JPH02202849A - Optically active dialkyl ester type sialosylglycerolipid and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is H or benzyl; either of R<2> and R<3> is COOR' and the other is formula II; R<4> is H, halogen or phenylthio; Ac is acetyl). USE:Useful as a tumor marker and cell molecule marker having differentiation inducing ability. PREPARATION:For example, a compound expressed by formula III (X is halogen; R is benzyl) and a compound expressed by formula IV are subjected to glycosidation reaction to provide the compound expressed by formula I (R<1> is benzyl; R<4> is halogen). Both a compound expressed by formula V (R<1> is OH or Br or, together with R<3>, forms single bond; R<2> is benzyl; R<3> is Br or phenylthio) including the compound expressed by formula III and a compound expressed by formula VI (R<1> is H or acyl) including the compound expressed by formula IV are new compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to dialkyl ester type sialosylglycerolipids, intermediates thereof, and methods for producing the same.

[Background of the invention]

Glycolipids in mammalian cells contain sugars such as glucose, galactose, N-acetylglycosamine, N-acetylgalactosamine, fucose, and sialic acid in a lipid structure called ceramide, which is an amide bond of a fatty acid to a long-chain amino alcohol called sphingosine. They have glycosidic bonds in various combinations and belong to the so-called glycosphingolipids. Among these, those having sialic acid are particularly called gangliosides.

Most of these compounds are generally localized in the outer molecular layer of the cell membrane bilayer, and recent studies have shown that they play a role in cell recognition, information reception, response receptor function, differentiation, cell proliferation, malignant changes, and It is thought to play an important role in behavior.

Therefore, it is necessary to synthesize ganglioside glycolipids and study their functions in order to clarify the role and function of ganglioside glycolipids as cell membrane components.
This makes them extremely useful as tumor markers, cell molecular markers with differentiation-inducing ability, and as synthetic intermediates thereof.

[Purpose of the invention]

An object of the present invention is to provide a novel dialkyl ester type sialosylglycerolipid and intermediates thereof.

[Structure of the invention]

The present invention is based on the general formula: (wherein R1 represents hydrogen or a benzyl group, one of R2 or R3 represents -CDOR' (however, R1 represents the same group as above), and the other represents (however, R1 represents hydrogen or a benzyl group, one of R2 or R3 represents -COOR' (however, R1 represents the same group as above), the other R4 represents hydrogen, bromine or a phenylthio group, and Ac represents acetyl (representing a group).

The present invention will be explained in detail below.

The novel compounds of the present invention have the general formula: R4 represents hydrogen, bromine or a phenylthio group, and Ac represents an acetyl group. ).

The compound represented by the above general formula (I) is a compound represented by the above general formula (■
): (However, X represents a halogen atom, usually a bromine atom, R2 represents a benzyl group, and Ac represents an acetyl group.) Compound (n) represented by the following and general formula (■): I-1 Skim It can be obtained by subjecting compound (III) represented by I-2 to a glycosidation reaction.

Compound (n) used here is prepared, for example, as shown in Scheme 1 below.

(1) Production of compound ll-1 Compound (1)-1 can be obtained by dehydrochlorinating a known compound represented by the general formula: and then deacetylating it.

(2) Production of compound n-2 Compound ll-2 is obtained by benzylating compound ll-1. The benzylation reaction is generally carried out in an anhydrous state in a solvent such as dimethyl sulfoxide or DMF with an odor. Using a benzyl halide such as halogenated pencil, in the presence of barium oxide, tetrabutylammonium iodide, potassium hydroxide, etc. as a catalyst, at 0 to 50°C, 1 to 24°C.
done in time.

(3) Production of compound n-3 Compound ll-3 can be obtained by benzylating the carboxyl group of compound I[-2. This benzylation reaction is carried out under anhydrous conditions in a solvent such as N,N-dimethylformamide, THF, or dichloromethane using a benzyl halide such as benzyl bromide in the presence of a catalyst such as potassium carbonate or cesium carbonate. It is carried out at 50° C. for 3 to 30 hours.

(4) Production of compound (1) Compound (1) can be obtained by subjecting compound 11-3 to a halogen addition reaction. The addition reaction is generally carried out in the presence of pyridinium bromide, perbromide, bromine, etc. in a solvent such as anhydrous dichloromethane, THF, ) toluene, or DMF under an inert gas atmosphere such as argon gas.
It is carried out for 15 minutes to 24 hours at ~40°C.

On the other hand, compound (1) can be produced according to Scheme 2 below.

Scheme 2 n[[-1 n-2 (1) Production of compound II[-2 Known compound I[-1(J, Lipid Res, 14
(1973) p438-445) with stearic acid chloride to obtain compound lll-2.

The acylation reaction is carried out in a solvent such as anhydrous pyridine, dichloromethane, or triethylamine at 0 to 40°C for 1 to 10 minutes.
It is held for 12 hours.

(2) Preparation of Compound (1) Compound (2) can be obtained by debenzylating Compound I-2. The debenzylation reaction is carried out in a solvent such as acetic acid ethynope ethanol in the presence of a catalyst such as Pd-C under a hydrogen stream at 0 to 50° C. for 1 to 40 hours.

The glycosidation reaction between compound (I[) and compound (I[I)] is carried out under an inert gas atmosphere such as argon gas,
Molecular sieve and silver trifluoromethanesulfonate, silver perchlorate, silver carbonate, in a solvent such as anhydrous benzene, toluene, dichloromethane, dichloroethane, THF, etc.
The reaction is carried out at -5°C to 50°C for 30 minutes to 24 hours in the presence of a glycosidation catalyst such as mercury bromide or mercury cyanide. This reaction results in general formulas (IV) and (■)
: (wherein, X represents a halogen atom, such as a bromine atom, and R represents a benzyl group) Compounds (rV) and (V) shown below are obtained.

Compounds (IV) and (V) were prepared in the presence of a catalyst such as tributyltin hydride (Bu, SnH) and α, α′-azobisisobutyronitrile (AIBN), respectively.
Compounds (V'I) and (
(2) (X in the above formulas (IV) and (V) is replaced with a hydrogen atom) is obtained.

These compounds (VI) and (■) are then prepared, respectively, in the presence of a catalyst such as Pd-C in a solvent such as an ethyl acetate-methanol solution under a hydrogen atmosphere.
By debenzylation at 5-40°C for 0 hours, compounds (■) and (IX) (formulas (IV) and (V) above)
(in which R is a hydrogen atom) is obtained.

The following Scheme 3 specifically shows compounds (■) and (I
The flow of the reaction up to X) is shown.

On the other hand, general formula X: (wherein R is a benzyl group, Ph is a phenyl group, and Ac is an acetyl group).

It is obtained by glycosidation reaction of compound n-8 shown by and compound (2).

Compound n-8 used in this glycosidation reaction
is obtained from compound 1-3 according to Scheme 4 below.

(However, R' is a benzyl group, R2 is a phenylthio group, and Ac is an acetyl group.) Compound X represented by the general formula ■-8: R Skim 4 f-5 II-7 ( 1) Production of compound ll-4 Compound I[-4 is obtained by halohydrinating compound ll-3. The addition reaction is generally carried out by reacting N-bromosuccinimide in a solvent such as acetonitrile-water.

The reaction is generally carried out at 20 to 100°C for 5 minutes to 3 hours.

Note that Compound 11-5 is obtained as a by-product.

(2) Production of compound 11-6 Compound I[-6 can be obtained by substituting the halogen atom of compound 11-4 with a phenylthio group.

The reaction is carried out under an inert gas atmosphere in a solvent such as anhydrous tetrahydrofuran, benzene, toluene, dichloromethane, ether, etc. in the presence of a catalyst such as potassium tert-butoxide, sodium hydride, etc.
It is obtained by reacting with thiophenol at 0°C, generally around 0°C, for 5 minutes to 2 hours.

In addition, compound ll-7 is obtained as a by-product.

(3) Production of Compound It-8 Compound n-8 can be obtained by substituting the hydroxyl group of Compound Il-6 with a halogen atom, such as a bromine atom. The substitution reaction uses a carbon tetrahalide such as carbon tetrabromide under an inert gas atmosphere, in a solvent such as anhydrous tetrahydrofuran, ethenopebenzene, or toluene, and with a catalyst such as hexamethylphosphorustriamide or triphenylphosphine. The process is carried out at -78 to 100°C for 2 to 50 hours.

The glycosidation reaction between compound 11-8 and compound 1 is carried out in the presence of a molecular sieve, in the presence of a glycosidation catalyst such as mercuric cyanide or mercury(II) bromide, and in an inert gas atmosphere. , anhydrous carbon tetrachloride, toluene,
This is carried out by holding in a solvent such as dichloromethane, dichloroethane, benzene, or nitromethane at 50 to 80°C for 10 to 48 hours.

Compound XI (in the above general formula X, R1 is a benzyl group, R2 is a hydrogen atom, and Ac is an acetyl group) is obtained by removing the phenylthio group from the compound X. The elimination reaction is carried out under an inert gas cloud using triphenyltin hydride or tri-n-butyltin hydride and a catalyst such as α,α′-azobisisobutyronitrile, to anhydrous toluene, benzene, dichloroethane, This is carried out by treatment in a solvent such as dichloromethane or THF at 40 to 100°C for 1 to 18 hours.

By debenzylating compound XI, compound X
n (in the above general formula X, R1 and R2 are hydrogen atoms and Ac is an acetyl group) is obtained. This debenzylation reaction is generally carried out by treating in a hydrogen atmosphere in a solvent such as ethyl acetate or methanol at 0 to 50°C for 1 to 40 hours in the presence of a catalyst such as Pd-C.

The steps leading to the production of compound XI are specifically shown in Scheme 5 below.

[Utility] The compound of the present invention is useful as a tumor marker, a cell molecular marker capable of inducing differentiation, and as a synthetic intermediate thereof.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Preparation of compound n-2 Compound 11.02g (added to 20d of anhydrous dimethyl sulfoxide solution of 3.44mm in an argon atmosphere,
benzylpromy)'4.8 d(40,0
Ommoj? ) was added and stirred.

Add barium oxide 3.05g (19.90mmol) to this solution.
3.05 g of tetrabutylammonium iodide (
0: 19 mmoA) and potassium hydroxide 2.23
g (39.70 mmof) was added thereto, and the mixture was stirred at room temperature for 23 hours.

Add 4ml of methanol to the reaction solution under water cooling! 4 at room temperature.
After stirring for 0 min, add 100 mf of ether and 100 mf of water.
mj! The mixture was diluted with water, acidified with a 2N aqueous hydrochloric acid solution, and extracted twice with 150 ml of ether. The ether layers were collected, washed with water and saturated saline using a trowel, dried over anhydrous bugnesium sulfate, and the solvent was distilled off.

The residue was subjected to silica gel column chromatography (Wakogel C-300, 200 g, hexane: ethyl acetate: acetic acid - 15:10:1). Coated colorless oil Compound I[-2
1,62 g (2,49 mmoβ) was obtained with a yield of 72.4%.

Example 2 Preparation of compound n-3 A solution of compound n-285.0 mg (0.13 mmoj?) in anhydrous N,N-dimethylformamide 1 under temperature.
After adding 21.2 mg of senlum carbonate (0.07 mmol) and stirring for 7 hours, 66.7 mg of benzyl bromide was added.
(0.39 mmoA) and stirred for 24 hours.

The reaction solution was filtered through Celite, the residue was washed with ether, the filtrate and washing solution were combined, and the solvent was distilled off. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. Residue, silium gel column chromatography (
Wakogel C300, 20g 1 hexane: ethyl acetate =
1.5:1), colorless amorphous crystal compound n-377,
4mg (0,'104 mmoA) yield 80.2%
I got it.

Physical property value Rf value of compound n-3 0.56 <Merck HPTLC, He 1'4
'N: ethyl acetate = 1:1) 500 MHz 'HNMRCDC, TMS,
δ1, 742 (3)1. S, C
L; zcON) I) 3.687 (LH, dd, J=
10.3.4.6Hz H-9a) 3.882 (
LH, dd, J=10.0.5.3Hz)
3.968 (1)1. dd, J=9.9, 4.
8Hz)4.150 (2H, m,
)6.144 (LH, d, J=
3.7Hz H-3a) Example 3 Production of compound ① Compound IF-3768, 9mg (1,03m+noj
l') c7) 4 m of anhydrous dichloromethane solution! of viridinium bromide at room temperature under argon atmosphere, 11/
7” o Phyto329, 4mg (1,03mmof
) and stirred at room temperature for 17 hours.

The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (Wakogel C-3
00,100g, hexane:ethyl acetate=2:1)
Colorless amorphous crystal compound I [700.2 mg (0,
777 mmoA) was obtained in a yield of 75.4%.

Physical property value of compound (Rf value) 0.38 (Merck HPTLC, hexane: 5
00 MHz 'HNMRCDCj7s, TλI
S, δ1.711 (3H,S,
C1l, C0NH) 3.675 (LH, dd,
J=11.0. 3.31 (z fl-9a)3.
736 (1)1. dd, J=11.0. 2
．． 2) 1z) l-9a>3.851 (IH, dd
, J=8.4, 1.5Hz I(-7a)3
．． 884 (LH, m, H-8
a) 4.111 (1)1. dd, J=19.11
1.0flz H-5a) 4.377 (IH, d,
J=8.4Hz CH3C0NJL)4.67
4 (ltl, dd, J=10.6. 1.5
Hz H-6a) 4.753 (1)1. dd,
J=10.3.3.3Hz H-4a)5.001
(ltl, d, J=3.3Hz fl
-3a) 125MHz ”CNMRCDC123+
δ23.7 (side. C0NH), 93.8 ([knee 2> 164.0, 170.54 (-C-, -).

Example 4 Preparation of Compound I[[-2 Stearic acid chloride 41
．． 4 g (136.6 mmoj2) was added and stirred at room temperature for 9 hours. After distilling off the solvent, the reaction solution was diluted with chloroform, washed with a 1N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (Merck, Kieselgel 5 Q,
600g, hexane:ethyl acetate = 10:O to 10:1
) to obtain 8 g of oily compound m-230.

Yield 94.6% Physical properties Rf value of compound m-2 0.6 (Merck HPTLC, hexane: ethyl acetate = 5: 1) Example 5 Production of compound Ⅰ Compound I [-233.4 g (46.7 mmol) To 200 ml of an ethyl acetate solution was added 3 g of 10% Pd-C, and the mixture was stirred at room temperature under a hydrogen cloud for 36 hours. The reaction solution was passed through Celite, the solvent was distilled off, and recrystallization was performed from petroleum ether to obtain 23.5 g of needle-shaped compound III (
Yield 80.5%).

Physical properties of compound ① Rf value 0.4 (Merck IIPTLC, hexane: ethyl acetate = 5:1) 500 MHz 'HNMR 0,880 (61 (, t, J l, 255 (561 (, m.)

1.614 (4H, m.

2.082 (ltl, m.

CDCj! 3. TMS, δ 7, 0Hz, CL X 2) CIL2X28) CIi2-3'
L -2') 2.344 (2H, t, J near,
7H2, CL 2' ) 3.729 (2t1.
m, H-3) 4.236 (
lfl, dd, J=11.9. 5.7Hz
ft −1>4.320 (LH, dd, J=
11.9. 4.6Hz H'-1)5.084
(IH, m, H-2) 12
5λ1Hz13cNλIRCDCl3. δ61.7
(C-3or C-1), 61.2(C-1or
C-3), 71.2 (C-2).

173.5. 173.9 (-1:,-).

Example 6 Preparation of Compound (1) 668.2 mg (1.07 mmof) of Compound M and 2.0 g of Molecular Sieves 4A were suspended in four bottles of anhydrous benzene and stirred at room temperature for 30 minutes. Next, 642.7 mg (0,713 mg) of compound U was added under water cooling under an argon atmosphere.
After dropping 2 ml of an anhydrous benzene solution of mmoj2), 274, 7 mg of silver trifluoromethanesulfonate was added.
(1,07 mmof> of anhydrous benzene solution 1.5 mi'
was added dropwise and stirred. This stirring was carried out for 1 hour at 0°C and for 1 hour at room temperature.
It lasted 5 hours.

The reaction solution was filtered through Celite, the solution was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (Wakogel C-300, 100 g, hexane:ethyl acetate=
4: Subjected to 1), 530 mg of a mixture of compounds ■ and V
I got it. The yield was 51.4%, and 530 mg of the mixture was applied to a Rover column (TYPEC, hexane:ethyl acetate=
3: 255 mg of compound IV and 1 mg of compound Vll for 1).

and their mixture (rV:V#1:1 by TLC
) 97 mg was obtained.

Physical property value Rf value of compound ■ 0.28 (Merck IIPTLC, hexane:
500 MHz 'HNλIRCDCL, Tλi
s, δ0.879 (6H, t, J=7.0H
z, CLx2 ) 1.253 (56H, m,
CLX28) 1.517 (4H, m,
C1123' X 2) 1,650 (3H
,s, CLCON)I)2.159 (
4) l, m, CL2'X2)
3.148 (IH, dd, J=10.3.4JH
z H-9a ) 3.565 (LH, dd,
J=10.6,4.8tlz H-9' a) 3.7
57 (LH, dd, J=10.8.4.6Hz
H-1) 3.825 (LH, m,
H-3) 3.952 (LH, dd, J=1
8.3,10.3flz H-5a) 3.025
(LH, m, H-3')4.
226 (ltl, dd, J=10.4, 1.7
Hz H-6a) 4.421 (LH, dd,
J=10.3.3.7Hz H-4a)4.603
(IH, d, J=3.3)1z H-
3a) 4.821 (LH, m,
H-2> Physical property value of compound (Rf sensitivity) 0.24 (Merck) IPTLc, hexane: ethyl acetate = 3: 1) 500! Jflz'HN! , lRCDCl3.
TMS, δ0.879 (68,t, J=7.
0Hz, CLX2) 1.255 (56H, m,
CLX28>1.518 (4H, m,
CL-3'X2)1.711<
3H,s, CL3CON+()2.1
85 (48, m, CL2-2'
X2 ) 3.133 (LH, dd, J=9.7.
6.4) 1z H-9a) 3.554 (IH,
dd, J=9.9,5.9Hz H-9'a
)3.736 (2ft, dd, J=11.0
,4.4Hz H-1)4.015 (IH,m,
H-3a)4.110 (1)1.
dd, J=18.4, 10.6Hz H-5
a) 4.214 (LH, dd, J=10.4,
1.711z H-6a ) 4.303 (IH, d
d, J=lO, 1,3,5Hz H-4a)4
．． 577 (IH, d, J=3.7Hz
H-3a) 4.949 < 18. d,
J=8.1JIz CH3C0LL)5.02
3 (LH, m, H-2) Example 7 Preparation of Compound (1) Compound 1'V 183.0 mg (0.13 mmojl) Ributyltin hydride 48 μj! (0,
4.5 mg (0.03 mmoA) of α,α'-azobisisobutyronitrile was suspended in 8 ml of anhydrous toluene and heated under reflux for 3 hours under an argon atmosphere. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous potassium fluoride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (Wako Gel C-300, 30 g 1 hexane:ethyl acetate = 3+1) to obtain 215 mg of colorless amorphous silica. Then, the obtained 215 mg was subjected to column chromatography (Sephadex LH-20, developing solvent chloroform) to obtain 110 mg of compound (1) (yield 63
．． 4%).

Physical property value Rf value of compound ■ 0.61 (Merck HPTLC, hexane: ethyl acetate = 2: 1) 5oo M) Iz 'HNMRCDC, TMS,
δ0.879 (6H, t, J=7.0Hz,
CLx2 )1,253 (56H,m,
CIL2 X28) 1.53244H, m,
CL 3' X2) 1.760 (3H,s,
CLCONH)2.187 (4H,m,
C11L2 2' X2) 2.494 (If
t, dd, J=13.0, 4.2Hz, H-3
a eq) 3.397 (1) I, dd, J=10
．． 6,4.8Hz, H-9a) 3.101 (LH
, dd, J=10.3, 4.8Hz, H-9' a
)3.707 (LH, +jd, J=10.6,4
．． 4Hz >3.827 (LH, dd,
J=5.9.1.5Hz)4.190(I
H, dd, J=11.7, 4.0flz
)4.890 (IH, m, H-
2) 5.056 (18, d, J=8.1) 1z
CH, C0 company) 125λI) Iz” CNMRC
DC1s, δ14.2 ((L), 22.8(
(JI3CONH), 36.9 (C-3).

5, 14 (C-5), 98.7 (C-2), 1
67, 2. 170.1.173.0゜173.7 (
-C,).

Example 8 Preparation of compound
jl') and α,α'-azobisisobutyronitrile 2.0■ (0.01 mmoA) were suspended in anhydrous toluene 4-, and after heating and refluxing for 3 hours under an argon atmosphere, compound ■
46.5 mg of compound (1) was obtained in the same manner as in the synthesis of (yield: 56.7%).

Physical property value Rf value of compound ■ 0.48 (Merck HPTLC, hexane: ethyl acetate = 2: 1) 500 MHz 'HNMRCDC, TMS,
δ0.879 (68,t, J=7.0Hz, C
11-x2)1.254 (56)1. m,
CLX28) 1.546 (4H, m,
CL2 3' X2) 1.804 (3N, s,
CH3C0NJ ) 2.178 (4H,
m, CL 2' X2) 2.450 (
l) I, dd, J=13.0, 4.6Hz, H-3
a eq) 3.386 (1)1. dd, J=10.
3,6.6Hz, H-9a) 3.550 (1)1.
dd, J=10.1, 6.1Hz, H-9' a)
3.692 (1M, dd, J=11.6, 4.9H
z, )3.835 (ltl, dd, J=5
．． 9.1.5) lz, )5.105 (ltl
, m, H-2) 5.254 (1N
, d, J=8.8 CH3C0NJ()1
25 MHz “CNλIR[”DCjl! , δ
14.2 (-I'11.,), 22.8 (11H3
CONl(>, 36.7(C,).

51.0 (C-5), 98.8 (C-2), 167
．． 3. 170.2,173.1゜173.6 (-
glance).

Example 9 Preparation of Compound (1) Compound VI 79.0 mg (0.06 mmoj of ethyl acetate-methanol solution (1:1) 10% Pd in 3-
-C20mg was added, and the mixture was stirred at room temperature under a hydrogen stream for 18 hours. The reaction solution was passed through Celite, and the solvent was distilled off from the solution. Column chromatography analysis of the obtained residue (Sephadex LH-20, developing solvent chloroform: methanol = 1
:1), white powder, compound 51. Omg was obtained (yield 96.0%).

Physical property value of compound (Rf value) 0.40 (Merck HPTLC, chloroform:
methanol:acetic acid=1.0:4:0.5) boo MH
z 'HNMRCDCl! 3+CD300 (1:1)
, TλIS, δ0.889 (6H,t, J-6,
8Hz, CIL3X2)1, 274 (56)1
．． m, CIL2 X 28>1.60
9 (4H, m, CL
3' X2) 2.051 (3H,s,
CLCONH)2.340 (4H,m,
C) L22' cutting) 2.436 (IH, dd, J
= 12.8, 4.8 Hz, H-3a eq) Example 10 Production of compound ■ 37.1 mg (0.03 mmof) of compound ■ 10% Pd-C in ethyl acetate-methanol solution (1:1) 4-
After adding 10 mg of the compound and stirring at room temperature under a hydrogen stream for 17 hours, compound IX 13.
2 mg was obtained (yield 53.4%).

Physical property value Rf value of compound ■ 0.34 (Merck HPTLC, chloroform:
Methanol:acetic acid=10:4:0.5) 500 MHz
')I NMRCDCj! 3+CD30D(CI)
, TMS, δ0.889 (6)1. t, J Near, OH2, CL3X2 ) 1.275 (56H, m,
CLX28) 1.611 (4H, m,
CL-3'X2)2.044 (3
t(,s, CLCONH)2.332
(4H, m, CL 2' X2)2.
387 (LH, dd, J=13.2, 4.8H
z, H-3a eq) 5.353 (LH, m,
H-2) Example 11 Preparation of compound n-4 Compound 11-350 mg (0,067 mmof) in acetonitrile-water solution (2,5:1) 3.5 mi!
to N-promosuccinimide 15.5 mg (0,08
7 mmol of the mixture was added, and the mixture was stirred at 85° C. for 25 minutes. The reaction solution was evaporated and subjected to silica gel column chromatography (Wakogel C-300, 10 g, hexane:ethyl acetate = 1.5:1) to obtain compound I [-438, 0 mg
The yield was 67.6% for Compound n-4 and 1% for Compound 1-5 as a by-product.

Physical property value Rf value of compound n-4 0.27 (Merck HPTLC, hexane: ethyl acetate = 1.5:1) 500 Mflz 'l (NMRCDCj'+,
TλIS, δ1.647 (3)1. s,
CIIL3CONH)3.369 (LH,br
oad s, 0) 1) 3.728 (1
N, dd, J=11.0, 4.4Hz H
-9a) 3.784 (LH, dd, J= 7.2
, 1.7flz H-7a) 3.895 (LH
,dd, J=18.5,10.48z H-5a
)4.409 (LH, dd, J=10!,
3.7Hz H-4a) Physical property value Rf value of compound n-5 0.49 (Merck HPTLC, hexane: ethyl acetate = 1.5:1) 500 M) lz'HNMRCDC, TMS,
δ1.724 (3H,s, CLCON
) I ) 3.637 (if, dd, J=10.6
,34Hz H-9a)4.877 (l)I,
d, J=9.16 Cl13CON ratio) Example 1
2 Production of compound ll-6 Potassium tert-butoxide 83.2 mg (0,
74 Ho j! ) in 4 volumes of anhydrous tetrahydrofuran solution under an argon atmosphere at 0°C.
After adding all (0,99 mmol) and stirring at 0°C for 15 minutes, compound 11-4493,5 mg (0,
59 mmol of anhydrous tetrahydrofuran solution 6i was heated to 0°C.
and stirred at room temperature for 40 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. :ethyl acetate-1,7:1) to give compound ll-6236,
7 mg and as a by-product Compound II-722,0 mg
Furthermore, 120 ■ of a mixture of both (compound ■-6: compound n-
7=1:1) (yield of compound n-6 was 46.3%).
Met).

Physical properties of compound n-6 Rf value 0.44 (Merck HPTLC, hexane: ethyl acetate = 1.5:1) 500 MHz 'HNMR 1,718 (3H, s.

3.610 (IH, dd.

3.9.40 (LH, t.

4.143 (LH, s.

CDCL, TMS, δC[aCONH) J=10.6,3.78z H-9a) J=10.3
)1z)I-4a)OH) 4.230 (LH, dd, J=19.8,10
．． 26Hz H-5a) 4.365 (11(,d
d, J=11.0. 1. IHz H-6a)4
．． 919 (lfl, d, J=9.5Hz C
)I:+COu )125 M)Iz 13C'N!
JRCDCj! 3 δ23.8 (Cl3CON ratio I
>, 96.7 (C-2>, 169.0. 169.
9(-C-).

Physical properties of compound 11-7 Rf value 0.24 (Merck HPTLC, hexane: ethyl acetate = 1.5:1) 500 MHz 'HNMR 1,688 (3H, s.

3.718 ('LH, dd.

4.339 (LH, dd.

4.724 (LH, d.

COCβa, TMS, δ CK, C0NH') J=11.0.4.0Hz H-9a) J=9.9
N-6a) J=10.9 CLI
CONH) Example 13 Preparation of Compound n-8 To 178.0 mg (0.54 mmoj) of carbon tetrabromide anhydrous THF solution 97.5 μl (0.5
4 mmoj? ) and stirred for 10 minutes, then compound l
l-6155,3 mg (0,18 mmol) of anhydrous T
HF solution 3mi! was added, the temperature was gradually raised from -70°C to room temperature, and the mixture was stirred for 7 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (Wako Gel C-300, 20 g, 1 hexane:ethyl acetate = 1.5:1) to obtain 5 mg of colorless amorphous crystals, Compound n-8135, yield 81.4. %).

Physical property value Rf value of compound ll-8 0.52 (Merck IIPTLc, hexane:ethyl acetate = L5:1) 500 MHz 'HNMRCDCj! s, TMS
, δ1.691 (3H,s, CL
CONft ) 3.584 (LH, dd, J=11.
0.3.3Hz H-9a) 4.170 (11(,
dd, δ49.8.9.9Hz 11-5 a)4.
544 (ltl, d, J=11.0Hz
H-6a) 4.814 (LH, d, J=8.8
Hz CH3C0U) Example 14 Preparation of compound X Compound I [92,3+++g (0,15mmo7)
, mercuric cyanide 37.1mg (0.15mmof
l), mercury(II) bromide 53.0mg (0,1
5 mmoj2) and molecular sieves 4 A 1.
Under an argon atmosphere, two jaws of anhydrous carbon tetrachloride were added to Og at room temperature, stirred for 15 minutes, and compound I [-89L
6 mg (0°l Q mmoj2) of anhydrous carbon tetrachloride solution 3rn1 was added, and the mixture was stirred at room temperature for 42 hours. The reaction solution was passed through Celite, diluted with ethyl acetate, washed with a saturated aqueous potassium iodide solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (Wakogel C-300, 20
g1 hexane:ethyl acetate-4:1) and column chromatography (Sephadex LH-20, developing solvent chloroform dimethanol-1:1) to obtain 114.3 mg of Compound X as colorless amorphous crystals in a yield of 79. 1
%).

Physical property value Rf of compound 3. T
MS, δ0.878 (6H, t, J=7.0H
z CLIX2 )1.254 (56fl, m
, CLX28) 1.527 (4H, m
, CL-3' x2 ) 1.650 (
3H,s, CL3CONH)2.147
(4N, m, CIL2 2' X2
)4.284 (Ill, d, J=9.5tlz
tt-6a) 4.660 (1)1. d, J
=9.2Hz CH3C0u )5.003 (L
H, m, H-2) Compound X is a mixture of the 8-form glycerol moiety and the R-form at a ratio of 3.3:1, but only the 8-form glycerol moiety was analyzed.

Example 15 Production of compound XI Compound X 43.8 mg (0, Q: 3 mmoj2)
,) 'J Phenyltine hydride 31.3mg
(0,09 mmoj7) and α,α'-azobisisobutyroni) IJ 1,1 mg (0,007 mmo
4? ) was suspended in 1 ml of anhydrous toluene, heated under reflux for 4 hours under a nitrogen gas atmosphere, and further added with 31.3 mg (0.09 mmol) of triphenyltin hydride, and heated under reflux for 15 hours. The reaction solution was diluted with ethyl acetate. After washing with a saturated aqueous potassium fluoride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous salt solution, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off.The resulting residue was subjected to silica gel column chromatography (Wako Gel C300, 10
g1 Hexane:ethyl acetate=3:1) to obtain 119.9 mg of Compound X (13.85 mg of raw material recovered Compound XI) as colorless amorphous crystals (yield 49.0%;
71.5% after subtracting the recovered raw materials).

Physical property value Rf value of compound XI 0.52 (Merck HPTLC, hexane: vinegar 5
00 MHz 'HN! , IRCDCjl! -, T!
, IS, aO,879 (6H,t, J=7.0
Hz cLx2 ) 1.254 (56H, m,
CIL2X28) 1546 (4H, m
, CL-3'X2) 1.728
(3H,s, CLCONH)2.2
19 (4fl, m, CL 2'
X2 )2.731 (LH, dd, J=12.8
．． 4.4tlz)I-3aeq) Analysis was performed in the same manner as for Compound X.

125 MHz RCD between 13C [l! ,, δ9
8.9 (C-2a), 167.9. 170.2.
173.0. 173.4 (-C-).

Example 16 Preparation of Compound XII Compound XI 10. Omg (0,007 mmoj
Ethyl acetate-methanol solution (1:1) of 2) 1.
5mi! 15 mg of 10% Pd-C was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 19 hours. The reaction solution was passed through Celite, and the solvent of the 0 solution was distilled off. The obtained residue was subjected to column chromatography (Sephadex LH~20, developing solvent chloroform:methanol = 1:1) to obtain 3.9 mg of Compound X II as a white powder (yield 58
．． 2%).

Physical property value Rf value of compound X■ 0.22 (Merck HPTLC, chloroform:
Methanol: Acetic acid = 10: Methanol = 11) 500 MHz 'HNMRC port, OD+CDCL
(C1), TMS, δ0.889 (6H,t
, J=7.0H2CLX2 )1.274 (568
, m, CIL-X28) 1.617 (
4H,m, C1L23'X2)2.
047 (3)1. s, CLICON
H) 2J26 (4H, m, CL-2
'X2 >2.784 (LH, m,
H-3a eq ) 5.169 (IH, m,
H-2) Analysis was performed in the same manner as for Compound X.

Claims (5)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1 represents hydrogen or an acyl group.) A compound represented by the following. (2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1 represents a hydroxyl group or bromine, or forms a single bond together with R^3, and R^2 is benzyl. (R^3 represents a bromine or phenylthio group, or forms a single bond together with R^1, and Ac represents an acetyl group). (3) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R^1 represents hydrogen or a benzyl group, and one of R^2 or R^3 is -COOR^1 (However, R
^1 represents the same group as above. ), and the other represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼, R^4 represents hydrogen, a halogen atom, or a phenylthio group, and Ac represents an acetyl group. ). (4) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, X is a halogen atom, R is a benzyl group, and Ac is an acetyl group.) A compound represented by the following and the general formula : ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The general formula shown in claim 3 characterized by causing a glycosidation reaction with the compound shown in
R^1 is a benzyl group, R^4 is a halogen atom, and Ac is an acetyl group. ) A method for producing the compound shown in (5) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, X is a halogen atom, R is a benzyl group, Ph is a phenyl group, and Ac is an acetyl group) Claim 3, characterized in that a compound represented by the general formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is subjected to a glycosidation reaction (provided that R^1 is a benzyl group and R ^4 is SPh (Ph is a phenyl group)
and Ac is an acetyl group).