JPH04124160A - Omega-acyloxycarboxylic acid derivative and production of acylglucocylceramide using derivative as raw material - Google Patents

Abstract

PURPOSE:To efficiently synthesize the subject compound which has been produced only by extraction by amidating an omega-acyloxycarboxylic acid derivative as a new intermediate with a glucosylated sphingenyl derivative in the presence of a base. CONSTITUTION:The objective compound of formula III such as (2S,3R,4E)-1-O-(beta- D-glucopyranosyl)-N-(30'-linoleyloxy)triacontanoyl-20C-sphingosine can be produced by amidating a compound of formula I (R<1> is linoleoyl; R<2> is p-nitrophenyl; (k) is 23 or 29) which is a new intermediate (e.g. 30-linoleoyloxytriacontanoic acid p-nitrophenyl ester) with a compound of formula II (R<3> is H or tert. butyldiphenylsilyl; (l) is 12 or 14) in the presence of a base (preferably pyridine) and, as necessary, deprotecting the product. The compound of formula I wherein (k) is 29 can be synthesized according to the reaction path shown by reaction formula.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an ω-acyloxycarboxylic acid derivative and a method for producing acylglucosylceramides using the same as a raw material.

[Conventional technology]

In the mammalian epidermal cell layer, there are so-called cerebrosides, which are composed of a long-chain amino alcohol called sphingosine, a fatty acid bonded to an amide bond, and a monosaccharide represented by glucose bonded to a glucosyl bond.

Among these, those in which the fatty acid is an ω-hydroxy fatty acid and a fatty acid represented by linoleic acid is ester-bonded at the ω-position are particularly referred to as acyl glucosylceramides. Generally, most of these compounds exist from the epidermal basal cells to the corneocytes, and are localized in the cell membrane bilayer, the interkeratinocyte lipid layer, and the lamellar granules. According to recent research, transglutaminase (Tr
ansglutaminase) activity and promotion of thickened cell membrane production, and is thought to play an important role in the production of healthy epidermis (Fragrance Journal, Sō 88, 71 (I988)).
. Therefore, stereoselective and efficient synthesis of acylglucosylceramides is essential for elucidating the relationship between the molecular structure and biological activity of acylglucosylceramides.

[Problem to be solved by the invention]

In the present invention, as a result of research into a method for synthesizing acyl glucosylceramides, which have hitherto been available only from natural extracts, an efficient method for synthesizing acyl glucosylceramides has been achieved by simultaneously carrying out amidation of a long ω-acyl chain.

Therefore, an object of the present invention is to provide an efficient method for synthesizing acyl glucosylceramides, as well as ω-acyloxycarboxylic acid derivatives, which are novel compounds useful as intermediates used in the synthesis of acyl glucosylceramides.

[Failure to solve the problem]

The present invention achieves the above object by formula (I) R'0-(C
112) k-C(I2-R' (I)
(In the formula, R' represents a lyluoyl group, R2 represents a p-nitrophenyl group, and k represents an integer of 23 or 29.) Regarding the ω-acyloxycarboxylic acid derivative represented by
In addition, a glucosylated product of a sphingenin derivative represented by the formula (n) (wherein, P represents a hydrogen atom or a tert-butyldiphenylsilyl group, and E represents an integer of 12 or 14) and the general formula (■- ) ・-R'0-(CH*)m-COt-R' (I
) (wherein, R' represents a lyle oil group, R2 represents a p-nitrophenyl group, and k represents an integer of 23 or 29.

) The ω-acyloxycarboxylic acid derivative represented by formula (II[) is characterized by subjecting it to an amidation reaction in the presence of a base and deprotecting it as necessary (wherein R1 is the same as above). has significance, when k is 23, l indicates 12, and k
When is 29, l indicates 14. ) The present invention relates to a method for producing acylglucosylceramides represented by:

The novel compound (I) represented by formula (I) above can be synthesized, for example, according to the following reaction route 1.

Reaction m± (-specifically in the case of -29 in formula (I))↓ R'0-(CHz) 2s(OtR' ↓ R'0-(CHz) as-CO□H ↓ R'0- (CHa) 1o-COJ" ↓ HO-(CH2) as-CO2R2 ↓ R'0-(CH2) 2s-CO□R2 (In reaction route 1, R1 represents a lyluoyl group, and R2 represents a p-nitrophenyl group. , X represents a halogen atom, Y represents a mesylate, tosylate or halogen atom, R4 represents a lower alkyl group, R5 represents (C, ~C's) hydrocarbon silyl group or hydroxyl group together with an oxygen atom (Indicates a group that forms an acetal bond.) Reaction Route 1 will be explained in detail below.

Compound (2) is obtained by preparing Compound (I) or its equivalent, ω-hydroxycarboxylic acid, in an alcoholic solvent such as methanol in the presence of an acid catalyst such as p-toluenesulfonic acid, sulfuric acid, or a cation exchange resin. From room temperature to reflux,
It is obtained by reacting for 1 to 50 hours. Compound(
3) can be obtained by protecting the hydroxyl group of compound (2), but in this case, the protecting group is tri(C, ~Ct
) A group that forms an acetal bond with the oxygen atom of a hydrocarbon silyl group or hydroxyl group can be mentioned. In the former case, compound (3) is prepared by combining compound (2) and tri(C, ~Ci) hydrocarbon silyl chloride in the presence of an amine such as imidazole in a solvent such as pyridine, THF (tetrahydrofuran), acetonitrile, or DMF (dimethylformamide). In the latter case, compound (3) is obtained by reacting at room temperature to 100°C for 1 to 50 hours.
and dihydrobilane in a solvent such as methylene chloride, chloroform, diethyl ether, dioxane, benzene or ethyl acetate in the presence of an acid catalyst at 0° C. to room temperature for 5 minutes to 5 hours. Examples of acid catalysts used include p-) toluenesulfonic acid, hydrochloric acid, PPTS (pyridinium salt of p-toluenesulfonic acid), or cation exchange resins. is a tri(C+~C,)alkylsilyl group such as triethylsilyl, triethylsilyl, tart-butyldimethylsilyl group, or diphenyl (CI-C,) such as tart-butyldiphenylsilyl group.
4) Examples include alkylsilyl groups, especially tert
-butyldiphenylsilyl group is preferred. Examples of the group that forms an acetal bond with the oxygen atom of the hydroxyl group include a methoxymethyl group, 1-ethoxyethyl group, 2-tetrahydropyranyl group, and 2-tetrahydrofuranyl group. Compound (4) is prepared by adding compound (3) to -1 in a solvent such as THF, diethyl ether, benzene or toluene.
LiAlH4 or ^ at 0~50℃, 30 min~IO time
It can be obtained by reduction with a reducing agent such as IH(iJu) 2 (in the formula, 1-Bu represents an isobutyl group).

Compound (5) is obtained by combining compound (4) with CX in acetonitrile.
, (wherein, X represents a halogen) and is obtained by reacting with halogenated carbon and triphenylphosphine at 0° C. to room temperature for 5 minutes to 5 hours. Here, in compound (5), X represents halogen, and bromine is particularly preferred.

Other synthetic methods for compound (5) include, for example, when X is bromine, a method in which compound (4) is reacted with phosphorus tribromide, phosphorus pentabromide, etc., and a method in which compound (4) is reacted with - There is a method of converting to a sulfonic acid ester such as mesylate or tosylate, and then substituting it with an alkali salt such as Liar or NaBr in a solvent such as DMF or DMSOIDGM (Gyglyme).

On the other hand, compound (6) combines compound (2) with methylene chloride,
It is obtained by treating with an oxidizing agent such as FCC (pyridinium chlorochromate) or manganese dioxide in a solvent such as chloroform or benzene at -30°C to room temperature for 5 minutes to 5 hours. Alternatively, compound (6) is compound (2
) can also be obtained by an oxidation method using a sulfonium salt as an active species, such as Swann oxidation.

Compound (7) is compound (5) when Y is a halogen atom.
) can be obtained by converting a hydroxyl group into a halogen atom in the same manner as the synthesis of compound (2), and when Y is mesylate or tosylate, compound (2) is mixed with the corresponding sulfonic acid chloride in the presence of pyridine at 0°C to room temperature. It is obtained by reacting for 30 minutes to 10 hours.

Next, compound (8) is obtained by Witteigh reaction between compound (6) and compound (5). That is, the compound (
A phosphonium salt was prepared from 5) and triphenylphosphine, and a ylide prepared from the phosphonium salt and a base such as n-butyllithium and compound (6) were heated at -78°C to room temperature in a solvent such as diethyl ether or THF. So, 5
It is obtained by reacting for minutes to 5 hours. Compound (9
) can be obtained by subjecting compound (8) to hydrogen reduction in a solvent such as ethanol or ethyl acetate under a catalyst such as Pd/C, Pt0z or Ni. Compound (9) is also a compound (
It can also be obtained by a Grignard coupling reaction between 5) and compound (7). That is, compound (7) is mixed with L Grignard reagent prepared from compound (5) and magnesium.
-78°C ~ in the presence of copper salt catalysts such as +2CuCL and Cu1
It is obtained by reacting at room temperature for 1 to 20 hours.

Compound (I0) is compound (9) as KOII, Li0
1 (obtained by hydrolysis in a hydroalcoholic solvent at room temperature to 80°C for 30 minutes to 5 hours in the presence of a base such as Na, etc.). Compound (I1) can be obtained by reacting p-nitrophenyl acetate in the presence of pyridine at 0 to 50°C for 30 minutes to 5 hours.
) and p-nitrophenol in the presence of DCC (dicyclohexylcarbodiimide).

In addition, when synthesizing each compound in which R2 of compound (I1) is a succinimide group, a phthalimide group, or a 2.4.5 to trichlorophenyl group, compound (lO) and N-
hydroxysuccinimide, N-hydroxyphthalimide or 2,4.5-trichlorophenol, respectively
Obtained by condensation in the presence of CC.

Compound (I2) is compound (I1) in which R5 is T! J In the case of a (C, ~C,) hydrocarbon silyl group, compound (I1) is mixed with a desilylating agent in a solvent such as chloroform, THF, acetonitrile, etc. at 0°C to room temperature for 1 to 50%
Obtained by reacting for hours.

Desilylation agents include BFs ・0Bt2, (n-Bu
), NF.

Examples include CsF or) IP/Py (pyridine).

In addition, when R5 is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, the compound <December, compound (I
It is obtained by reacting 1) in a solvent such as THP, diethyl ether, acetone, etc. with an acid catalyst at 0° C. to room temperature for 5 minutes to 50 hours.

Examples of acid catalysts include acetic acid, hydrochloric acid, p-toluenesulfonic acid, and cation exchange resins.

Compound (I3) can be obtained by reacting compound (I2) with an acylating agent in a solvent such as methylene chloride in the presence of pyridine at 0° C. to room temperature for 30 minutes to 50 hours.

The acylating agent is linoleic acid chloride or linoleic acid chloride.
Examples include acid anhydrides of fluoric acid. Also, compound (I3)
can also be obtained by condensing compound (I2) and linoleic acid in the presence of DCC.

Note that R1 of compound (I3) is a valmitoyl group,
The synthesis of each compound having an oleoyl group or a stearoyl group is explained by replacing linoleic acid in the above explanatory text with valmitic acid, oleic acid, or stearic acid, respectively.

The case where the starting material compound is cyclobentadecallide has been described above, but by changing the starting material compound, ω acyloxycarbon II2 derivatives having various numbers of carbon chains can be obtained.

As described above, it is possible to obtain an ω-acyloxycarboxylic acid derivative represented by the general formula (I) % formula % (in the formula, R', R' and k have the same meanings as above). can.

Furthermore, this novel compound (I) can be synthesized according to the following reaction route 2.

Reaction route 2 (-In formula (I), specifically -23
) CH2=CH(CH2) X (I5)X(CI(2
), OX (I4) Y(CH2),. co2R'(I7)CIl,=
CH(CH2),,X (I6)C1,-C)I(
C)If)2. CD, R' (I8) No (C) 1
．． )23CO□H(I9)R'0(CH2),,C02
H(20)R'[](CH,)2. CO,R'
(21) (In reaction route 2, R' represents a lyluoyl group,
R2ftp-nitrophenyl group, R4 represents a lower alkyl group, X represents a halogen atom, and Y represents a mesylate, tosylate or halogen atom. ) Reaction route 2 will be explained in detail below.

Compound (I6) is obtained by adding Grignard reagent prepared from compound (I5) and magnesium to compound (I4) and adding +2 cu.
It is obtained by reacting at -78°C to room temperature for 1 to 30 hours in the presence of a copper salt catalyst such as c1n or Cu1.

Similarly, compound (I8) is added to compound (I7) to compound (I6).
) in the presence of a copper salt catalyst,
It is obtained by reacting at -78°C to room temperature for 1 to 30 hours.

Compound (I9) can be synthesized by hydroboration of compound (I8). That is, after reacting the compound (I8) with the hydroboration reagent, an aqueous solution of IJ hydroxide and then an aqueous hydrogen peroxide solution were added, and the mixture was heated at room temperature to 80°C for 30 minutes.
Obtained by stirring for 5 hours. Hydroboration reagents include BH3.T)IP, B)1.・5(C)
1. )2. 9-BBN (9-borabicycloC3,3
, 1] nonane), etc.

Compound (20) can be obtained by reacting compound (I9) with an acylating agent in the presence of pyridine at 0°C to room temperature for 30 minutes to 50 hours. Examples of the acylating agent include acid chloride of linoleic acid and acid anhydride of linoleic acid.

Compound (20) also combines compound (I9) and linoleic acid with D
It can also be obtained by condensation in the presence of CC.

Note that the R' portion of compound (20) is a valmitoyl group,
The synthesis of each compound having an oleoyl group or a stearoyl group is explained by replacing linoleic acid in the above explanatory text with valmitic acid, oleic acid, or stearic acid, respectively.

Compound (21) can be obtained by reacting compound (20) with p-nitrophenyl trifluoroacetate at 0 to 50°C for 30 minutes to 5 hours in the presence of pyridine. Alternatively, it can also be obtained by condensing compound (20) and p-nitrophenol in the presence of DCC.

In addition, when synthesizing each compound in which R2 of compound (21) is a succinimide group, a phthalimide group, or a 2.4.5-)lichlorophenyl group, compound (20) and N-
Hydroxysuccinimide, N-hydroxyphthalimide or 2.4.5 trichlorophenol, respectively, were added to DC
It is obtained by condensation in the presence of C.

Above, the raw materials are X (CL) 1oX (I4), CH2
=CH(CH2)X (I5) and Y(CH,), 6C
Although the case of O, R' (I7) has been described, by using these raw materials with different numbers of carbon chains, it is possible to obtain ω-acyloxycarboxylic acid derivatives with various numbers of carbon chains.

Moreover, 24-hydroxytetracosane Wj in the case of reaction route 2! (I9) can also be synthesized, for example, according to the following reaction route 3.

Reaction route 3 HO□C(CL) 11cO2H(22) -m-
→R'LC(C)1. ),,C02R'(23)
-1 →) 10 (CL) 1308 (24)
--→)10(CHI)13X (25)
-m-→THPO(CH,),,X (26
)THPO(C)12)! , CD2R' (2B
)+ )In(C)12)23COJ
(I9) (In reaction route 3, R1 represents a lower alkyl group, X represents a halogen atom, and THP represents a tetrahydropyranyl group.) Reaction route 3 will be explained in detail below.

1.13-Dihydroxytridecane (24) is prepared by converting tridecanedioic acid (22) from room temperature to reflux temperature in an alcoholic solvent such as methanol in the presence of an acid catalyst such as sulfuric acid, p-toluenesulfonic acid, or a cation exchange resin. The diester compound (23) is obtained by esterification for 1 to 50 hours, and this compound (23) is heated at -10 to 50°C in a solvent such as diethyl ether, THF, or toluene.
In 30 minutes to 5 hours, Li formula 184, (+-Bu
)28Iff (in the formula, 1-Bu represents an isobutyl group) or the like can be synthesized by reaction in the presence of a reducing agent. Compound (26) is 1,13-dihydroxytridecane (24),! : Compound (25
), and this compound (25) and dihydrobilane are PPT
By reacting at 0°C to room temperature for 30 minutes to 5 hours in the presence of an acid catalyst such as S(p-)pyridinium salt of luenesulfonic acid) in a solvent such as methylene chloride, chloroform, diethyl ether, or benzene. Can be synthesized. Compound(
I9) is a mixture of compound (26) and Grignard reagent prepared from magnesium and compound (27),
Compound (28) is obtained by reacting at -10 to 50°C in the presence of a copper salt catalyst such as CuT, and this ester compound (28) is reacted with NaOH, KOH,
After hydrolysis at room temperature to reflux temperature for 30 minutes to 5 hours in the presence of a base such as t, ioH, etc., acidification with hydrochloric acid etc., and further in the presence of an acid catalyst such as p-)luenesulfonic acid, tetrahydropyranyl It can be synthesized by removing the group.

In the above manner, an ω-acyloxycarboxylic acid derivative represented by the general formula (I) (where R1, R2 and k have the same meanings as above) can be obtained. .

General formula (n) (In the formula, Rs represents a hydrogen atom or a tert-butyldiphenylsilyl group, and l represents an integer of I2 or 14.)
The compound represented by can be synthesized according to the following reaction route 4.

Reaction route 4 11■ NHR” (In reaction route 4, R3 is a hydrogen atom or (Mato IJ (C1
~Ct) represents a hydrocarbon silyl group, R'l--/' represents a rogen-substituted acetyl group, R1 is a trianolmethyl group, )! J (C, -C,) represents a hydrocarbon silyl group or acyl group, R' represents) IJ (C1 to C, +) hydrocarbon silyl group or acyl group, provided that R7 and R@ are the same , R11 represents an acetyl group, and ! represents an integer of 12 or 14. ) Reaction route 4 will be explained in detail below.

Compound (29) was prepared by the method of P. Garner et al.
rg, Chem, .

52, 2361 (I98 Ryo) and J, Org, Ch.
It can be synthesized from L-serine by Em., 53.4395 (I988)).

Compound (30) can be obtained by reacting compound (29) with a halogen-substituted acetylating agent in the presence of pyridine at 0 to 50°C for 10 minutes to 20 hours. Examples of the halogen-substituted acetylating agent include p-nitrophenyl trifluoroacetate, p-nitrophenyl trichloroacetate, trifluoroacetic anhydride, trichloroacetic anhydride, or halogen Wl-converted vinegar 1! Examples include p-nitrophenyl and mono- or dihalogen-substituted acetic anhydrides. If an 0-acetyl compound is produced as a by-product during this N-acetylation, it can be easily converted to compound (30) by treating it with an alkali such as Na01jla, NaOH, or the like. Here, in compound (30), R8 represents an α-halogen-substituted acetyl group, and examples thereof include a trifluoroacetyl group, a trichloroacetyl group, a difluoroacetyl group, a monochloroacetyl group, and the like. Compound (31) is prepared by adding an equivalent or a small excess of triarylmethyl chloride, tri(C, to Ct) hydrocarbon silyl chloride to compound (30) in a solvent such as methylene chloride, chloroform, DMF, or acetonitrile in the presence of an amine. or with acyl chloride at 0 to 50°C for 1 to 2 hours.
Obtained by reacting for several days. As the amine, pyridine, imidazole, DMAP (4-N,N-dimethylaminopyridine), etc. can be used, but the amine itself acts as a solvent, such as pyridine.

Here, in compound (31), R7 represents a triarylmethyl group, a tri(C1-C7)hydrogensilyl group, or an acyl group, and the triarylmethyl group is particularly preferably a triphenylmethyl group; , ~C7) Hydrocarbon silyl groups include those mentioned above, especially t
An ert-butyldiphenylsilyl group is preferred, and examples of the acyl group include a benzoyl group and a pivaloyl group,
Particularly preferred is a benzoyl group. Compound (32) is prepared by combining compound (31) and (C, ~C,) hydrocarbon silyl chloride or acyl chloride in a solvent such as DMF or acetonitrile when R7 is a triarylmethyl group in compound (31). Medium, pyridine, imidazole, DMA
It is obtained by reacting in the presence of an amine such as P at room temperature to 100°C for 1 hour to 2 days. At this time, the amine itself can also be used as a solvent. In addition, when R7 is a tri (C, ~C,) hydrocarbon silyl group, compound (31) and acyl chloride [1? is an acyl group, the compound (31
) and tri(C,-ct) hydrocarbon silyl chloride under the same conditions as above to obtain compound (32). Here, in compound (32), RI' represents a tri (C, ~Ci) hydrocarbon silyl group or an acyl group, but)! Examples of the J(C', ~C'l) hydrocarbon silyl group include those mentioned above, especially tert
A -butyldiphenylsilyl group is preferred, and examples of the acyl group include those mentioned above, with a benzoyl group being particularly preferred. When R7 is a triarylmethyl group in compound (32), compound (33) can be prepared using acetic acid, hydrochloric acid, p-)luenesulfonic acid, Amberlyst-15, or cation exchange in a solvent such as methanol, chloroform, or THF. Under acidic conditions in the presence of resin, etc., at room temperature to 100°C for 30 minutes to 2
Obtained by reacting for several days. Also, R7 is)I
In the case of J(C, ~C?) hydrocarbon silyl group, the same desilylation conditions as in the synthesis of compound (I2) described above, and in the case of R7 being an acyl group, methanol, TH
Compounds (33) are obtained by alkali treatment with Na0CL, NaOH, etc. in a solvent such as F or the like.

In addition, compound (33) is synthesized by compound (32),
When R7 is a triphenylmethyl group, R1 may be removed during the purification process by silica gel column chromatography. Compound (34) is compound (3
Obtained by the glucosylation reaction of 3).

That is, compound (33) and tetra-0-acetyl-α-
D-glucopyranosyl bromide and nitromethane-
In benzene solvent, using mercury cyanide as a catalyst, from room temperature to 1
The compound (
34) is obtained.

Alternatively, compound (33) and tetra-0-acetyl-α
-D-4 Rucobyranosil trichloroacetimidate in a solvent such as methylene chloride or dichloroethane, BF
It is obtained by reaction at -20 to 60°C for 2 to 12 hours using a Lewis acid such as 3.EtzO1^1clff as a catalyst. Compound (n) can be obtained by preparing compound (34) using a conventional method (
For example, it can be obtained by deprotecting the ester and amide moieties by a deacylation reaction using Na0CL, Nako, KOII, etc.). Here, in compound (34),
When R8 is an acyl group, R3 of compound (II) is a hydrogen atom, but when R6 is a (C, ~C,) hydrocarbon silyl group, R3 is )! J(C, ~C,) becomes a hydrocarbon silyl group. In the latter case, if necessary (nBu)
, NF, etc., to convert R3 into a hydrogen atom.

From the above, the compound of general formula (IT) (In the formula, R3 and l have the same meanings as above.

A glucosylated sphingenin derivative represented by can be obtained.

Note that E in compound (n) represents an integer of 12 or 14; however, by using compound (29) as a raw material with a different integer for l, sphingenin derivatives with various numbers of carbon chains can be produced. Glucosylated products of can be synthesized.

Next, a glucosylated product of a sphingenin derivative represented by the general formula (n) (wherein R3 represents a hydrogen atom or a tert-butyldiphenylsilyl group, and l represents an integer of 12 or 14) and a general formula (I ) %Formula %(I) (In the formula, R1 represents a lyle oil group, R2 represents a p-nitrophenyl group, and k represents an integer of 23 or 29.

) The ω-acyloxycarboxylic acid derivative represented by the formula (II[) is subjected to an amidation reaction in the presence of a base, and if necessary, deprotection is performed to obtain the general formula (II[) (wherein, R' has the same meaning as above) , when k is 23, l represents 12, and when k is 29, l represents 14.) A method for producing acyl glucosylceramides represented by the following will be described.

Examples of the base used in this method include pyridine and triethylamine, with pyridine being particularly preferred.

As a solvent, DMSO (dimethylsulfoxy)')
, DMF (dimethylformamide), etc., but pyridine, triethylamine, etc. used as bases can also be used as solvents.

In addition, the reaction temperature was room temperature to 100°C, and the reaction time was 1 to 5.
It can be done in 0 hours.

- Although R3 in formula (n) represents a hydrogen atom or a tert-butyldiphenylsilyl group, the above reaction can also be carried out with a tri(C, -Ci) hydrocarbon silyl group other than the tart-butyldiphenylsilyl group. to! I(C, ~C
, ) hydrocarbon silyl groups include tri(C,~C,)alkylsilyl groups such as trinotylsilyl, triethylsilyl, tertbutyldimethylsilyl groups, tert
- diphenyl (C,
-C,)alkylsilyl group.

Furthermore, although R2 in the compound of formula (I) represents a p-nitrophenyl group, the reaction can be carried out without particular limitation as long as the R2 moiety is an active group in the above-mentioned amidation reaction. However, other than p-nitrophenyl group, for example, succinimide group, phthalimide group or 2,4
．． Examples include 5-trichlorophenyl group.

However, even in the case of ω-acyloxycarboxylic acid in which R2 is a hydrogen atom, the amidation reaction can be carried out in the presence of a condensing agent such as DCC (dicyclohexylcarbodiimide), although the yield is low. Further, at that time, the yield can be improved by coexisting a carboxylic acid activator such as p-nitrophenol, N-hydroxysuccinimide, N-hydroxyphthalimide, 2,45-trichlorophenol, or 1-hydroxybenzotriazole.

This means that in the present invention, the amidation reaction is effectively carried out after isolating the ω-acyloxycarboxylic acid derivative represented by the general formula (I), but it is clear that the same effect is obtained. show.

In the present invention, - a compound of the formula (II) where 1 is 12 and a compound of the general formula (I) where k is 23;
) is reacted with a compound in which 1 is 14 and a compound in general formula (I) in which k is 29, - formula (I[I) in which 1 is 12 and k is 2.
A compound with l=14 and a compound with k=29 were obtained. The former compound is a glycolipid whose presence in the epidermis of guinea pigs has been reported (Japan, J, BXP
, Med.

58.153 (I988)>, the latter compound is a glycolipid isolated from normal human skin and whose structure was determined by Hamanaka et al. (J. Bincham, 105.684 (I9
89)) have effects such as physiological activity, and both are expected to have further effects such as physiological activity, and are industrially useful compounds that can be applied to cosmetics and the like.

Here, in the compound of formula (I), R1 represents a lyle oil group, but the same applies to other compounds in which R' is a hydrogen atom, valmitoyl group, oleoyl group, or stearoyl group, as in the case where R1 is a lyle oil group. was synthesized.

In the epidermal cell layer of mammals, there are not only compounds with linoleic acid attached to the terminals such as the compound of general formula (III), but also compounds with ester bonds of other fatty acids. There are also some that are not.

Therefore, compounds in which R1 in the formula (II[>) is a hydrogen atom, a valmitoyl group, an oleoyl group, or a stearoyl group are also expected to have various physiological activities and are useful compounds.

Also, when k of the compound of formula ([[) is 23, l is 12
, and when k is 29, l is 14, but these compounds with this number of carbon chains are not the only ones present in the epidermal cell layer of mammals, and compounds with various numbers of carbon chains are mixed.

Compounds having various numbers of carbon chains can be synthesized in the same manner as in the present invention by simply changing the raw materials.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. In addition,
The following examples of equipment and methods for mass vector non-measurement,
The conditions are as follows.

Example 9: Hitachi M-80B (manufactured by Hitachi, Ltd.) EIMS method, direct introduction method, ionization voltage 20 eV Examples 14 to 16: Hitachi M-4000 (manufactured by Hitachi, Ltd.) (-) SIMS method, Triethylenetetramine-(m-nitrobenzyl alcohol) 1:1 (capacity ratio) Accelerating voltage 10 kV Examples 32, 33: JEOL JMS DX303 (manufactured by JEOL Ltd.) (-) or (+) FABMS method m-nitro Benzyl alcohol accelerating voltage 3kV Example I TBDPSO(CH-)1sBr (
Synthesis of 1-bromo-15-(tert-butyldiphenylsilyloxy)pentadecane (35): 10.0 g (41.6 mma+) of cyclobentadecanolide was dissolved in 400 d of methanol. Dissolved in p-)luenesulfonic acid 0.
3 g was added and refluxed for 24 hours. Add this solution to 400 rt of water.
Extract (400 ml x z times) with a mixed solvent of beef sanitation and ethyl acetate (volume ratio 5:1) into a TL, wash the extract with saturated aqueous soap, then with saturated saline, dry over anhydrous sodium sulfate, and remove the solvent. was distilled off to obtain 12.3 g of crude methyl 15-hydroxypentadecanoate.

This crude methyl 15-hydroxypentadecanoate 7,0
g Wotert-butyldiphenylsilyl chloride 1
3.0 g (47,3+nmol) and imidazole 3
．． 23 g (47,3 mmol) with DMF 50
- Stirred at medium room temperature for 17 hours. Add this solution to 1N-HCl
Pour into 500ml of aqueous solution and extract with 400ml of hexane-ethyl acetate (volume ratio: 5:1) mixed bath M.The extract is washed twice with water and then with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off. Remove coarse 15- (te
19.7 g of methyl rt-butyldiphenylsilyloxy)pentadecanoate was obtained.

19.7 g of this crude methyl 5-(tart-butyldiphenylsilyloxy)pentadecanoate was dried in TH
F (40ad solution and Li^IL0.86g (22,
7 mmol) of dry THF (45d) solution was added dropwise at 0° C. while stirring in the hollow, and the solution was further stirred for 6 hours to raise the temperature of the solution to room temperature. This solution was poured into an ice-cooled 1N-HCl aqueous solution (300ml) and extracted with 300ml of diethyl ether.The extract was washed with water, saturated aqueous sodium chloride, and saturated saline, and dried over anhydrous sulfuric acid. The solvent was distilled off to obtain 1.9.7 g of crude 15-Dart-butyldiphenylsilyloxy)pentadecanol.

This was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 12.3 g of 15-(tart-butyldiphenylsilyloxy)pentadecanol.

This 15-(tert-butyldiphenylsilyloxy)pentadecanol 12.3g (23.60mol)
and carbon tetrabromide 11.0 g (33.2 mmol) were dissolved in acetonitrile 150-, and to this was added triphenylphosphine 8.7 g (33.2 mmol) at 0°C, stirred for 1.5 hours, and then further stirred at room temperature. Stirred for 25 hours. Pentane 100- was added to this solution and left to stand for 12 hours, followed by extraction with pentane (I00 dX 4 times), the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 16.3 g of a crude product. This was purified by silica gel column chromatography (hexane-ethyl acetate), and 1-
Bromo-15-(tert-butyldiphenylsilyloxy)pentadecane (hereinafter referred to as compound (35))
1.5 g (yield from cyclobentadecalide 89.
2%) was obtained.

Rf = 0.78 (hexane: ethyl acetate = 5: 1 (
Capacity ratio)) nP=1.5230'HNMR (I00MHz, CDC1,, δ)
: 1.0? (s, 9H.

(Ctl-)-C), 1.30 (br s,
24) 1), 1,87 (brt2H,J=
7Hz, )1. C(I4)), 3.42 (
t, 2H, J=7HzH, C(I)), 3.6
7 (t, 2H, J=6Hz, H, C(I5
)).

7.25~7.85 (m, 108.ρhx
2) IR (neat, cm-'): 3075
．． 3050°2930, 2860. 1590.
1460°1430, 1110. 700 Example 2 0HC(CH2),,CD,CH314-
Synthesis of methyl formyltetradecanoate (36): 1.0 g of crude methyl 15-hydroxypentadecanoate obtained in Example 1 was added to 58 g of PCCL (7J4alIno
1) and four powdered molecular sieves were added to a solution of 1.84 g of dry methylene chloride (I5d) and stirred at room temperature for 20 minutes. This solution was decanted three times with 50 parts of diethyl ether, filtered through silica gel, and the solvent was distilled off to obtain 79.9 parts of a crude product. This was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 70.7 ml of methyl 14-formyltetradecanoate (hereinafter referred to as compound (36)) (yield 77.4%).

m, p, = 27-29°C Rf = 0.33 (ethyl hexane diacetate = 5; 1 (volume ratio)) 'HNMR (I00MHz, CDCl5. δ)
+ 1.29 (br s.

18tl), 1.60 (m, 48.H2C(3
), H-C(I3)).

2JO(t, 2)l, J=7Hz, HzC(2)
), 2.42 (dt.

2H, J=7tlz, J=2Hz, LC(I4))
, 3.68 (s, 3H, C02CL), 9.7
8 D, IHJ=2Hz, CHD)I R(CHC
+, solution, Cl1l-'): 2950°28
80.2750, 1730.14601440.117
0 Elemental analysis ClsL. 0. : Calculated value (%) C near LO7,H: 11.18 Actual value (%) C near 0.89. H:1117 Example 3
TBDPSO(CL),C)I=CH(CH2)
1scOacL3 Q-(tert-butyldiphenylsilyloxy)-15-)methyl liacontinate (3
Synthesis of 7): Compound (35) 2.0 g (3,67
mmol> and triphenylphosphine 101 g (3
, 85111 mol) at 120° C. for 12 hours to prepare a phosphonium salt. To this ^r under air flow, 100℃
After adding 20rr11 of dry THF and dissolving the salt,
2.32 ml of n-butyllithium under cooling at -30°C (
3.67 mmol.

1.58M) was added under stirring, and the mixture was further stirred at room temperature for 30 minutes. Then, cooled again to -30°C, compound (36)
0.70 g (2,58 mmn1> dry ffiTH
F (7 ml of solution was soaked under stirring and stirred for 30 minutes, then poured into ice-cooled saturated ammonium chloride water (50°C), extracted with diethyl ether (50ml x 3 times),
This extract was washed twice with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 3.27 g of a crude product. This was subjected to silica gel column chromatography (benza:/) tJIII L 30- (tart-butyldiphenylsilyloxy-15-methyl triacontinate (hereinafter referred to as compound (37)) to obtain 1.42 g (yield 7).
6.5%) was obtained.

Rf = 0.67 (hexane: ethyl acetate = 5 = 1 (volume ratio)) n = 1.4994 HNMR (I00MHz, CDCl5. δ
): 1.08 (s, 9) 1゜(C
H3)3C), IJO(br s, 46H)
, 2.00 (m, 4H, HiC(I4),
H, C (I7)), 2.31 (t, 2
H, J・7Hz.

H-C(2)), 3.66 (t, 2H, J=6
Hz, 82C(30)).

3.69 (s, 3H, C02CHi), 5
．． 36 (t, 211. J=5Hz, I
l[:(I5), HC(I6)), ? , 30
~7.85 (m, 101, phX2) IR (neat, cm-'): 3080. 3
060°3010, 2940. 2870. 1,7
45°1650, 1590. 1460. 1430
゜1110, 740. 700 Elemental Analysis C1Ja. O-, Si: Calculated value (%) C near 8.49. H: 10.93 Actual value (%) C near 8.36. H:LL, 06 Example 4
TBDPSO(CHa) 2scO2cHs30
- Synthesis of methyl (tert-butyldiphenylsilyloxy)triacontanoate (38) Compound (37) 2
00x (0,2?8 mmol) in 10%-Pb/C
Hydrogenation was carried out by stirring in 5 d of ethyl acetate at room temperature for 24 hours in the presence of 10 ml of ethyl acetate. The catalyst in this solution was filtered through Celite and the solvent was distilled off to obtain 196 ml of crude product. This was purified by silica gel column chromatography (hexane-ethyl acetate) to produce methyl 30-(tert-butyldiphenylsilyloxy)triacontanoate (hereinafter the compound (
38)) was obtained in an amount of 181 cm (yield 90.4%).

m, p, = 62-63°C Rf = 0.67 (hexane: ethyl acetate-5 = 1 (volume ratio)) 'HNMR (I, 00 MHz, COCl5.
δ): 1.07 (s, 9)
1゜(CHs)sC), 1.31 (brs, 54
．． H), 2J2 (t, 2N.

J=7Hz, LC(2)), 3.67 (t, 2
H, J=6Hz, H-C(30)), 3.69 (s
, 3[1,C02CH3), 7.30-7,85
(+n, 10)1. ph X 2) I R(C
HCI, solution, cm-'): 3090°3025.
2950, 2880.1730゜1590.1465,
1430,111.0゜Elemental analysis C=-H-,03
Si Calculated value (%) C near 8.27. H: 1.1.18 Actual value (%) C near &27. H:1.1.25 Example 5 7BDPSO(CH2)2. CD, [:H330
Synthesis of methyl -(tert-butyldiphenylsilyloxy)triacontanoate (38): 3.26 g of crude methyl 15-hydroxypentadecanoate synthesized in Example 1
(I1.0 mmol) was dissolved in 10 d of pyridine, and 3.15 ml of p-)luenesulfonic acid chloride was added to the solution under water cooling.
g (I6,5mmo+) was added and stirred for 30 minutes, and then stirred at room temperature for 2 hours. This solution was cooled with 5%-H,S.
O.

Pour into aqueous solution 100- and extract with ethyl acetate (I00I
Ij! The extract was washed with water, saturated sodium chloride water, and then saturated brine, dried over anhydrous sulfuric acid, and the solvent was distilled off to obtain 4.39 g of a crude product. This was recrystallized with 80 volumes of a mixed solvent of pentane-diethyl ether (volume ratio 5:3) to obtain 4.04 g (yield: 86.0%) of methyl 15-)siloxypentadecanoate.

^ “Under air flow, 0.50 g of methyl 15-tosyloxypentadecanoate synthesized as above (I, 1,7 mm
ol) in dry diethyl ether (30 mf).
, CuCl4 (0.1M-THF, 0.12++Ll
Compound (35) 1 synthesized in Example 1
．． 28g (2.35mmol), MgO,07
g (2,88 mmol) and dry diethyl ether 2
The Grignard reagent solution prepared from 01R1 was heated to -60~
The mixture was added dropwise over 20 minutes while stirring at -65°C, and then the temperature was returned to room temperature over 4 hours, followed by stirring for 10 hours. This solution was mixed with I N -H*SO, aqueous solution 50 ai! Pour into a glass of water and extract with diethyl ether (501IIj! x 2 times).
The extract was washed with water and saturated brine (twice), dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain the crude product 1.
57 g was obtained. This was purified by silica gel column chromatography (benzene).
93.7 ml of methyl butyldiphenylsilyloxy)triacontanoate (38) was obtained (yield: 11.1%).

Example 6 TBDPSO(CH2)2sCO,H3
Synthesis of 0-(tert-butyldiphenylsilyloxy)triacontanoic acid (39): Compound (38) 1.19 g (I, 65 mmol)
85.5% in 95% ethanol 25d
(I, 98 mn+ol) at 60° C. for 2.5 hours. After half of the ethanol in this solution was distilled off, 20-diethyl ether was added, and under water cooling, the 1N-HCl aqueous solution was adjusted to pH 1.
Add dropwise until
The extract was washed twice with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off to obtain 16 g of crude product L. This was purified by silica gel column chromatography (chloroform-methanol) and
- (tert-butyldiphenylsilyloxy)triacontanoic acid (hereinafter referred to as compound (39)) at 1.01
g (yield 85.8%) was obtained.

m, p, = 63-65°C R, f = 0.21 (hexane: ethyl acetate = 5:1 (volume ratio)) 'HNMR (I00 klHz, COCl3.
6): 1.06 (s, 9H.

(CL)3C), 1.27 (brs, 54
H), 2.35 D, 21°J-7Hz,
H, C(2)), 3.65 (t, 2iL
J=6Hz, 82C(30)), 7.3(
I ~ 7.75 (m, ], Of (, pH x 2) I
R (r, cm-') + 3300
~2500°3075, 3025. 2925.
28601?1.0. 1,590. 1470. 1
430゜11.10.700 Elemental analysis C,6H,,03Si: Calculated value (%)
C Near 8.1.2. H: 11.12 actual value (%)
C Near 7.82. H:1.1.1830- (tert
-butyldiphenylsilyluoquine) triacontanic acid p
-Synthesis of nitrophenyl (40): Compound (39) 599 mg (0.84 Tmmol) and p-nitrophenyl trifluoroacetate 398 μ (L 6
9 mmol) was stirred in pyridine 8d at room temperature for 1.5 hours. This solution was ice-cooled IN-)IC+aqueous solution 100
Pour into a bar and extract with diethyl ether (I00mfx twice), wash this extract with water and saturated brine, dry with anhydrous sulfuric acid), dry over IJum, and distill off the solvent to obtain crude product 891. . This was purified by silica gel column chromatography (chloroform) and 30-(tert-
butyldiphenylsilyloxy)triacontanic acid p-
Nitrophenyl (hereinafter referred to as compound (40)) at 671
(2) (yield 95.3%) was obtained.

m, p, = 65 to 67°C Rf = 0.63 (hexane: ethyl acetate = 5 = 1 (volume ratio)) IHNMR (I00Mflz, CDC1, δ)
: 1.06 (s, 9H.

(CH=)-C), 127 (brs, 52H),
1.72 (m, 2H.

H2C(3)), 2.60 (t, 2H, J=7H
z, LC(2)).

3.65 (t, 2)1. J=6Hz, H2C(
30)), 7.27 (d.

2L J=9Hz, o-2)1), 7.30~? ,
BO(+n, 10t(.

ph X 2), 8.27 (d, 21L J=9
Hz, II+-28) IR (KBr, cab-'):
3080.3050°2940.2860.1?6
0,1615°1590.1520,1470,134
0°50°1.215. 1], 10. 8 Elemental analysis C==HslNOsSI Calculated value (%) C near 5.4 N: L 6 9 Actual value (%) C near 5.36. H N: 1.6 7 H: Ol 9.88 Synthesis of p-nitrophenyl 30-hydroxytriacontanate (41): Compound (40) 634u (0,762 mmol) was mixed with A
Chloroform 307 under r air flow! Dissolve in water and cool at 47%
-1]F, 4.0 mg of 0Bta was added dropwise, and the mixture was stirred at room temperature for 28 hours. This solution was cooled with ice-cold saturated deuterated water 5
00 solution and extracted with chloroform (I50afx3
After washing this extract with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off and further purified by silica gel column chromatography (chloroform) to obtain white crystals of 30-hydroxytriacontanoic acid p-nitrochloride. 396 ml of phenyl (hereinafter referred to as compound (41)) was obtained (yield: 88.1%).

m, p, = 106 ~ 108 ° C. Rf = 0.14 (hexane: ethyl acetate = 5: l (volume ratio)) HNMR (I00 MHz, COCl5. δ)
: 128 (brs.

52)1), 1.72 (m, 2t(, H2C(3
)), 2.60 ct.

2H, J=HIz, LC(2)), 3.65 (t
, 2H,J: 6Hz.

H, C(30)), 7.27 (d, 2H, J=9
Hz, o-2)1).

8.27 (d, 2N, J=9Hz, m-2H)
IR (KBr, cm-'): 3425.2925°2860.1?55,1,615,1590°1535
．． 1470.1350.1,200゜1140.850 Elemental analysis Cs5L-NO-: Calculated value (%) C near 3.30. H: 10.77N
: 2.37 Actual value (%) C: T3.04. H: 10.59N
: 2.31 Synthesis of p-nitrophenyl 30-lyloyloxytriacontanoate (42): Compound (4), > 300 ■(0,509111+0
01) of dry methylene chloride (40d)-pyridine (2d
) to a mixed solution of linoleic acid chloride 304■ (LO2
(1 mol) was added to the solution under stirring and stirred at room temperature for 5 hours. This solution was ice-cooled IN-)IC+aqueous solution 40++d! This was extracted with chloroform (50 dXa times), and the extract was washed with saturated brine, dried over anhydrous sulfuric acid, and then the solvent was distilled off to obtain 643 ml of crude product.

This was purified by silica gel column chromatography (chloroform) to form a white wax-like p-nitrophenyl 30-lyloyloxytriacontanoate (hereinafter the compound (
42)) was obtained in an amount of 356 cm (yield: 82.1%).

s, p, = 69 to 70°C Rf = 0.63 (hexane: ethyl acetate = 5:1 (volume ratio)) HNMR (I00MHz, CDC1,, δ)
: 0.88 (t, 3tl, J=
6Hz, LC (I8'>), 1.30 (brs
, 66tl).

1.70 (m, 4H,H,C(3), 82C(
3')), 2. [11(m, 4ft, H,C
(8'>, )I-C(I4')), 2.29(
t, 2H, J=7tlz, Il, C(2')),
2.60 (t, 2B.

7Hz, 82C (2>), 2.77 (m, 2N
, f12C(I,1')).

4.06 (t, 2H, J-6Hz, H2C(30
)), 5.35 (m.

4H, HC(9'), )IC(I0'), IC
(I2'>, nc(I3')), 7.27 (
d, 2H, J=9Hz, o-28).

8.27 (d, 2tl, J=9Hz, m-28
) I R (CtlCIs solution, cm-'): 302
0°2940.2870,1760,1725°161
5.1595.1530.1470゜1350.119
0.1160,1135゜1110.865 Elemental analysis Cs4HssOsN: Calculated value (%) C near 6, lO, H: 11.0ON
: 1.64 Actual value (%) C near 5.21. H: 10.77N
: 1.5 9 (Regarding the elemental analysis value, the best value is shown because the olefin part of the lyluoyl group of compound (42) is very unstable and difficult to measure.) MS (m/e): 8
21 CM-30 (NO> )”712 CM-139
<p-nitrophenol)]1 11M (23,3R,4E)-N-trichloroacetyl-C3
Synthesis of °-sphingosine (43): (2S, 3R, 4
E) -C,,-sphingosine 1.00 g (3,0
Dissolve 6a + mol) in 20d of dry methylene chloride, add 0.8-pyridine, and add 92.83 g of anhydrous trichlorovine vinegar.
(9.17ml1al) was added dropwise and stirred at room temperature for 15 hours. This solution was poured into 100 bottles of an ice-cooled 0.1N-11cI aqueous solution and extracted with diethyl ether (I00
7! x2 times) and 100m of water! ! , washed with 50 mf of saturated NaHCO-aqueous solution and 50,000 mf of saline solution, and washed with anhydrous Na
After drying with 2SO4, the solvent was distilled off under reduced pressure to obtain a crude product 2.
24 g was obtained.

This was dissolved in a mixed solvent of THF (20mE) and methanol (30mE), and 28%-NaOMe methanol solution 0.0% was heated at room temperature. 0.9 g (0.46 mmol) was added dropwise and stirred for 30 minutes. This solution was poured into 100% water and then extracted with diethyl ether (I00dx2 times)
After washing with 50 d of saturated brine, the solvent was distilled off under reduced pressure to obtain a crystalline crude product 1. 51 g was obtained.

This was mixed with 36ml of hexane-ethyl acetate (volume ratio 5:1)! Recrystallize white crystals (2S, 3R.4
E)-N-)Chloroacetyl-02. -Sphingosine (hereinafter referred to as compound (43)) in 1. 2 2 g was obtained. Recrystallization was performed again in the same manner from this mother liquor to obtain the compound (43
) to 0. 12 g was obtained, total 1.34 g (yield 92.
7%).

m. p. =85~86℃ Rf=0.17 (hexane:ethyl acetate=2:1 (volume ratio)) [α] C'=+5.0° (C=1.1 6.CHC
l,)'HNMR (I00MHz, CDCl3
．． δ): 0.88 (t, 3H, J
=6Hz, H=C(20)), 1.27 (br
s, 26H).

2.03 (brt, 2H, J=6Hz, 82C
(6)), 2.25(brt, 2H,2XOH
), 3.77 (dd, 1)1. J=1
1Hz, J=3Hz, HC(I)), 3.90
(rD, IL HC(2)).

4. 13 (dd, IH, J=11Hz, J=
3Hz, HC(I)).

4. 43 (brt, 1B, J=6Hz,
HC(3)), 5.55(dd, LH,J
=16Hz, J=6Hz, )IC(4)), 5
．． 87 (dt, IH, J=16flz, J=6
Hz, HC(5)), 7.50(brd,
IH, J=6Hz, NH)IR(CHCl, solution, cm-'): 3620°3450, 3430.
3020. 294.0°2860, 1710.
1510. 1465°1045, 970. 820 Elemental analysis C22H-8NOsC]s: Calculated value (%
') C: 55.87. H: 8.53N: 2
．． 9 6 Actual value (%) C: 56.17. H: 8.55N
: 2.9 8 (In the formula, Tr represents a trityl group) (25,3R,4E)-N-trichloroacetyl Jl/-
1-0-) Lythyl-02゜-sphingosine (44) synthesis co-compound (43) LOOg (2.11 mmol) and triphenylchloromethane 0.71 g (2.54 m
+nol) was dissolved in 10 d of dry methylene chloride, 0.34 g of pyridine was added, and the mixture was stirred under reflux for 19 hours. This solution was poured into 100 M of water and extracted with diethyl ether (
I00dx 3 times), and the extract was diluted with 50d of saturated saline.
After washing with and drying with anhydrous Na25O-, the solvent was distilled off under reduced pressure to obtain 1.73 g of a crude product.

This was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 5:1 (volume ratio)) to obtain a colorless oil (2S, 3R).

4E) -N-trichloroacetyl-1-〇-trityl-C2゜-sphingosine (hereinafter referred to as compound (44))
1.31 g (yield: 86.4%) was obtained.

n:=1.5340 Rf=0.39 (hexane:ethyl acetate-5=1 (volume ratio)) [α]ε'=+5.7° (C=1.47, CH
Cl3)HNMR(I00M)lz, CDCl3.
δ): 0.89 (t, 3H, J=6H
2, H3C (20)), 1.30 (brs, 26
H).

1.90 (brt, 2H, J=6H2,)12C(
6)), 2.66(d, 1)1. J=BHz,
OH), 3.43 (m, 2H, HaC(I)),
3.96 (m, IH, HC(2)), 4JO(b
rq.

LH, J=6Hz, )IC(3), 5.25 (d
d, IH, J=16tlz, J=6Hz, HC(
4)), 5.73 (dt, LH, J=16Hz.

J=6Hz, HC(5), 7.05-7.55
(m, 15L 3Xph), 7.56 (d, 1
)1. J=8Hz, NH)IR(film, (:O
l-'): 3500.3430°3070.304
0,2930.2860°1710.1595,151
0,1490°1450.1220,1090.970
゜900, 820. 745. 705 Elemental analysis C41H,, N03C1a: Calculated value (%
) C:68.85. H near, 6N: 19
6 Actual value (%) C: 69.24. H near, 3N:
1.9 2 (In the formula, TBDPS represents a tert-butyldiphenylsilyl group) (2S, 3R, 4E)-3-〇-(tert-butyldiphenylsilyl)-N-trichloroacetyl-CaO-
Synthesis of sphingosine (45): Compound (44) 2.3
6 g (3,30meal), tart-butyldiphenylsilyl chloride 4.53 g (I6,5m
aIal) and imidazole 1.12 g (I6,5a
imol) in DMF 35ial! Dissolved in 100
The mixture was stirred at ℃ for 44 hours. This solution was water-cooled with 1N-HC.
After pouring into 150 liters of aqueous solution, extract with diethyl ether (I00 mj! x 2 times), and add this extract to 90 liters of water.
, saturated NaHCD, aqueous solution 70 - then saturated saline 80
Wash with water and anhydrous Na25O.

After drying with
)-3-〇-(tert-butylschiff ni'-lucilyl)-N-)lichloroacetyl-1-〇-trityl-C
6.06 g of 3°-sphingosine was obtained.

127u (0,069mmol) of this crude product was mixed with methanol 6+al! Dissolved in p-toluenesulfonic acid l
Six inches of hydrate was added, and the mixture was stirred at room temperature for 2 hours. This solution was poured into 30ml of water and extracted with diethyl ether (3ml).
The residue was washed with 30 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 129 ml of a crude product. This was subjected to silica gel column chromatography (hexane: ethyl acetate = 20:1 → 5:1 (
A colorless oil (2S,
3R,4E) -3-〇-(tertbutyldiphenylsilyl)-N-trichloroacetyl-C2G-sphingosine (hereinafter referred to as compound (45)) at 36.9
(2) (yield 75.1% from compound (44)) was obtained.

n:5=1.5194 Rf=0.29 (hexane:ethyl acetate-5:1 (volume ratio)) [α]'? ,'--17.6° (C=1.22,
ClCl5)HNMR (90MHz, CDC
1,, δ): 0.88 (t, 31
tJ=6Hz, )13C(20)), 1.09 (
s, 9H, ((:f13)-C).

1. 29 (brs, 26H), 1.80 (m
, 2B, H, C (6)).

2.38 (brs, LH, O old, 3.62
(dd, IH, J=11Hz, J=3Hz,
HC(I)), 3.83 (m, IH,HC(2)
).

4.04 (dd, IH, JlIHz, J=3Hz
, HC(I,)).

4.35 (brt, IL J=6)1z, HC(
3)), 5.15-5.60 (m, 2H, HC(
4)=C(5)H), 7.20-7.85(m, I
IL 2x ph, NH) IR (film, c+n-
'): 3500.3420°30?0.3050.
2930, 2850° 1710.1585, 1510.
14.60°1425, 1110. 1050. ,
970°820, 735. 700 Elemental analysis C5e) IsaNOsCIsSi: Calculated value (%) C: 64.16. H:8.22N:
L 9 7 Actual value (%) C: 64.25. H:8.19N
: 1.9 1 Example 13 (In the formula, 8C represents an acetyl group) (2S, 3R, 4E)-3-0-(tert-butyldiphenylsilyl)-1-0-(tetra-〇-acetyl Synthesis of β-D-glucopyranosyl)-N-trichloroacetyl-C7°-sphingosine (46): Compound (45) 197 g (2,77ffimol
> in a mixed solvent of benzene-nitromethane (volume ratio 1:1) 180-, and the remaining amount is reduced to 4 by heating the solvent at normal pressure.
It was distilled down to 5mf. This solution was cooled to room temperature under a stream of air, and 2.27 g of tetra-O-acetyl α-D-glucobylanosylupromide (5,53++++no
l) and mercury cyanide 1.40 g (5.53 mmol>
was added, and the mixture was stirred at 80°C for 1 hour. Furthermore, Tetra-O
-acetyl-α-D glucobylanosylbropro 0.5
7g (I, 38vno+) was added and stirred for 20 minutes to eliminate compound (45). This solution was cooled to room temperature, diluted with 300 d of diethyl ether, and then diluted with 50 d of saturated hydrogen sulfide water.
The black precipitate of mercury sulfide was filtered through Celite.

Extract the aqueous layer with diethyl ether (400IILi! x 2
times) and 500ml of saturated heavy water! Then saturated saline solution 5
After washing with 00ml and drying with anhydrous NazsOa, the solvent was distilled off under reduced pressure to obtain 4.45 g of a crude product. This was purified by silica gel column chromatography (benzene:ethyl acetate = 10:1 (volume ratio)) to obtain a highly viscous colorless oil (2S, 3R, 4E) -3-0-(te
2.04 g of rt-butyldiphenylsilyl)-1-0-(te)cy0-acetyl-β-D-gulfpyranosyl>-N-trichloroacetyl-C20-sphincosine (hereinafter referred to as compound (46)) (yield 70. 7%) obtained.

no' = 1.494.6 R, f = 0.49 (hexane: ethyl acetate - 2:1 (volume ratio)) [α] g' = 13.5° (C = 1.07,
CHCl, )HNMR (I00MHz, CDCl,
, δ): 0.8B (t, 31J=6H
z, 1l-C(30)), 1. ．． 06 (s, 9
H, (Ctl, ), C).

1.28 (br s, 26H), 1.68 (L
n, 2H,)I-C(6)).

1.98 (s, 3H, -CO-CH,), 2.0
3 (s, 3H, -CO-11:M3), 2.0
5 (s, 6)1. 2x -CD-("H,)
, 3.50-4.40 (m, 7H),
4.48 (d, Iff, J=8Hz,
Anomeric H), 4.80-5.40 (m
, 5H), 6.76 (d.

IH, J=BHz, NH), 7JO~7.80 (
m, IOH, 2X ph) IR (film, cm-'): 3430.
30803050.2930.2870.1755゜1
720 1590.15] 0.1460°1430,
1365. 1225. 117011.10. 1
045. 970. 820°740, 705 Elemental analysis [:5JtsNO1zCisS+: Calculated value (%) C: 59.96. H near, 36N:
1.3 5 Actual value (%) C: 60.26. H near, 25N
: 1.3 2 Example 14 Synthesis of (2S, 3R, 4E)-1-0-(β-D-glucopyranosyl)-3-〇-(tert-butyldiphenylsilyl)-〇2o-sphingosine (47): Compound (46) 88.7 mg (0,085 mmo
l) in THF (4,3mf)-methanol (2,1d)
4.3 d of IN-KOH aqueous solution was added dropwise while stirring at room temperature, and the mixture was stirred for 19 hours. This solution was neutralized with about 4.0 d of IN-) ICI aqueous solution under water cooling, and then mixed with 50 rnl of chloroform, 20 ml of methanol, and 25 ml of water.
1d! was added and extracted. The aqueous layer was further extracted with chloroform (50 m7! x 2 times), the combined organic layers were dried over anhydrous ia*so<, and the solvent was distilled off under reduced pressure to obtain 1.15.6 ml of crude product. This was subjected to silica gel column chromatography (chloroform:methanol = 10:1).
(volume ratio)) to produce a highly viscous colorless oil (2S, 3
R.

4E)-1-0-(β-D-glucopyranosyl)-3-
0-(tert-butyldiphenylsilyl)-C2O-
55. Sphingosine (hereinafter referred to as compound (47)).
0■ (yield 88.7%) was obtained.

na'=t, 3298 Rf=0.41 (chloroform:methanol=5:1
(Capacity ratio)) Ccr]B”=-24,4° (C=1.42,
CHCl.

'HNMR(I00Mflz, CDCl5-C
D-00(44), δ): 0.85 (
t, 3H, J=6Hz, H, C (20)),
0.93 (s98, (CH,)-C),
1.15 (brs, 26H),
1.65 (m, 2H, LC(5) >, 2.8
7 (m, IH, HC(2>).

3.00-3.90 (m, 10H), 4.
．． 04 (d, IH, J=8Hz Anomeric H), 4. ．． 90-5.35 (m,
2)1. IC(4)=C(5)H), 7.1
(I~7.70 ([11,IOH,2Xρh) IR (film, cm-'): 3370
．． 3350°3080, 3050. 3020.
29302860, 1590. 1,465. 14
30°1160, 1110. 1070. 970°760, TOO Elemental analysis c<2Ls)lLsi・3/4)120 Calculated value (%) C:68.022, H:9.5
82N + 1 889 Actual value (%) C: 68.206, H: 9.3
32N + 1.913 M5 (m/e): 7 2 6 [:M-
H] Example 15 (In the formula, R1 represents a lyloyl group) (2S, 3R, 4E)-1-〇-(β-D-glucopyranosyl)-N-(30'-lyloyloxy)triacontanoyl- Synthesis of 3-〇(tert-butyldiphenylsilyl) C2o-sphingosine (48): Compound (47) 77.2 mg (0,106 mmo
l) and p-nitrophenyl 30-lyloyloxytriancotanoate (42) synthesized in Example 9 107.6
mg (I, 27 mmol) was dissolved in 2.3 bottles of pyridine and stirred at 45°C for 21 hours. Benzene 5 in this solution
The pyridine was removed by adding 0- and decomposing the mixture under reduced pressure three times to obtain 188.7 quartz of a crude product. This was purified by silica gel column chromatography (chloroform:methanol = 20+1 → 10:1 (volume ratio)) and a highly viscous colorless oil (2S, 3R, 4E)-1-0-<B-D
-glucopyranosyl)-N-(30'-lyloyloxy)triacontanoyl-3-0(tert-butyldiphenylsilyl)-C,,-sphingosine (hereinafter referred to as compound (48)) at 127.7μ (yield 83.7%
)Obtained.

ng'=1.4974 Rf=0.38 (chloroform:methanol-9=1
(capacity ratio)) [α) g”−25,0° (C= 2.34,
CHCl, )'HNMR (I, OOMHz, CDC
I=-CD30D (4:1), δ): 0.75 (b
rt, 6H, J=6tlz, 2XCH3), 0.9
1 (s.

9N, (CHa)=C), 1.17 (brs,
96H), 1.88 (01,8H,)I2CCON
, 3XH2C-C=C), 2.17 (t2H,
J4Hz, flacfl-), 2.63 (br
t, 2H, J=6Hz, C=C-Ctl--C=C
), 3.00-4.05 (m, 1Ofl).

4.10 (d, 1)1. J=8Hz,
D-j Ripku H), 5.00-5.40 (m,
6N, 6xHC=(:), 7.10~7.70
(m.

10H, 2x ph) IR (film, c+++-'): 3360,30
80°3050, 3030. 2940. 2870
゜1740, 1650. 1590. 1540°1
470, 1430. 1165. 1110°108
0,970. 705 Elemental Analysis Cs. Hl,? N01-3+ ・2'A
tl-0: Calculated value (%) C near 2.727,
H: 10.986N: 0.942 Actual value (%) C near 2,708, H: 10
．． 651N: 0.951 M5 (m/e): L 4 3 8
CM-HE Example 16 Synthesis of (2S,3R,4E)-1-〇-(β-D-glucopyranosyl)-N-(30'-lyloyloxy)triacontanoyl-C2G-sphingosine (49): Compound (48) 97.7 ■(0,068+nmol
) dried T HF 3.4 IILf! 1.0M-tetra-n-butylammonium=
THF solution of fluoride 0.34 mi! (0,34
+n+++ol) was added dropwise and stirred for 8 hours. The operation of adding 10 d of chloroform to this solution and co-evaporating it under reduced pressure was repeated three times to distill off THF, and the total volume was concentrated to 1/10.

This was subjected to silica gel column chromatography (chloroform:methanol = 20:1 → 10:1 (volume ratio)).
It was purified with white crystals (2S).

3R,4E)-1-0-(β-D-glucopyranosyl)
-N-(30'-lyloyloxy)triacontanoyl 〇. - Sphingosine (49) 74.2■ (
Yield: 90.9%).

m, p, = 122-125°C R, f = 0.58 (chloroform:methanol-5:1
(Capacity ratio)
l, -CH,OH (capacity ratio 9:1)) HNMR (400 MIIz, CDC1, -CD
, OD (421), δ ) 20, 88
(m, 6H, 2xCH-), 1.30 (brs,
90H).

1.62 (a, 6H, H2C(3'),
H, C(29'), )1. c(3')),
2.03 (m, 6H,H,C(6),
H, C (8').

LC(I4')), 2.17 (t, 2H
, J=7.6Hz, H-C(2')), 2.
30 (t, 2N, J=7.5Hz, L
C(2')).

2.77 (t, 2H, LC(I1')),
3.26 (t, ill.

J=7.8Hz, HC(2''')), 3.29
(m, LH, HC(5”>), 3.36
~3.4.5 (m, 2H, HC(3″′).

HC(ji)), 3.60 (dd, it(,
J=10.2Hz, J-3,3Hz, IIC(
I)), 3.72 (dd, LH, J=12
．． 0Hz.

J=5JHz, HC(6”)), 3.87
(dd, 18. J=12.0Hz, J=
2.6Hz, HC(6”)), 4.00(m
, IH.

1 (C(2)), 4.07 (t, 2H, J=6.
7Hz, HzC(30')).

4. 10 (t, if, J=7.4Hz
, HC(3)), 4.16 (dd.

IH, J40. :llz, J=4.6Hz, H
C(I)), 4.27 (d.

1, H, J=7.8flz, )IC(I”)),
5.36 (m, 4H,)IC(9'),
HC(I0'), )IC(I2'>,
HC(I3')).

5.46 (dd, IH, J=15JHz,
J=7.4Hz, HC(4)).

5.70 (dt, 1)1. J=15.3)
1z, J=6.7Hz, HC(5))IR(K
Br, cm-'): 3400. 3320°3020, 2930. 2860. 1?40°16
50, 3550. 1470. 1165°1090
, 985. 720 Elemental analysis C,,H,3,NO,o・3/4 H2O
: Calculated value (%) C near 3.067, H: il
, 643N: 1.151 Actual value (%) C near 3,186, H: 11.
529N: 1,167 M5 (m/e): 1200C
M-H] Example 17 Synthesis of (2S,3R,4E)-1-0-(tetra-0-acetyl-β-D-glucopyranosyl)-N-trifluoroacetyl-C20-sphingosine (50): Implementation Synthesis was carried out according to Examples 10 to 13, except that trifluoroacetic acid p-nitrophenyl ester was used instead of trichloroacetic anhydride in Example 10, and a highly viscous colorless oil (2S) was synthesized.

3R,4E) -3-0-(tert-butyldiphenylsilyl)-1-〇-(tetra-0-acetyl-β-
D-glucopyranosyl)-N-trifluoroacetyl-
C20-sphingosine was converted into 26In ((2S, 3
R,4E) -3-〇-(tertbutyldiphenylsilyl)-N-)lifluoroacetyl-C20-sphingosine (yield 72.4%) was obtained.

This 103# (0,106 mmol) was added to dry THFO
, 7μll of tetra-n-butylammonium fluoride at room temperature.
1, 1.0 M/T HF) was added dropwise and stirred for 20 minutes. This solution was ice-cooled 1N-H[:1 solution 20d
After washing with saturated brine and drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 129 ml of crude product. This was purified by silica gel column chromatography (benzene-ethyl acetate) to form white crystals (2S, 3R,, 4E)-
86.5 mg (yield 97.3%) of 1-0-(tetra-0-acetyl-β-D-glucobyranone)-N-trifluoroacetyl-C2G-sphingosine (50) was obtained.

m, ρ, = 112-115°C Rf = 0.51 (chloroform:methanol-9:1
(capacity ratio)) 'HNMR (I00MHz, CDCl, δ)
:0.88 (t, 3H, J=6Hz, H=C(2
0)), 1.28 (brs, 26H).

2.02 (s, 3H, CH, CO), 2.05
(s, 6H, 2XC)1. CO), 2.10 (s
, 3H, CH, CO), 2.00 to 2.30
(m, 2H, H, mouth (6)), 3.50-4.
40 (m.

7H), 4.47 (if, ], H, J=8
Hz, 7 Nomeribuku H).

4.80-5J3 (Tian, 3rd), 5.45 (dd
, LH, Jl, 6Hz, J=6Hz, HC(4)
), 5.78 (dt, LH, J=16Hz, J
・6Hz, HC(5)), 6.82 (brd,
IH, Jll) 1z, NH) I R (CIIC+, solution, cm-'): 3550
゜3425, 1755. 1,730. 1,530
゜1370, 1220. 1,170. 1040 Example 18 (In the formula, R' represents a lyloyl group) (2S, 3R, 4E)-1-〇-(β-D-glucopyranosyl)-N-(30'-lyloyloxy)triacontanoyl~ Synthesis of C2[1-sphingosine (49): Compound (50) 21.9 mg (0,029++o
nol) in THF (LOmj2)-methanol (I,O
mf), 28%-NaOCIla methanol solution 52.5 mg (0,272 mmol)
was added, heated to 50°C, and stirred for 4 hours. This solution is
After diluting with a mixed solvent of HF (lae) and methanol (I-), it was neutralized with 95 μ of Amberlyst-15 under water cooling,
After filtering through Celite using a solvent of chloroform-methanol (5:1 (volume ratio)), the solvent was distilled off and 2S, 3
R,4E)-1-0-(β-D~glucopyranosyl l-
Crude product of C,,-sphingosine (51) 32.6■
I got it.

To this compound (51) 32.6■, 47.4■ (0,056 smol) of 30-lyloyloxytriacontanoic acid p-nitrophenyl (42) synthesized in Example 9 and 1.0 ml of pyridine! was added and stirred at 50°C for 18 hours. This reaction solution was mixed with benzene 3 (Iml).

The solvent was distilled off three times to remove pyridine, yielding 72.9 square meters of a crude product. This was purified by silica gel column chromatography (chloroform-methanol) using 2S and 3R.

4E) -1-0-(β-D-glucopyranosyl)-N-
(30'-lyloyloxy)triacontanoyl-C
2゜-sphingosine (49) in 19.7μ (yield 56
゜1%) was obtained.

Example 19 CH2=CI+(I:H2)++Br
Synthesis of 3-promo 1-tridecene (52) 1,. 1
A solution of 24.0 g (80 mmol) of 0--dibromodecane in THF (I00mj') was cooled on ice and added to L12CuCl.
4 (0,IM THF solution, 4-), then 50 Wf of a diethyl ether solution of Grignard reagent prepared from 12.1 g (0,1 nof) of 3-promonypropene and 2.43 g (0,1 mol) of magnesium,
Slowly drop the solution, gradually return to room temperature, and leave at room temperature for 24 hours.
Stir for hours. This reaction solution was poured into an aqueous ammonium chloride solution and extracted with diethyl ether. The ether layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography and then distilled to obtain 11.9 g of 13-bromo-1-tridecene (52).
(yield 57%).

b, p, ~159-160°C (I6mmHg)'HNM
R (270MHz, CDCl, δ):
1.28 (brs14H), 1.35-1.5
0 (m, 2N), 1.80~1.90 (m
, 2H), 2. OO~2.08 <m, 2
H), 3.39 (tJ26.987., 2H)
, 4.92 (ddt, J=2.2.11
4and L, 1tlz, LH), 4.98
(dat, J=2.2.1?,0゜1,,I
Hz, LH), 5.81 (tdd, J
=5.1. 1? , 0°10.4Hz, 1ll) IR (neat, cm-'): 3100
．． 2940°2870, 1650. 10・00
, 910 elemental analysis [:+*LsBr: Calculated value (%) C: 59.77.8: 9.65 Actual value (%) C: 59.68. H: 9.69 Example 20
Synthesis of HD(CH2),3COJ24-hydroxytetracosanoic acid (I9): 8.37 g (0.03 mmol) of methyl 11-bromoundecanoate in THF (30
me) Cool the solution on ice and add LizCuC14 (0.1M
THF solution, 3-), then 13- obtained in Example 19
Bromo-1-tridecene (52) 7.83 g (0,
03 mol) and magnesium 802. (0,033mo
THF (30mf) of Grignard reagent prepared from l)
) solution was added, the temperature was gradually warmed to room temperature, and the mixture was stirred at room temperature for 24 hours.

This reaction solution was poured into an aqueous ammonium chloride solution and extracted with hexane. An attempt was made to purify the obtained crude product by silica gel column chromatography, but 9.43 g of a crude product of methyl 23-tetracosenoate containing about 10% of inseparable substances (according to CC analysis) was obtained. Proceeded to the previous reaction without further purification. The crude product of methyl 23-tetracosenoate obtained was 6.84 g of THF (3
0-) The solution was cooled on ice, and []H3-TIIF (I M
A THF solution (Example 9) was slowly added dropwise, the temperature was returned to room temperature, and the mixture was stirred at room temperature for 2 hours. Add 1.2-liter of water to this solution, cool it on ice again, add 151 nl of 3M-NaOH aqueous solution,
Then 30%-H5Dz 2mi! was added while maintaining the solution at 40°C, and then stirred at 50°C for 1 hour. After cooling to room temperature, a 2N-HCI aqueous solution was added to make it acidic, and a white solid was collected by filtration.

After washing this white solid with water, it was recrystallized from a mixed solution of chloroform-hexane to obtain 5.77 g of 24-hydroxytetracosanoic acid (I9) (yield 69.0% from I3 bromo-1-tridecene). Ta.

m,p,=101~b'HNMR<270MHz, C[]CI-,l)
: 1.26 (brs.

42H), 1.46-1.71 (m, 4H),
2.34 (t, Jl, 4Hz, 2B), 3.6
4 (t, J=6.6Hz, 21t)IR(KBr
, cIll-'): 3400, 2920°28
50.1705.1470,1410゜Elemental analysis C
2, +1. ．． 0. : Calculated value (%) C near 4.94. H: 12.58 measured value (%) C near 4.88. H: 12.64 Example 2
1 H3CO,C(CH2),,C02C)I.

Synthesis of dimethyl tridecanoate (53): Tridecanoic acid 20. Og (82,0 mmol) and methanol 1oo7! , 0.5-98% sulfuric acid was added, and the mixture was refluxed for 5 hours. After removing methanol under reduced pressure, hexane was added to the residue, and the hexane layer was washed with water. After drying the organic layer over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to obtain 21.9 g (yield 98.4%) of a crude product of dimethyl tridecanoate (53).

m,p,=35~37℃ HNMR(27(lIJIIz, C[]C1,,δ
): 1.27 (brs14H), 1.6
2 (m, 4H), 2.30 (t, J=7.6
Hz4H), 3.67 (s, 6H) IR (neat, cm-'): 2940,2870
゜1?40,1440.1260,1200゜1170
Example 22 Synthesis of HO (CH2), 30H 1,13-dihydroxytridecane (54) A solution of 76 g (0.08 mol) of dimethyl tridecanedioate (53) was heated to 0°C.
The mixture was slowly added dropwise into a diethyl ether (500-) solution containing 46.07 g (0.16 mol) of IH.

After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes.

Water 12rn1.2N-NaO)112m was added to the reaction solution.
1! was added, the precipitated solid was filtered, the solvent was removed under reduced pressure, and 1,13-dihydroxytridecane (54) was dissolved in 1
7.10 g (yield 99.0%) was obtained.

, p, = 75-76.5 °C HNMR (270 klHz, CDCl, δ)
: 1.28 (brs18H), 1.48
~1.63 (m, 4H), 3.63 (
t, J=6.6Hz, 4N>IR (KBr, cm): 3300,2940
゜2860, 1470. 1410. 11.30 Elemental analysis C,3H2,O,: Calculated value (%) C near 2.17. H: 13.04 Actual value (%) C near 2.07. H:1.2.92 Example 23 ll0(CII2LJr1-Bromo-13
-Synthesis of hydroxytridecane (55): 1.13-dihydroxytridecane (54) 4.32
g (0.02 mol), add 40 mf of benzene and 2.5 ml of 48% hydrobromic acid, and while removing water,
Reflux was performed for an hour. After cooling, the reaction solution was diluted with 6N-NaOH.
The mixture was washed successively with 110% HCI and water, dried over anhydrous magnesium sulfate, and then benzene was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate-3:2 (volume ratio)), and 1-
Bromo-13 hydroxytridecane (55) 4.07
g (yield 72.9%) was obtained.

ω, p, = 56-57°C HNMR (270MHz, CDCL, δ)
: 1.27 (brs18H), 1.49-1
．． 63 (m, 2tl), 1.78~], 92
(ω, 2H), 3.4.1 (t, J=
6.9tlz, 2tl), 3.64(t,
J = 6.6Hz, 2H) IR (KBr, cm□'): 3400, 2920° 2850.1460, 1380, 1150° 720.6
40 Elemental analysis C+*HztOBr: Calculated value (%)
C:55.91. H: 9.75 Actual value (%) C 5
5.89. H: 9.74 Example 24 7HPO(CH
a) 1-8r (in the formula, T) IP represents a tetrahydropyranyl group) Synthesis of 1-bromo-(I3-tetrahydropyranyloxy)tridecane (56): 1-bromo-13-hydroxytridecane (55 )
11.75 g (42,1+y++nol) and 06 g (84,0 mmol) of dihydrobilane'A were dissolved in methoxychloride I/740, and PPTS
105■ (0.42 mmol) was added and stirred at room temperature for 5 hours. 20 d of diethyl ether was added, and the mixture was washed with saturated heavy water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate-9=1 (volume ratio)) to obtain 1-bromo-(I3
-Tetrahydropyranyloxy)tridecane (56) was obtained in an amount of 14.85 g (yield: 97.4%).

'HHR (270MHz, CDCl, δ)
: 1.25 (brs.

18)1), 1. ．． 40~1.74 (+n, 8H
), 1.84 (m 2H), 3.39 (ω,
2H), 3.51. (Out, IH), 3.7
2 (o, LH), 3.86 (m, IH),
4.57 (t, J=3.6Hz, LH) rR(neat, c+n-'): 3040,295
0°1460.1360,1,260.1210°11
20.1080, 1030.760 elemental analysis C1-
tl-sOJr: Calculated value (%) C: 59.50.
H: 9.71 Actual value (%) C: 59.52. H:9
．． 63 Example 25 No(CH2)2scOJ24
-Synthesis of hydroxytetracosanoic acid (I9): 1.75 g of methyl 11-bromoundecanoate (6,28 aon
The THF (I5d) solution of ol) was cooled on ice, and Lia
CuCl-(0.1M-T HF solution, 0.63ml
') and then 3.42 g of 1-bromo-(I3tetrahydropyranyloxy)tridecane (56) (
9,42++onol) and magnesium 229u (9
, 42 mmol) Grignard reagent THF
(30 atl') solution was slowly added, and the mixture was stirred for 2 hours under water cooling and further stirred at room temperature for 24 hours. The reaction solution was poured into ice water, 2N-HCI was added thereto, and then extracted with hexane.

The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure.

The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate - 9:1 (volume ratio)) to obtain 1.62 g of methyl (24-tetrahydropyranyloxy)tetracosanoate (yield: 53.4). %)Obtained.

1.10 g (2,42 mmol) of the resulting methyl (24-tetrahydropyranyloxy)tetracosanoate was dissolved in 30 ml of ethanol and 242 u of sodium hydroxide.
(6.05 mmol) was refluxed for 2 hours. After removing ethanol under reduced pressure, 1 cI of 2N-) was added to make it acidic.
Furthermore, 50IIIg of p-toluenesulfonic acid was added and the mixture was refluxed for 5 hours. After cooling, the obtained white solid was collected by filtration and washed with water. Furthermore, 24-hydroxytetracosanoic acid (I9) was recrystallized from a chloroform-hexane mixed solvent.
．． 83 g (yield 89.7%) was obtained.

Synthesis of p-nitrophenyl 24-lyloyloxytetracosanoate (42'): 24-hydroxytetracosanoic acid 38 obtained in Example 20
746 mg of pyridine 3- and linoleic acid chloride in a solution of 4 (I,0a + mol) of chloroform (7cI)
(2.5 mmol) was added and stirred at room temperature for 5 hours. The reaction solution was poured into water and extracted with chloroform, and the organic layer was washed with a 2N-1+Cl aqueous solution, then with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, methanol was added to the residue, and the insoluble matter 24-
IJ luoyloxytetracosanoic acid was collected by filtration.

The obtained 24-lyluoyloxytetracosanoic acid was dissolved in 5 rnl of pyridine, and trifluorovinegar was added to this solution. 235 μm (I, 0 mmol) of p-nitrophenyl was added, and the mixture was stirred at room temperature for 2 hours.

After removing pyridine under reduced pressure, it was purified by silica gel column chromatography (hexane:ethyl acetate = 9:1 (volume ratio)) to obtain 24-lyluoyloxytetracosanoic acid p.
-Nitrophenyl (42') was obtained in 384 cm (yield 50.0% from 24-hydroxytetracosanoic acid).

m, p, = 60~61.5℃'HNMR (270MHz, CDCl3. δ)
: 0.89 (t, J6.71(z, 3
H), 1.25 (brs, 50)1),
1.52-1.65 (m, 6H), 1
．． 70-1.84 (m, 2H), 1.99
~2. IO (m, 4H), 2.29 (t,
J=7.6Hz, 211).

2.60 (t, J=7.6Hz, 2N),
2.77 (m, 2H).

4.05 (t, J=6.7Hz, 2H),
5.30-5.41 (m.

4H), 7.27 (d, J=9.3tlz
, 2H), 8.28 (d, J=9.3
Hz, 2H) IR (KBr, cm-'): 3040. 2
940°2870, 1?70. 1740. 154
0°1470, 1360. 1,230. 1180
゜1.140.870 Elemental analysis C1H,, NO,: Calculated value (%) C near 5.05. ,H:10.63N
: 1.8 2 Actual value (%) C near 5.00. H: 10.43N
: 16 2 H (2S, 3R, 4E)-N-)lifluoroacetyl-C
Synthesis of 1,-sphingosine (57) (2S, 3R, 4
E) -C,s-sphingosine 322.31g (I
078 mmol) and 380.2 ■ (I, 617 mmol) of p-nitrophenyl trifluoroacetate were dissolved in pyridine 5
- and stirred at room temperature for 15 hours. Pyridine in this reaction solution was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1 (volume ratio)) to obtain white crystals (25,3R,4E-N-trifluoroacetyl -CIO-sphingosine (57)
(hereinafter referred to as compound (57)) was obtained in 408.3 cm (yield 96%).

m, p, = 89.5-90.5°C'HNMR (270MHz, C[1CIs, δ
) + 0.88 (t, J=6.6Hz, 3
8), 1.26 (brs, 22H), 20(
I-2,11 (m, 2H), 2.23 (brs
, 28), 3.74 (dcl, J=11.4 an
d 3.4Hz, IH), 3.93 (+n, I
H), 4.09 (dd, J41.4 and 2
．． 8Hz, LH＞.

4J9 ct, J=5.4tlz, IH), 5.
54 (dd, J=15.4 and 6.5Hz,
LH), 5.83 (dt, J=15.4and
7.2Hz, IH), 7.08 (br
s, IH) IR (KBr, cm-'):
3450. 3300169[), 1560.
1460. +180°1050, 970 Elemental analysis C20H36NO3F3: Calculated value (%
) C:60.74. H: 9.18N: 3.
5 4 Actual value (%) C: 60.75. H:9.15N
: 3.4 8 lH (In the formula, Tr represents a trityl group) (2S, 3R, 4E) -N-trifluoroacetyl-
Synthetic compound (57) of 1-〇-trityl-C+s-sphingosine (58) 721.4■ (I, 826 mmol)
and trityl chloride 559.5■ (2, D 09
Dissolve nonol) in pyridine 10rIIl and heat at 45°C.
The mixture was stirred for 14 hours. Pyridine was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane, ethyl acetate - 9:1 (volume ratio)).
R,4E)-1'l) Lifluoroacetyl-1-0-)
1.0402 ■ lytil-CI8-sphingosine (5B) (hereinafter referred to as compound (58)) (yield 89%)
Obtained.

HroR (270MHz, CDCl3δ
): B 8g (tJ=6.6Hz, 3H),
1.26 (brs, 22H), 1.93 (m
.

2H), 2.52 (d, j=7.7Hz, LH)
, 3.42 (d, J-3,6Hz, 2H), 4
．． 00 (m, IH), 4.26 (I11,18
).

5.29 (dd, J=15.5 and 6.3H
z, LH), 5.72 (dd, J=15.5 a
nd 6.7Hz, 18), 6.91 (d.

J=8.2Hz, LH), 7.21~7.40 (
m, 15H) IR (nrat, cm-'): 34
50.3080°2950.2870.1?20,15
95゜1.530, 1490, 1450, 1210゜1
160.1070.970 Elemental analysis C,, H5°NO, IF, : Calculated value (
%) C near 3.44. H near, 90 actual value (%) N: 2.2 0 C near 3.49. HN: 2.0 8 (In the formula, BZ represents a benzoyl group) (2S, 3R, 4E)-3-0-benzoyl N-)lifluoroacetyl-1-0-) lythyl C+a sphingosine 59) Synthesis: Compound (5B) 998.0+a
g (I, 567 mmol) in pyridine (I5M!> solution with benzoyl chloride 242.3■ (I゜? 23 +u
+ol) was added and stirred at room temperature for 18 hours. Pyridine was removed under reduced pressure, and the residue was purified by licage gel column chromatography (hexane:ethyl acetate = 9:1 (volume ratio)).
N-trifluoroacetyl-1,-0-) I) Chil C+s-sphingosine (59) (hereinafter referred to as compound (
1.0760 g (yield 93%) of 59) was obtained.

'HNMR(270M)tz, CDCL, δ)
+ 0.87 (t, J6.6Hz, 3H)
, 1.23 (brs, 22H), 1.99
(m.

28), 3.25 (dd, J=9.9 and
4.4Hz, 1ff).

3.48 (dd, J=9.9 and 3.8)1
z, 01) 4.42([0,LH), 5.4
3 (dd, J=15.4 and 7.4Hz,
IH), 5.71 (t, J=7.4 and
6.6Hz, 1B).

5.91 (dt, J=15.4 and 6°6f
(z, L)I), 6.55(d, J=9.1H
z, IH), 7.11~7.98 (m, 20H
)IR(neat, cm-'): 3450,334
0゜3080.3040.2940,2860゜1?2
0,1600,1540,1490°1450.126
0,1210,1170゜1090.970 Elemental analysis C, 6H,, NO, F, : Calculated value (%
) C Near 4.47. H near, 34N: 1.89 Actual value (%) C near 4.43. H near, 47N:
1.80 (2S, 3R, 4E) -3-〇-benzoyl N-)'
J Fluoro T Cetyl-Cl11-Sphincosine (60
) Synthesis of compound (59) 990.1 (I, 336 mmol) in chloroform-methanol (volume ratio 1:1) (7) fi
The mixture was dissolved in 15 tl' of a combined solvent, and Amberlyst-15500 was added to this solution, followed by stirring at room temperature for 40 hours. The liquid after filtering through Celite was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate-9=1 (volume ratio)) to obtain white crystals (2S,
3R.

4E)-3-0-Benzoyl-N-trifluoroacetyl-C+a-sphingosine (60) (hereinafter referred to as compound (60)) was obtained in an amount of 594.6 μm (yield: 89%).

Mark, p, m80.5-81.5℃ 'HNMR (270MHz CDC1, δ):
0.88 (t, J6.7Hz, 3H),
1.25 (brs, 22H), 2.05
(m2H), 2.50 (brs, 1t
l), 3.70 (dd, J=12.1an
d 3 4Hz, IH), 3.82 (d
d, l12. l and2 8Hz 1ft)
, 4.26 (m, 1.H), 5.53
~5.65 (m, 2H), 5.91 (dt
, J=14.3 and 6.6Hz).

6 87 (d, 8.8Hz, 1M),
7.43-7.49 (m28), 7.57
~7.63 (m, 1ll), 8.02~
8.05 (m, 2H) IR (KBr, crB-'): 345
0. 33203120, 2940. 2860.
1?20°1.700. 1560. 1260. 1
, 210° 1180, 1070. 970. 880
Elemental analysis C2511,, No, F, : Calculated value (
%) C: 64.91. H:8.07N:2
．． 8 0 Actual value (%) C: 64.89. H:8.05N
: 2. 7 1 Example 31 (In the formula, Ac represents an acetyl group) (2S, 3R, 4E)-3-0-benzoyl-1, -0
Synthesis of -(tetra-0-acetyl-β-D-glucopyranosyl)-N-)lifluoroacetyl C11l-sphingosine (61): Compound (60) 399.2[(0,
800 mmol) was dissolved in a mixed solvent of benzene (25d>-=tromethane (25ml), and concentrated under normal pressure by heating until the remaining amount was 12 mmol. After cooling to room temperature under argon, tetra-0-acetyl- α-D-glucopyranosyl bromide 493.2■ (I, 200 mol)
and mercury cyanide 303.2■ (I, 200o+mol)
was added and stirred at 80°C for 4 hours. The mixture was cooled to room temperature, diluted with diethyl ether, washed with saturated hydrogen sulfide water, and the black precipitate of mercury sulfide was filtered through Celite. The filtrate was washed with saturated deuterated water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 7:
(2S,3R4E)-3-0
-benzoyl-1-〇(tetra-0-acetyl-β-D
-glucopyranosyl)-N-)'II fluoroacetyl-C11 sphingosine (61) (hereinafter referred to as compound (6)
1)) was obtained in an amount of 468.4 cm (yield 71%).

p, = ioo~102℃'HNMR (270MHz, CDC1,, δ)
: 0.88 (t, J65)1z, 3H),
1.24 (brs, 22H), 2.02 (a+
.

2N), 1.97 (s, 3tl), 2.00
(s, 6H), 2.01 (s, 38), 3.
6:3-3.69 (m, 1tl), 3.76 (
dd.

J=12.4 and 4.1)1z, 18), 3
．． 99 (dd, l12.4 and 2.5Hz,
LH>, 4.06-4.15 (+n.

2H), 4.45 (m, LH), 4.50 (
d, J=8.0Hz, LH>, 4.96 (dd
, J=9.6 and 8.0Hz, LH).

5.03 (t, J=9.611z, 1N), 5
．． 20 (t, J=9.6Hz, 1.)I),
5.47 (dd, J=15.2 and
6.9Hz, IH), 5.60 (m,
1) 1), 5.94 (dj, J=15.
2 and 7.6Hz, IN), 6.79
<d, J=9.1Hz, IH).

7.41-7.52 (+n, 2)I), 7
．． 52-7.60 (m, IH) 7, 98-8.
05 (m, 2H)rR(Kbr, am-
'): 3400. 17801720 1
560.1380, 1240°1180, 1050.
980 Elemental analysis C,,ll52N0.3+;, :Calculated value (%) C:59.34. H Near, 04N:
1.6 9 Actual value (%) C: 59.1g, H: 6.79N
: 1.6 8 Example 32 (2S, 3R, 4E) Synthesis of -1-0-(β-D-glucopyranosyl)-C,6-sphingosine (52): Compound (61) 346.0 +og (0, 417m
mol) of chloroform-methanol (volume ratio 3:2)
20ml of mixed solution! Sodium methoxide (purity ~
95%) 225μ was added and stirred at room temperature for 3 hours.

After neutralizing the reaction solution with acetic acid, it was poured into water and extracted with a mixed solvent of chloroform-methanol (volume ratio 9:1).

After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol = 7:3 (volume ratio)).
2S, 3R, 4E)-1-C)-(β-〇-glucopyranosyl)-〇16-sphingosine (62) (hereinafter,
139.2■ (yield 72%) of compound (62)
Obtained.

'HNMR (270MHz, CDCl!-CDSO
D (capacity ratio 4:1), δ): 0.8
8 (t, J=6.6Hz, 18), 1.26
(brs, 228), 2.06 (+n.

2H), 3,00 (m, 1)1), 3.23~
3.46 (m, 4H).

3.68-4.12 (m, 5)1), 4.28
(d, J=7.7Hz.

IH), 5.42 (dd, J=15.2
and 7.5Hz, IH).

5.78 (dt, J=15.2 and 6.9
Hz, LH) IR (Kbr, cm-')
: 3300. 2940°2870, 1380
．． 1070. 1030M S (m/e,
F A B (positive): 4 6 2
[:M+H]”, 4 8 4 [M
+Na]" Example 33 (In the formula, R1 represents a lyloyl group) (2S, 3R, 4E)-1-0-(β-D-glucopyranosyl)-N-(24'-lyloyloxy)tetracosanoyl = CR8 -Synthesis of sphingosine (63): Compound (62) 12. Ou (0,026+omo
39.9 μ (0,052 mmo
and stirred at room temperature for 15 hours. Pyridine was removed under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform:methanol = 20:1 (volume ratio)).
(2S, 3R.

4E) -1-0-(β-D-glucopyranosyl)-N-
(24'-lyluoyloxy)tetracosanoyl-Cz
+-sphingosine (63) in 22.7μ (yield 80%)
)Obtained.

m, p, = 125-127°C HNMR (270 MHz, CDCl5-CD-00
(Capacity ratio 4:1) ): 0.88 (t
, J=6.9Hz.

18), 0.89 (t, J=6.9Hz, LH
), 1.26 (brs.

748), 1.56-1.69 (m, 61(),
1.97-2.1CI (m, 641), 2.17
(t, J=7.6Hz, 2)1), 2.30(
t, J=7.611z, 2fl), 2.77 (
t, J=5.6Hz, 2Ill, 3.22~3°34 (m, 2H), 3.34~3.46 (m.

2H), 3.61 (dd, J=10.0 and
3.0Hz, LH).

3.73 (dd, J=11.7 and 4.8H
z, 1ft), 3.86(dd, J=11.7
and 2.5) 1z, LH), 4.
03 (+m.

IH), 4.06 (t, J・6.7Hz, 2H
), 4.13 (ijd.

J:10, Oand 4.0Hz, IH), 4
．． 27 (d, J=7.7Hz, IH),
5.35 (m, 4tl), 5
．． 46 (dd, J-1,5,2and7
．． 1Hz, IH), 5.71 (dd,
J=15.2and 6.7Hz, 1)1),
6J5 (d, J=8.0Hz, IH) rR
(Kbr, cm-1) + 3340.3300
゜1740, 1640. 1550. 1470°1
080, 960 M S (m/e, F A B
(negative)) 21 0 88 [
M-H] (m/e, F A B (positive
)) :1, 0 9 0 [M+H] ”1 1
1 2 CM+Nal'' [Effects of the Invention] According to the present invention, it is possible to synthesize acylglucosylceramides present in the epidermal cell layer of mammals, which could conventionally only be obtained by extraction.

These acyl glucosylceramides play an important role in the production of healthy epidermis, and are expected to have various physiological activities, making them industrially useful substances that can be applied to cosmetics and the like.

Claims (1)

[Claims] 1. General formula (I) R^1O-(CH_2)_k-CO_2-R^2(I
) (In the formula, R^1 represents a linoleoyl group, and R^2 is p
-Nitrophenyl group, and k represents an integer of 23 or 29. ) An ω-acyloxycarboxylic acid derivative represented by: 2. General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^3 represents a hydrogen atom or a tert-butyldiphenylsilyl group, and l represents an integer of 12 or 14. ) Glucosylated products of sphingenin derivatives and general formula (I) R^1O(CH_2)_k-CO_2-R^2(I)
(In the formula, R^1 represents a linoleoyl group, and R^2 represents p-
It represents a nitrophenyl group, and k represents an integer of 23 or 29. ) General formula (III) characterized by subjecting an ω-acyloxycarboxylic acid derivative to an amidation reaction in the presence of a base, followed by deprotection if necessary. ▲Mathematical formulas, chemical formulas, tables, etc. are available▼( III) Acyl glucosylceramides represented by (wherein R^1 has the same meaning as above, when k is 23, l represents 12, and when k is 29, l represents 14) manufacturing method.