij), 1.0~1.4.1.45~1.70 (m
. 62H+ 2H, -CH2-), 2.04(~q,
2H,j,, 6 YuJ, ,, ~7) 1z, -
C) I-CH-0%-), 2.21(t, 1)1
, J7~8 Hz, -Go-CHz -),
3.65 (dd, 1) 1, Jgem ~11
, J,, 23-4Hz, H-1), 3.81 (
dd, l 1 (. J ~ 11. Jl, 2 4.8Hz, H-1'
), 3.8-3.9am (m, IH, H-2), 4.14 (~t, IH, J
6-7Hz, H-3), 5.48(~dd,
IH, h, 4 7. Ja, s15.4Hz, H-4
), 5.73 ppm (m, 1) 1. Ja,s 15
．． 4゜Js, a (11') 7 Hz, H
-5). Elemental analysis value (as C42H62NO*) Actual value m:
c 77.85. H12,78; N 2.08 Calculated value ($): C77,57, H12,8? , N 2.1
5 Example 3゜(11(2S, 3R,4E)-2-azido-4-octadecene-1,3-diol [WE] Synthesis Compound [ff
Dissolve 2 g of aE] in 40 ml of acetic acid, and add 2 g of water to this.
．． 4- was added, 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 subjected to column chromatography [filling material: Lycogel C-200,
Eluate: chloroform/methanol (400/l)], and then crystallized from ether-n-hexane.
Crystals of compound [■E] were quantitatively obtained. m, p: 50.5-51.5°C. tciD knee 33.5° (C-0,441, chloroform). IR (fit■) Niji 3700-3100 (OH
), 3000-2800 (CH), 2100c
m (N3). 'H-NMR (90MHz, (:D(13): δ
0.88 (~t. 3 H, -CkhCHs'), 1. l”1.5
(m, 22B, -(:Hz-). 2.08 (m, 2H, H-8), 2.48
(broad s, 2 H. OH), 3.48 (~q, IH, J 5~6H
z, H-2). 3.78 (~d, 2 H, J 5~6Hz,
H-1), 4.22 (~t, L H, J
~6Hz, H-3), 5.49(m, Jl, 4B-5
*J4+S 15-4*Ja, 6 1.5H
z l H-4), 5.82 PPM (no
Ja,s 15.4. Js, a<n
~8H2, H-5) Six elemental analysis values (C1aHz
s Ns 02) Actual measurement value (X): C88, 17,
H11,OO,N 12.83 Calculated value ($): C88
,42;H10,84;N 12.91(11'C
Synthesis of Example 1 (11,
(21, compound synthesized according to (31 and (4)°) [
IVaZ], according to the synthesis method of [■E] in (1), the inpropylidene group of [■aZ] was removed, and the same post-treatment was performed to quantitatively obtain crystals of compound [WZ]. Ta. Layer, ρ: 42.5-43.0°C. Same D Knee 53.1 @ ((Knee 0.557. Chloroform). IR (fil Peng) Niji 3700-3100 (O
H), 3000-2800 (OH), 2100c
m-' (N,). IH-NMR (90MHz, (:DC13):
δ 0.8B (~t. 3H, -〇H2CH2), 1.1~1.5(
m, 22H, -CH2-). 2.11 (m, 2 H, H-8), 2.27 (
broads, 2H. OH), 3.49 (~q, IH, J 5~6Hz,
H-2). 3.79 (~d, 28.J 5~6Hz, H-1)
, 4.58 (dd. IH, J2.s ~6+h, 4~8Hz,
H-3), 5.45 (m, I H, J2.
a to B, J4+5 11. J41~IHz. H-4), 5.87ppm (m, LH, J4,
5 It, J5,11 ~7Hz, H-5)
. Elemental analysis value (as Cr aH3s Nt 02) Actual value ($): C88,25, H10,77; N13
．． 12 Calculated value m:c 88.42. H10,84,N
12.91 (21 (2S, 3R, 4K)-2-7
Synthesis of minnow 4-octadecene-1,3-diol (sphingosine) [NE] From the compound [■aE] described in (5) of Example 1 (V
According to the synthesis method of aEl, the compound [■E] obtained with fil was heated under reflux with excess sodium borohydride in 2-propanol, and the obtained product was subjected to silica gel column chromatography [filling material: Fuco- Gel C-200, eluent dichloromethane/methanol (20/1)] and then purified with ether-petroleum ether! Crystallization gave sphingosine [Vll E] (7) crystals with a yield of 85%. Layer, p: 81.5-82.5°C. IR (fil fat) Niji 3B00~305G (O
R, KH2). 3000-2800 (CH), 1780-1500
c+s-' (NH, -C-C-). Complete disappearance of the N3-based absorption peak (2100 cm-'). 'H-NMR (270MHz, CD0h): δ
5.43 (m. I H+ J2 +4 8-J J4.5 t5.a
, J4+6 1.5Hz, H-4), 5.7
5ppm (m, LH, J4,5 15.4.
J5,1+~? Hz, H-5). (21'(2S, 3R,4Z)-2-amino-4-octadecene-1,3-diol (cis-sphingosine) [VIZ] Synthesis of compound (1) [■Synthesis of compound [E] from El According to the method, the azide group of [■Z] obtained in (1)° was reduced to the 7-mino group, and the product was similarly purified and crystallized with ethyl acetate to obtain crystals of cis-sphingosine [VIIZ] at 94°C.
% yield. Heel, ρ, = 72-73°C. IR (film):y 3800~3000(
OH,N)12). 3000~2800(CH), 1750~1500c
m-' (NH, -C-C-). Complete disappearance of the N3-based absorption peak (2100 cm). 'H-NMR (270MHz, COO!s):
δ 0.88 (t. 3 H, -C) 120H3), 1.00"1.43 (
m, 24H, -CHz-). 1.9-2.2 (m, 2H, H-8,8°),
2.84 (broadm, l H, H-2), 2
．． 90-3.25 (broad m. 4H,N)I, 0)1), 3.5-3.8 (b
road m, 2h. H-1,1°), 4.41 (m, l H,H-2
), 5.43 (~t, L H, J2.a 9~I
O, Ja, s 10.8) 1z, H-4), 5.
80ppm (m, I H, J5, 610.8. J
@, 77.3Hz, H-5). (31(2S, 3R,4E)-2-octadecanamide-4-octadecene-1,?-diol (N-stear0
Ilsphingosine; ceramide) [Vi[E]Ig obtained in IXEtl synthesis (2) was dissolved in 20 ml of dichloromethane-dioxane (1:1), and 1.28 g of stearic acid and 1.24 g of DCC were added thereto. After the reaction was stirred at room temperature for 5 hours, insoluble materials were removed,
The syrup obtained by concentrating the furnace liquid under reduced pressure was subjected to silica gel column chromatography (filling material: Wakogel C-200).
, eluent: chloroform) and crystallized from ethanol to obtain ceramide [IXEtl in 90% yield. The physical constants and spectral data of the obtained ceramide FIX E, ] were consistent with those obtained in Example 1 (7). (31'(2S, 3R,4Z)-2-octadecanamide-4-old tadecene-1,3-diol (N-stearylcis-sphingosine; stereoisomer of ceramide)
Synthesis (3) of [■zt] Compound [VD[E] Color compound [IXEtl
(7) According to the synthesis method, in the presence of DCC, the compound obtained in (2)
XZ1] crystals were obtained in a yield of 91%. The obtained N-stearoyl cis-sphingosine [
The physical constants and spectral data of IXZ,] were consistent with those obtained in Example 1 (7)°. Example 4゜(1) 4,6-0-benzylidene-D-galactopyranose 1 step 1 synthesis - 7.2 g of galactose was added to 10100 liters of DMF.
14ml of dimethoxybenzyl and p-
Toluenesulfonic acid 17011y was added and the reaction was stirred for 2 hours at 35 - 0°C. After the reaction, a large excess of sodium hydrogen carbonate was added to neutralize, the insoluble matter was removed, and the furnace liquid was heated under reduced pressure a. The residue obtained by condensation was dissolved in chloroform and subjected to silica gel column chromatography (filling material: Wakogel C-200, eluent: chloroflume/methanol (100/1) → chloroform/methanol (5G/l).
) → Chloroform/methanol (subject to 20 ml, 4.
8-0-benzylidene-〇-galactose [I;,]
of cyclo was obtained in 80% yield. The resulting syrup was a mixture of α and β-7 nomers, and while one of the 7-nomers precipitated as crystals, it was used as a mixture in the next step. Physical constant LP of the crystal of the compound [Product]: +80-182°C. [ciD: +128.5''' (c = 0.51.methanol). Elemental analysis value (as CuHtaOs) Actual value (X):
C58,41; H111,13 calculated value m:c 5B,
20; H111,01(2) 2. Compound obtained in synthesis (1) of 4-0-benzylidene-〇-threose [I (H)b] and its formate [1(F)b] [Process] 4sr to methanol 2
0〇-, and add sodium metaperiodate to it.8.
After 0 reaction, 3 g was added and stirred at room temperature for 3 hours. Insoluble materials were removed, the solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography [filling material: Wako Gel C].
-200, eluent: chloroform/methanol (150
/1)] to give 2.4-0-benzylidene-D-
3.1 g of a mixture (approximately 1:1) of threoose [1()I)I,l and its formate [I(F)b] was obtained. This mixture is separated M! It was subjected to the next reaction without being washed. (3) (2R,3R,4E)-1,3-0-benzylidene-4-octadecene-1,2,3-)liol [
■lb El and (2R, 3R, 4Z) -1,3-0
-benzylidene-4-tadecene-1,2,3-)
! J All[111bZl(F) (3 of Synthesis Example 1)
), the compound obtained in (2) [I (H)b]
A mixture of 4.4 g of compound [I(F)b] and compound [I(F)b] was reacted with tetradecyl triphenylphosphonium bromide in the presence of phenyllithium. After treatment in the same manner as in Example 1 (3), 4.5 g of trans olefin [■tbE] and 4.5 g of cis olefin [n
10.9 g of 1bZ was obtained. Compound [II, 5E] @, P, 53.5-54.5°C. [cdD: -0,8” (cxO,50B, ri0
tlll,mu). IR (Nujol): 3B00 (free OH)
, 3450 (hydrogen bonding Q)I), 310ON
30GO (benzene ring CI). 1780~1860 (-CH=CH-), 780~
880 cm (benzene ring). 'H-NMR (2?QHz, C0CjL2):
6 0.8B (t. 3H, CHI), 1. l~1.5(m, 22H
, -CH2-), 2.08(~q, 2H,H-8,
8°), 2.88 (broad s, IH
,OH), 3.53 (~s, IH,H-2
), 4.08 (dd, I H, Jge, 1
2. Jleq, 21-1.5Hz, H-1eq
), 4.25 (dd, IH, JLax, 21
．． 8Hz, H-1ax), 4.41 (d,
IH, Jz, a 8.2Hz, H-3). 5.82 Cs, IH, φ-CH%), 5.88
(m I I H, J4 +S15.8. Js, a
fl, 2Hz, H-4), 5.88 (m,
LH, J4. S 15.8. JS,, w7
Hz, H-5), 7.3-7.8 ppIl (
m, 5H, phenyl). Elemental analysis value (as 02S84゜0.) Actual value ($)
:C77,43,H10,2B calculated value (X):C77,
27,H10,38 Compound [■1-Z] Syrup. Group D: +ao, s° (c = 0.485.chloroform). I R (film): y 3800 (Freedom D
H), 3450 (hydrogen bonding OH), 3100~
3000 (He7-t/y Ring C)I). 1760-1580 (-1)1-1;H-), 78
0-880 c+s-' (benzene ring). 'HNMR (270Hz, CDCf13):
δ 0.88 (t. 3H,C)! 3), 1.0 to 1.5 (m, 22H,
-C)12-), 2.00-2.25 (m, 2H,
H-8,8'), 2.75 (broad s. IH, OH), 3.49 (~s, IH, H-2)
, 4.12 (dd, l H, J 12.
J19q+2 1.0-1.5Hz, H-em leq), 4.25 (dd, IH, Jgem
12+ Jtax, 218Hz, H-1gm),
4.73 (d, IH, J2, 45.1Hz,
H-3), 5.88 (5, IH, φ-C) Ite),
5.5-5.8 (m, 2)1. H-4,5),
7.3-7.8 ppm (m.5H, phenyl). Elemental analysis value (actually measured mc% as 02SH4゜03)
:C7? , 88. H10,52 calculated value ($): C77,
27;H10,38 Example 5゜(1) (2111,3R,4K) -1,3-0-benzylidene-4-eicosene-1,2,3-triol (IIzbε1 and (2R,3R,4Z) - 1,3-
0-Benzylidene-4,-eicosene-1,2,3-)
Synthesis of liol [■211 Zl Using hexadecyl triphenylphosphonium bromide as a Wittig reagent, the compound [I (H
), ] and compound [I(F)bl] was reacted with this in the presence of phenyllithium, Example 4
After the post-treatment in the same manner as in (3), trans form [r12bE
] 4. l11g and cis form [ll2b211.0 g
I got it. Compound [112bE] Layer, p: 83.0-63.5°C. [4D knee 1.9° (c-0,537+chloroform)
. Elemental analysis value (02)) 14403) Actual value (%)
):C7? , 78; H10, 82 calculated value (ri: C77,
83; H10,85 compound [H2bZ] s, p: 47-48°C. [dD: +42.3@(c = o, ao, chloroform/mu). Elemental analysis value (as C2tH4mOs) Actual value C%
): C7B, 05. )! 10.78 Calculated value ($):
C? 7.83. H10,65 Example 6゜+1) (2R,3R,4E) -1,3-0-4sopropylidene-4-eicosene-1,2,3-)suool (IItaEl and (2R,3R,4Z) - 1,
3-0-isopropylidene-4-eicosene-1,2,
3-) Synthesis of liol [ll2aZ] 18.8 g of the tetradecyl triphenylphosphonium bromide in Example 1 (3) was converted into hexadecyl
In exactly the same manner as in Example 1 (3) except for replacing with 113.8 g of triphenylphosphonium bromide F,
Compound [H2aE] 3.5g and compound [■2aZ]
3.3g was obtained. Compound [112aE] Temperature: 50-51°C. Compound [■2aZ] m, p, : 50-51"O. ,3R,4E) -1,3-
Synthesis of 0-inpropylidene-2-〇-mesyl-4-eicosene-1,2.3-)liol [m2aE] Using the compound [112aE] obtained in (1), the (
Compound [m2aE] was synthesized and isolated according to the method of 4) (it). D knee 34° (C+0.788, chloroform)
(21'C2S, 3R,4Z)-1,3-0-impropylidene-2-〇-mesyl-4-eicosene-1,
2.3-triol [MtaZl synthesis (1) Using the compound [112aZ] obtained in Example 1 (
Compound [mtaZl was synthesized and isolated according to method 4) (i). [dD: -38,4' (C-0,544, chloroform). (31(2S, 3R,4E)-2-azido-1,3
-0-Inpropylidene-4-diicosene-1,3-diol [Synthesis of N2aE1 (2) Using the obtained compound (In2aEl), Example 1 (
F) Compound [ff2aE
] was synthesized. [io: -313,4"(c+0-50-chloroform)(31' (2S, 3R,4Z)-2-
Synthesis of azide-1,3-0-inpropylidene-4-eicosene-1,3-diol [rVzaZ] (2) Using the compound [m2aZ] obtained in Example 1
Compound [rVzaZ] according to the method of (4) (il)
was synthesized. coiD knee 77.7° (c=0.48.chloroform) (41(2S, 3R, 4E) -2-amino-1,
3-0-impropylidene-4-eicosene-1,3-
Synthesis of diol [V 2aE] (3) Using the obtained compound [ffzaE], compound [V 2aE] was obtained according to the method of Example 1 (5). [dD: +7.5° (c=o, f144, chloroform) (4)' (2S, 3R,4Z)-2-amino-1,3-0-inpropylidene-4-eicosene-
Synthesis of 1,3-diol [V2aZ] Compound [V2aZ] was obtained using the compound [IV2aZ] obtained in (3)' according to the method of Example 1 (5)°. [cdD: +23.1@(C=0.407, chloroform)(51(2S, 3R,4E)-1,3-0-
Impropylidene-2-octadecanamide-4-diicosene-1,3-diol [Compound [V 2aE] obtained in synthesis (4) of VT2aE1 was used in
Compound [VI 2aE] was obtained according to the method of 6). m, ρ, = 71 to 72°C [Be D: +0.48° (c = 0.852. Chloroform) (51' (2S, 3R, 4Z) -1
,3-0-impropylidene-2-octadecanamide-
Synthesis of 4-eicosene-1,3-diol [VI2aZ] Compound [V12aZ] was obtained using the compound [V2aZ] obtained in (4)' according to the method of Example 1 (6)'. Layer, p: 79.5-80.5°C Point D Knee 9.8° (c = 0.531. Chloroform) [Effects of the Invention] As described above, the present invention can be used as a treatment for blurred vision or as an anticancer drug. It is an important constituent of glycosphingolipid gangliosides, which is expected to be developed. The present invention provides a novel and useful method for producing ceramide or its homologues and its intermediates. According to the method of the present invention, the number of steps is 8 from D-xylose or D-galactose (protected xylose or protected (7 steps from galactose) and much shorter processing time compared to conventional methods (for example, the method that is said to have the least number of steps among existing methods (12 steps from D-glucose, 12 steps from D-glucose,
11 steps from dlD-glucose). ), it has a remarkable effect in terms of being extremely advantageous in terms of synthesis, and its contribution to this industry is enormous. Patent applicant Wako Pure Chemical Industries, Ltd. Procedural amendment June 3, 1986

Claims (6)

[Claims] (1) Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (However, R^1 and R^2 both represent a methyl group, or one is a phenyl group and the other is a hydrogen atom. and R^3 represents a hydrogen atom or a -CHO group) is reacted with an onium salt of a phosphorylene compound in the presence of an alkyl, aralkyl or aryllithium to form a compound of the formula [II]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (However, n represents an integer from 0 to 20, R^1, R^2
is the same as above. ), and then the hydroxyl group of this is protected with a protecting group such as mesyl group, trifluoromesyl group, tosyl group, brosyl group, etc. to form the formula [III] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [III] However, R^4 represents a protecting group such as a mesyl group, a trifluoromesyl group, a tosyl group, a brosyl group, and R^1, R^2
and n are the same as above. ) After making the compound shown by, this is reacted with azide to form the formula [IV] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] (However, R^1, R^2 and n are the same as above. ), and then (i) reduce it to form the formula [V] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[V] (However, R^1, R^2 and n is the same as above), and this is further acylated with a fatty acid to form the formula [VI] ▲ Numerical formula, chemical formula, table, etc. ▼ [VI] [However, R^5 is − NHCOR^6 group (wherein R^6 represents a saturated or unsaturated alkyl group having 1 to 30 carbon atoms, and may be linear or branched),
^1, R^2 and n are the same as above. ] After forming the protected ceramide or its homolog represented by the formula, the protective group is removed by hydrolysis with an acid to form the ceramide or its homolog, or (ii) an azide compound represented by the formula [IV] is hydrolyzed with acid to remove the protective group to form a compound represented by the formula [VII] ▲Mathematical formula, chemical formula, table, etc.▼[VII] (However, n is the same as above), and this is further reduced. After forming sphingosine or its analog represented by the formula [VIII] ▲Mathematical formulas, chemical formulas, tables, etc.▼[VIII] (where n is the same as above), this is acylated with a fatty acid to form ceramide or A method for producing ceramide or its homologue, which is represented by the formula [IX] ▲Mathematical formula, chemical formula, table, etc.▼[IX] (However, R^5 and n are the same as above.) (2) Formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (However, R^1 and R^2 both represent a methyl group, or one is a phenyl group and the other is a hydrogen atom. and R^3 represents a hydrogen atom or a -CHO group) is reacted with an onium salt of a phosphorylene compound in the presence of an alkyl, aralkyl or aryllithium. , Formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (However, n represents an integer from 0 to 20, R^1, R^2
is the same as above. ) A method for producing an olefin compound shown in (3) Formula [II] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [II] (However, R^1 and R^2 both represent a methyl group, or one is a phenyl group and the other is a hydrogen atom. In addition, n represents an integer of 0 to 20.) The hydroxyl group of the olefin compound represented by: mesyl group, trifluoromesyl group,
By protecting with a protecting group such as tosyl group or brosyl group, the formula [III
] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[III] (However, R^4 represents a protective group such as mesyl group, trifluoromesyl group, tosyl group, brosyl group, etc., and R^1, R^
2 and n are the same as above. ) Formula [IV] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [IV] (However, R^1, R^2 and n is the same as above.) A method for producing an azide compound. (4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 and R^2 both represent a methyl group, or one represents a phenyl group and the other represents a hydrogen atom, and R^
7 is a hydrogen atom, or a mesyl group, a trifluoromesyl group,
Represents a protective group such as tosyl group or brosyl group, and n is 0 to 2.
Represents an integer of 0. ) A trans-type or/and cis-type compound represented by (5) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [However, R^1 and R^2 both represent a methyl group, or one represents a phenyl group and the other represents a hydrogen atom, and R^
5 is -N_3 group, -NH_2 group, -NHCOR^5 group (
However, R^5 represents a saturated or unsaturated alkyl group having 1 to 30 carbon atoms, and may be either linear or branched. ), and n represents an integer from 0 to 20. ] A trans-type and/or cis-type compound represented by the following. (6) Formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (However, n represents an integer from 0 to 20.) A trans-type and/or cis-type compound represented by