JPS6335591A - Globoside neutral glycolipid and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is H, acetyl; R<2> is formula II, formula III (R<3> is H, benzoyl) OH, F]. USE:Diagnostic and therapeutic agent for malignant lymphoma. PREPARATION:For example, a compound of formula I (R<1> is acetyl; R<2> is acetyloxy) is dissolved in a solvent such as dimethylformamide and allowed to react with H2N.NH2.AcOH (Ac is acetyl) at 50 deg.C under stirring. The reaction mixture is diluted with ethyl acetate, rinsed with water and dried over magnesium sulfate. The solution is concentrated under reduced pressure and purified using flash chromatography to give the compound of formula I (R<1> is acetyl; R<2> is OH).

Description

DETAILED DESCRIPTION OF THE INVENTION [Description of Industrial Field of Application] The present invention relates to novel globo-based neutral glycolipids, trisaccharide compounds constituting their sugar chain moieties, and methods for producing them.

[Prior art] Glycolipid Gaf (αl-4)Gaj2 (β1-4)G
j'c(β1-1)Cer(Bl) is called a globoglycosphingolipid and is known to exist in trace amounts in normal tissues and cells.In particular, recently this glycolipid has been
kitt was found to be present in particularly high concentrations in lymphoma cells (200-800μg/10mgcell).
residue), is considered to be an antigen specific to this cell [J. Waels et al. Journal of Biological Chemistry (J, B, C,) (1
984) 259 14783;Science
ce) (1983) 220 509:l. Therefore, based on this fact, glycolipids (B) and their lipid moiety isomers (
It is expected that antibodies against B-cis) will be created and these antibodies will be applied to the diagnosis and treatment of malignant lymphoma.

In addition, positional isomer Gaβ(β1-3)G of glycolipid (B)
aJ2(β1-4)Gjl! c(β1-4) Cer
(Al is characteristically present in murine breast cancer cells and has been isolated from them. Therefore, the glycolipid diagram is also malignant @
It is expected that it will be applied to the diagnosis and treatment of cancer (
H, Ar1taetal J, Biochem, (To
(1974) 761067).

Furthermore, it has been found that the sugar chains of glycolipids (Bl and (B-cis)) act as receptors for E. coli causing E. coli to adhere to the human ureter, and these glycolipids are responsible for the attachment of E. coli to the human ureter. There is a high possibility that it will be effectively used for diagnosis and treatment (K, Back et al., J, B, C9 (1985) 260
．． 8545].

U (A) [Objective of the Invention] Based on the above findings, the present invention provides novel robot-based glycolipids that are expected to function as antigens for malignant tumors and trisaccharides constituting their sugar chain moieties. The object of the present invention is to provide a compound and a method for producing the same.

[Structure of the invention]

That is, the present invention relates to a glycolipid compound represented by -Katsu CI).

(wherein R1 is a hydrogen atom or an acetyl group, and is a benzoyl group) or a fluorine atom. ) Specific examples of the compounds of the present invention are shown below.

The method for producing the compound of the present invention will be explained below.

[Synthesis of compound θ force]

The synthetic route for compound θ'71 is shown in Scheme 1.

First, compound GD, which is a raw material for the synthesis of compound zero, is synthesized from compound (1) through compounds (2), (4), and αQ as follows.

DB compound (1) is a compound that can be easily prepared by acetylating D-galactopyranose.

Compound (2) is obtained by thiomethylating compound (1). That is, a thiomethylating agent such as thiomethyltributin is reacted with compound (1) in the presence of tin tetrachloride or the like. The reaction is carried out in a solvent such as 1,2-dichloroethane at a temperature of -30°C to 100°C.
It is preferable to carry out for 0 minutes to 24 hours.

The reaction product can be used in the next reaction after being purified by known means if desired.

Then, compound (4) is obtained by converting compound (2) into methanol and N
Obtained by reacting with aOCH3.

The reaction is preferably carried out by stirring at -50°C to 50°C for 30 minutes to 24 hours. The reaction proceeds almost quantitatively, and the reaction product can usually be used as a raw material for the next step as it is.

Compound σQ can be obtained by first reacting compound (4) with NaH and benzyl bromide in a solvent such as DMF. The reaction is preferably carried out by stirring at -50°C to 100°C for 30 minutes to 24 hours.

Compound OD is then compound αQ and Hg CI! 2 and C
It can be obtained by reacting with aCO3 in a solvent such as an 80% C83CN aqueous solution. The reaction is 0
It is preferable to carry out the reaction at a temperature of 30 minutes to 48 hours under stirring at a temperature of 30 minutes to reflux.

The compound mouth is the compound 0υ and SOα2 in dichloromethane,
It is obtained by reacting at -30 to 50°C in a solvent such as 1,2-dichloroethane. Next, compound 04) was prepared by combining compound 02) and compound 03) with Ag5O□CF, and molecular sieve 4A.

It can be obtained by reacting in the presence of a catalyst such as Agα04N HgBr2, Hg(CN)2, etc. The reaction is preferably carried out in a solvent such as 1,2-dichloroethane, dichloromethane, c, HscHzNOz, etc. by stirring at -50°C to 100°C for 30 minutes to 24 hours. Compound 03) can be obtained as follows.

Compound 09 is obtained by mixing compound 04) in a solvent such as formic acid or acetic acid for 1
It can be obtained by contacting with a hydrogen stream in the presence of a catalyst such as 0% Pd-C. Preferably, the reaction is carried out at a temperature of 4°C to reflux.

Compound (B) can be obtained by reacting compound QSI with acetic anhydride in a solvent such as pyridine.
It is preferable to stir at a temperature of 30 minutes to 24 hours at a temperature of 100°C to 100°C.

Compound Q71 is the compound αB and H obtained in this way.
It is obtained by reacting 2N-NH2.AcOH in a solvent such as DMF. The reaction is carried out at -30°C to 100°C.
It is preferable to carry out the reaction by stirring for 1 minute to 24 hours. The obtained reaction product can be made into a pure compound θ by known purification means such as flash chromatography.

[Synthesis of Compound 08)] The synthetic routes of Compounds 08), 09, (21), (23), (24) and (25) are shown in Schemes 2 and 3.

Compound 08) is compound 07) with CCl3CN and NaH
can be obtained by reacting them in a solvent such as dichloromethane under an inert atmosphere such as Ar.

The reaction is preferably carried out by stirring at -30°C to 50°C for 10 minutes to 24 hours.

[Synthesis of compound ■]

The compound 08) and the ceramide compound were mixed with molecular sieve A W 300, BFJhOlTrOS.
O2CF, , TsOH, 5nC1, , Feα3, TrO
3O□CF, and Snα4, Trα04 and Snα2,
Ag03O2CF3 and Snα2, Ag1JI04
It can be obtained by reacting with Sn in the presence of a ceramidation catalyst such as Sn CJ12. The reaction is preferably carried out in a solvent such as chloroform by stirring at -50°C to 100°C for 30 minutes and 24 hours.

Compound (2) can also be synthesized from compound 0η via compound (25) as shown in Scheme 3.

Compound (25) can be obtained by reacting Compound 0 and DAST (diethylaminosulfur trichloride) in a solvent such as dichloromethane.

The reaction is preferably carried out by stirring at -50°C to 100°C for 30 minutes to 24 hours. Compound (2) can then be obtained by reacting compound (25) with 0:1 of a ceramide compound in the presence of the same ceramidation catalyst as above, such as Agα04, Snα2, and molecular sieve 4A. The reaction is carried out in a solvent such as chloroform.
It is preferably carried out by stirring at 0°C to 100°C for 30 minutes to 24 hours.

The reaction mixture containing compound (a) thus obtained can be purified as appropriate by known means such as flash chromatography.

[Synthesis of compound (21)] Compound (21) can be obtained by reacting compound (a) with NaOCH3. The reaction is THF.

! It is preferably carried out by stirring in a solvent such as Je OH or a mixture thereof (e.g. 1:1 mixture) at -20<0>C to 100<0>C for 30 minutes to 24 hours.

Compound (21) CGa1α1-4Ga is obtained by purifying the reaction mixture containing freshly obtained compound (21) using known means such as flash chromatography.
nβ1-4 G Ecβ1-1'CerCE (GbOs
e3Cer) ) can be obtained.

[Synthesis of compound 23)] Compound (23) is a combination of compound 08) and ceramide compound (22).
) and molecular sieve AW300, BF3Et20
It can be obtained by reacting in the presence of the same ceramidation catalyst as mentioned above. The reaction is preferably carried out in a solvent such as chloroform at -50°C to 100°C with stirring for 30 minutes to 24 hours.

Compound (23) can also be synthesized from compound α via compound (25) as shown in Scheme 3.

The method for synthesizing compound (25) is as described above, and compound (25) is synthesized as described above.
23) can be obtained by reacting compound (25) and ceramide compound (22) in the presence of the same ceramide catalyst as described above. The reaction is carried out in a solvent such as chloroform, -
It is preferable to carry out the reaction by stirring at 50°C to 100°C for 30 minutes to 24 hours.

[Synthesis of compound (24)] Compound (24) is obtained by reacting compound (23) with Na0CH1. The reaction is performed using THF, Me
It is preferably carried out by stirring in a solvent such as OH or a mixture thereof (for example a 1:1 mixture) at -20°C to 100°C for 30 minutes to 24 hours.

The reaction mixture containing compound (24) thus obtained was purified using known means such as flashcochromatography to obtain compound (24) CGaβα1-4G.
a, &β1-40 Ilcβ1-1' Cer(z)
) can be obtained.

Compound 071.08), which was asked as above, ■
, (21), (23), (24) and (25) are new compounds.

〔Usefulness〕

The compounds of the present invention are globoglycosphingolipids and intermediates for their synthesis, and can serve as useful reagents for elucidating the biological functions of these glycolipids. That is, the compounds of the present invention can be expected to be applied to the diagnosis and treatment of malignant lymphoma, malignant tumors, and the like.

The present invention will be explained below using reference examples and examples.

In the reference examples and examples, ``-'' in the reaction formula represents an acetyloxy group, and □ represents a benzyloxy group.

Reference Example 1 Compound (1) 37.7 g (96,58+++mo
le) and 36.9 g of thiomethyltributin (109,
45+ nmole) was dissolved in 600 ml of dry dichloroethane, cooled to ice methanol temperature, and under stirring a solution of 17 ml (145,71 mmole) of tin chloride in 200 ml of dry dichloroethane was added dropwise. After the dropwise addition, the mixture was stirred for an additional 3 hours, and then the reaction solution was poured into a saturated potassium fluoride solution, sodium bicarbonate, and ice chips, and the mixture was vigorously stirred. It was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1 liter of acetic acid, washed with sodium bicarbonate, water, and saturated saline, and dried over anhydrous magnesium sulfate.

Recrystallization from ethanol yielded 2.42 g of compound (2). The reconsolidation mother liquor was subjected to flash chromatography (C-300,80
0 g, toluene = AcO (9:1)), and the raw material compound (1) was purified to 2.219 g, compound (2)
is 27.796g (yield 80.81%) including recombination.
) Compound (3) 0.965 g (yield 2.81%) was obtained.

Note that the ratio of α and β was (1:28.8).

[Physical properties of compound (2)] Rf value 0.296 () Luene: Ac0Bt (2:
1))mp, 113-113.5℃ Ethanol [α
]. +1.99° (C=0.94, CH (J 3) elemental analysis calculated value CI sH2□09S: C, 47
, 61%; H, 5, 86%; S, 8.47% actual value C
,47,56; H,5,85,S,8.44'tl-
NMR (400MHz, TMS, CDα3):
δ=5.440 (Ill), dd.

C4-H, J=0.25.3.42Hz; 5.269
6(LH), t, C2-H.

J=10.01Hz; 5.0598(ltl),
dd, C3-H, J=3.42゜10.01
Hz; 4.3966(1)1), d, C1-H,
J=10.01Hz; δ=4.15988. (1N
), dd, C6-H, J=6.59.11.23;
δ=4.12242. C(H), dd, J
=6.59. 11.47; 3.96466 (LH),
dt, C5-H, J=0.25.6.59Hz; 2
, 2015(3H), s, thiomethyl group; 2.161
8(3H), s, acetyl group; 2.1246(3H
), S, acetyl group; 2, 0843 (3N),
s, acetyl group; 2.0537 (3H), s, acetyl group; 1.9939 (3H), s, acetyl group"C-NMR (100MHz, CDα3+ 77,
05ppm): δ=170.331ppm, 170
．． 136.169.990.169.600>0:8
3.385. α, J=151.4Hz, 78.31
? , C;? 1.835. c; 67.302. C
, 66, 523, c; 61.405. C6;20,
613. Acetyl; 11.353. Thiomethyl Reference Example 2 n■ Compound (2N, 171 g (3,09 mmole)
was dissolved in 30ml of methanol and added 0.0ml. I N N
aOCH32mI! was added dropwise. Stir once at room temperature,
When neutralized with Amberlyst 15 and concentrated under reduced pressure, the compound (
4) was obtained in an amount of 646 mg (yield 99.43%).

Samples for analysis were recrystallized from ethanol.

Rf value 0.350 (Rioform:!JeOH(7:
3) ) mp, 132-133°C (ethanol) [α) D-5,08° (C = 0.59, CH30H)
Elemental analysis Calculated value As C7H140SS: C, 39
,99%, H, 6,71; S, 15.25 actual value
C, 39,86; H, 6,72j S, 15.22
'H-NMR (400MHz, T!, lS, d, -
HeOH): δ=5.21219ppm.

d, C1-H, J=9.52Hz; 3.88151
．． dd, (LH), C4-H.

J=1.23.3.41; 3.57677, t,
C2-H, J=9.28; 3.52853. ddd,
(IH), C5-H, J=1.23.5.37.
6.6;3.74685. dd, (1)1),
C6-H, J=6.84.11,47; 3.67937
．． dd, (1)1), C6-H', J=5.3
7.11.48;4.46380. dd, C3-H
, J=3.41.9.27; 2.19358. s.

S-S-C H313C-N (100MHz, d6-MeOH
,49,3ppm): δ=87.217pHm (C-
1, J=153.8)1z; 80.004. C5;
75.618. C3; 70.208. C2; 6
9.916. C4; 62.02°C-6,11,4
81, Thiomethyl group Reference example 3 2.1 g (10 mmole) of compound (4) was dried D
3.2 g of NaH (60%) dissolved in MF
(80 mmole) was added dropwise into a solution of 80 ml of dry DMF at ice methanol temperature. Stir at the same temperature for 30 minutes, and add Bendisib C1? id 9.6 m i7
(80 mmole) was added dropwise at the same temperature. The mixture was stirred at room temperature for 3 hours, methanol was added under water cooling until foaming ceased, and the mixture was concentrated under reduced pressure. Dissolved in 100 ml of ethyl acetate, washed with water, washed with saturated saline, dried over Mg5Os, concentrated under reduced pressure, and subjected to flash chromatography (C-300, 300).
g, hexane: Ac0Et (8:2)) and purified to give 5.22 g of compound αQ (yield 9 L 46%)
I got it.

Rf value 0.413 (hexane: AcOεt (8:
2)) mp, 58-59°C (Hex 7: THF) [
α)n +1.59° (C=2.265, CHα3)
Elemental analysis Calculated value As C35H380SS: 'C,
73,66; H, 6,71; s, 5.62 Actual value C, 73,69; H, 6,71; S, 5.60'
H-NMR (400MHz, TMS, CDα3):
δ=7.16-7.40ppm(20)1), m,
Bn 4-phenyl: 4.95509 (LH), d
, χHz of Bn, J=11.72)1z; 4.8
6227. s, C5-CH2-φ.

(1) 1) , d, an x H2, J = 10.25
Hz; 4.80975 (1N).

d, Bn': X, H2, J=10.26. 4.7
2791 (2H), s, XH2 of Bn:
4.61005 (LH), d, Bn::H2
, J=11.72; 4, 456155 (IH), d,
Bn XH2, J = 11.72; 4.40425 (
IH), d, On: XH2, J=11.72;
4.33616(LH), d, CI-It, J
=9.52; 3.96639 (IH), d, C4-
H.

J=2.93; 3.84364(18), t,
C2-II, J=9.52; 3.55-3.62 (4
H), m, C3-H, C5-H, C6-H, H';
2.20518(3H), s, s-CH3I3C-
NMR (100M)12. [”DCIls, 7
7.001ppm>:δ=138.750. 138.
214. 137.824. 128.369°128
．． 125. 127.833. 127.589. 1
27.492. 85.578° (C1, J=153.
8Hz), 84.819.77.878.74.41
8 degrees? 3.492. 72.615. 68.618.
12.669 Reference Example 4 σ'1 Qll Compound α17
49mg (1,297mn+ole), Hg C12
775mg (2,855mmole), CaCO32
86mg (2,857mmole) of 80% C83CN
The solution was added i:i to an aqueous solution and stirred overnight under reflux.

The mixture was filtered through Celite, concentrated under reduced pressure, dissolved in 100 ml of ethyl acetate, washed with water, washed with saturated saline, and dried over anhydrous magnesium sulfate.

It was concentrated and purified by flash chromatography (C-300, 90 g, toluene:Ac0Bt (8:2)) to obtain 579 mg (yield 82.57%) of the compound Uυ (oil).

Rf value 0.134 () Luene: Ac0tEt (9:
l ) ) [α]o +13.12° (C=1.6
35, CHCl,) Elemental analysis Calculated value C34H360
As 6CH3CO□C2Hs, C,72,59;
H, 7,05 actual measurement value C, 72,79; H, 6,49
13C-NMR (90MHz, CDα3.77.04
5): δ=140.059. 139.678. 13
9.193. 130.198°129.601.12
9.44.129.166, 128.95.128.
79°127.975.99.099.93.03.8
3.546.82.138゜80.027.78.02
．． 76.451.76.234.75.909°74.
717.74.5.74.227.70.708.70
．． 545.70.328 Reference Example 5 579 mg (L 071 mmole) of compound QD was dissolved in 4 ml of dry dichloroethane, and S 0 (J2 1 m
f! (13.7 mmole) and several drops of dry DMF were added and stirred overnight at room temperature. The reaction was stopped by adding a small amount of silica gel and concentrated under reduced pressure.

The product was purified by flash-cut 07 (C-300, 50 g, n-hexane: AC○εt (9:1)) to yield 558 mg (yield 93.19%) of compound Q21.

Rf value 0.230 (n-hexane + Ac0Et (9
: l)) Oil [α)o +55.56° (C=0.63.C
Hα3) Elemental analysis Calculated value: C3-H3sOsα%Ac
2C as 0Et, 73,04%; iL6.31; α
, 6.34 actual measurement C, 72, 34, H, 6, 42'
H-NMR (40MHz, TMS, CDα3.) δH6
, 139 (d, 1 μ.

J = 3.611z, H-1) "C-N!JR (90MHz, CDα3+ 77
．． 045): δ= 138.270°137.72
8. 128.136. 128.027. 127.
867, 127.594°127.325. 94.
869° (C1, J・180.67)1z), 78.181.
76.178.74.770°74.444. 73.
196. 73.087. 72.654. 72.2
77°67.889. 30.449 Reference Example 6 03) Foot ■ Compound (13H, l g (1,131 mmole), compound surface 0.759 g (1,358 mmole) and Ag
03O2CF30.872 g (3,390 mmol
e) was dissolved in 20ml of dichloroethane and stirred overnight at room temperature in an argon stream in the presence of 4g of molecular sieves 4A.

50 ml of ethyl acetate was added and the mixture was filtered onto Celite. Concentrate under reduced pressure and perform flash chromatography (C-300, 200
Purified with g,n-hexane:AgOεt (8:2>),
924+ng of α-compound 04) with a yield of 82.51%
, 284 mg of β-compound a9 was obtained. α.

The ratio of β was 3.25:1.

[Physical properties of compound 04)] Rf value 0.423 Oil [α]o +24.05° (C=0.895.C
HcI23) Elemental analysis Calculated value: Cs s H980
+ As s: C, 76, 28%; H, 6, 60% C, 76, 57%; H, 6, 61% "C-NMR (100 MHz, CDCl 3.77.0
50): δ= 139.140°138.799. 1
38.652. 138.457. 138.068.
137.629°128.515. 128.223
．． 128, 125. 127.833. 127.5
89°127.492. 127.199. 102.
880. (C1b, J = 157tlz) 102
．． 539 (C1a, J456.3Hz),
100.784 (C1c, J=164.8),
82.703. 81.728. 79,486.
76.660. 75°246, 75.051°74.905. 73.736. 73.199. 7
3.102. 72.468°72.127. 70.
958. 69.495. 68.326. 67.7
90 [Physical properties of compound u9] Rf value 0.283 Oil [α) o +18.61° (C=1.89.C
Hα3) Elemental analysis Calculated value: Cs s Hs a O
+ As s: C, 76, 28%; H, 6, 60 Actual value C, 75, 59%; H, 6, 59I3C-NM
R (1001, lHz, CDα, 77.045):
δ= 139.245°139.137.138.
92.138.704.138.539.138.43
゜137.997.137.62.128.626.1
29.136.128.028゜127.919. 1
27.811. 127.65. 127.542.
127.325°127.109. 102.835
(C1, J=162.35Hz), 102.61
9 (C1, J=161.14), 102.51
(C1, J=161.13)1z), 83.114.
82.463. 82.03. 81.813. ．． 80
．． 513°79.971. 76.612. 75.1
47. 74.822. 74.553°73.849
．． 73.361. 73.09. 72.494.
70.815,? 0.11. 69.08. 68.7
56. 68.268 Reference Example 7 Compound 041906.8mg (0,606mmole
) in 45 nl of acetic acid, 10% PdC, 450 mg
was added and hydrogenated at 80°C for 2 hours.

Filtered onto Celite, washed with 50% ethanol and dried under reduced pressure, yielding 305.21 T1 g of compound QSI (99,
8%).

Rf (direct 0.285 n BuOH:Et
OH:H2O(2:2+1) [α)o +87.95° (C=0.475.H
2O)'H-NMR (400M) lz, acetone,
D20.60℃): δ=5.221495ppm (0,
4H, d, H-1aα, J=3.91Hz); 4.
96990 (LH, d, H-1c, J=3.42H
z); 4.65631°(0,6H,d, H-1
aβ(3), J=8.06Hz); 4.5073H
IH, d.

H-1b, J=7.56Hz) ;4.314(t,
LM, J = 6.3Hz, H"5c); 3, 2
84 (t, a6H, J = 8.3Hz, H-2aB
)13C-N! , IR (90!JHz, dioxane, 6
4.637 D20): δ=103.971. LQ
l, 102.96.494.92.541. ? 9.6
46°78.237.76.12275.528.75
．． 146.74.661, 73.035°72.169
, 71.679. 70.923. 69.839.
69.351゜67.347.61.441.61.1
16.21.130°Compound αS1316mg (0,
627 mmole) was dissolved in 3 mff of anhydrous pyridine, 6.5 ml (68.99 mmole) of acetic anhydride was added, and the mixture was stirred at room temperature overnight. It was concentrated under reduced pressure and subjected to flash chromatography (C-300, 50g 1 toluene: Ac0Et (
1:1.5) to give compound 051342mg (
Yield: 6 g, 16%).

Rf value 0.471.0.426 () Luene: Ac0
Bt (1: 2)) (αl o +62.51°
(c=0.58. cHat3) Elemental analysis Calculated value:
C4oHs*o□t ・As %C7H8: C, 51
,58%; H, 5,77 Actual value C, 51,11%; H, 5,83' H-NM
R (400MHz, CDα, TMS) δ86.25
2 (d, 0.5tl, J = 3, 6Hz; H-1
a α), 5.690 (d, 0.5H, J=8.
Hz, -1a8).

5,591 (bs, IH, H-4c) I3C-N!
, lR(90Ml(z, CDα,, 77.045)
:δ= 170.7221)I)m, 170.236
．． 170.02. , 169.69°169.153.
168.554. 128.79. 127,975
．． 125.049゜180.884.100.616
．． 99.315.91.405.88.804°? 6.
72.73.36.72.55.71. skin 70,599
．． 69.624゜69.353.69.082.68.
974.68.649.67.836°67.07? ,
66.969. 66.752. 61.768.
61.497°60.251. 29.096. 2
0.536. 20.319. 20.211 Example 1 Compound 061326 mg (0,3371 mmole)
was dissolved in 1 mA of dry DMF, and 82N -NH2.Ac
0840, 3 mg (0,4383 mmole) was added and stirred at 50°C for 30 minutes. The mixture was diluted with 50 ml of ethyl acetate, washed with water, and dried over magnesium condensate sulfate. Concentrate under reduced pressure and flash chromatography (C-300, 50g: toluene; Ac
Compound Q61 was purified with 0Bt (1:2) at 27.
8 mg was recovered, and 242.8 mg of compound 0η (yield 84
．． 03%) was obtained.

Rf value 0.184 Toluene: Ac0Bt (1:
2)'H-NMR (400MHz) δH5,590
(bs, LH, M-4c) 13C-NMR (90MH
z, CDα,, 77.045),: δ= 17
0.397°170.233. 169.851. 1
69.366, 169.261. 168.715°100.7?6. 99.259. 89.832.
76.720. 76.287°72.711.71.
896.71.410.69.7g5.69.134゜68.755.67.943.67.076, 61.5
49.60.357°20.58g, 20.426.
13.978 Example 2; Gohe/Shi! ? Compound Q7) 237mg (0,2530mmole)
, CCl3CN 101μj2 (1,012mmol
e) was dissolved in dry CH2Ce21rr+j2, and NaH (60%) 12.1 mg (0,303
6 mmole) was added thereto, and the mixture was stirred for 5 hours under water cooling. It was concentrated under reduced pressure and purified with flash chroma) (C-300, 10 g, toluene; Ac0Et (l:2)) to recover 66.6 mg of compound 0, and 95.9 mg of compound 08) (
A yield of 4 g, 76%) was obtained.

Rf value 0.420.0.460) Luene: Ac0B
t (1: 2) Elemental analysis Calculated value: C41H5□0
□As 6; C, 45, 55%, H, 4, 85, N,
1.30°C9,80 Actual value C,46,73,H,5,16,N,1.33
') l-NMR (400MHz) δH, 8,648
(S, LH, C=NH), 6.482(d,
LH, J = 3.8Hz, fl-1a), 2.1
32.2.109.2.096°2, 092.2.0?
4.2.066, 2.063.2.042.2.011
．． 1.987 (S x 10.30H, Ac x 10
)"C-NMR (90MHz, CDcis, 77.
045): δ= 170.397°170.233
．． 169.851.169.261.168.664.
160.913°128.894. 128.084.
125,210. 100.828. 99.476
゜92.974. 76.772. 75.853.
72.762. 72.060°? 0.652. 68
．． 864. 67.997. 67.238. 67.
076°61.603. 60.357. 20.48
0. 14.086 Example 3 Compound 0 in the presence of 100 mg of Lili eye-dried MS (acid resistant)
8) 50mg (0,0462+nmole), compound (1'l134.9mg (0,0462mmole)
) was dissolved in 1 ml of chlorophore/Llk, 6 μl of BF3Et20 was added under ice-cooling in a stream of air, and the mixture was stirred at room temperature overnight.

After filtering on Celite and concentrating under reduced pressure, flash chromatography (
C-300, toluene; Ac0Et (1:2')
or (1:1)) and purified compound (a), 10 mg
(yield: 13.03%).

Rf value 0.62) Luene: Ac0Et (1: 2
) e [α] b +35.47 ° (C=0.5.
CHC3) Elemental analysis Calculated value: C5qHrx702a
As N; C, 62,91%, 'H, 8,31; N
, 0.84°Actual measurement C, 62,77; H, 8,3
0; N, 0.84°' H-NMR (400MHzC
Dα3. TMS) δH, 5,867 (dt, IH, J
= 6.9 and 15.4 Hz, H-5 ceramide).

5, 751 (d, IH, J=9.0Hz, NH).

5,581 (d, IH, J = 2.4Hz, H
-4c) 5,540 (t, IH, J = 7-3)
1z, H-3 ceramide) 5.471 (dd, IH, J
=7.8 and 15. IHz, H-4 Ceramide) 5.384 (dd, ill, J = 3-2 and 11.0.
Hz, H-3c).

4,979 (d, IH, J = 3-7Hz, f
l-1c).

4,480(d, IH, J=8.1t(z, H-1
b).

4,461 (d, LH, J = 7.8Hz, H-
1a) Example 4 2IIm 4 〇Compound□l Omg (0,00602mmole)
Dry 1 mjl of a mixture of THF:MeOH (1:1)
' and 5% NaOCH310pR (0,021
4 mmole) and stirred at room temperature for 5 hours.

After neutralizing with Amberlyst 15, it was concentrated under reduced pressure and Sephadex 2H20 (lx30cm, chloroform:MeOH:
Purification with H2O (60:30:4.6) gave 5.7 mg (83,30%) of compound (21).

Rf value 0.398 Riooform:MeOH:
H2O (60: 30: 4.6) [α)o +19.04° (C=0.355.pyridine) 1-NMR (400MHz, 49 Knee I
DMSodg-ro, OTMS): 5.564 (d,
IH, J = 6.8 and 15.4 Hz, H-5 ceramide) 5,385 (dd, 1N, J = 6.6 and 15-
2Hz, H-4 ceramide).

4,825 (d, LH, J = 3.9) 1z, H
-1c).

4.284(d,1)I,J =7.3)1z,)l
-1b).

4,179 (d, LH, J = 7.8Hz, H
-1a).

4,068(t, LH, J =6.8Hz, H-
5c).

3, '944 (dd, IH, J=5.4 and 10.3H
z, H-1 ceramide).

3,925 (t, IH, J = 7.3Hz, H-
3 ceramide).

3,826 (d, LH, J = 3. (lHz
, H-4c).

3,776(d, 1)1. J = 3.0Hz,
H-4b).

3,063(t, 1)1. J = 8.1) 1z,
)I-2a) Example 5 Compound 18134.9mg (0,03228mmol
e), compound 22.24 mg (0,03179 mmo
In the presence of 100 mg of MS and AW, 100 mg of MS and AW were dissolved in 0.71 g of chloroform, and phoron-trifluoronite terretro μβ (0,04878 mmole) was added dropwise under water cooling, followed by stirring overnight at room temperature. Flash chromatography (C-300,
The product was purified with 6 g of toluene and ethyl acetate (1:1) to obtain 17.8 mg of compound (23) (yield: 33.71%).

Rf value 0.632) Luene:ethyl acetate (1:2) [α
)o +39.70° (C=0.845.CHα
,) Elemental analysis Calculated value: CayH+3tNO2s・H
As 2O; C, 62, 24%, ! (,8,34,N
, 0.83 actual value C, 62, 13, ) 1, 8.19.
N, 0.97 Example 6 U Compound (23), 47 mg (0,02830 mmol
e) Dried THF:! , 1eOH (1:1) dissolved in 2m of a mixed solution, 5% Na0CH, 347pi! (0,
1 mmol was added under water cooling, and the mixture was stirred at room temperature for 2 hours. Neutralize with Ambust 15, Sephadex 2H-2 (IX30
cm, chloroform:MeOH:H2((60:30:
4.6) to obtain the compound (228.6 mg (yield: 8
8.93%).

Rf (m O, 528 chloroform; methanol H2
0 (60: 30: 4.6) (:αl o +18.02° (C= 1.355
．． Pyridine) Example 7 Compound 0η49.1mg (0,0524mmole)
was added to 21 ml of dry CH2G and DAST12 was added under ice cooling.
．． 3 μβ (0,1048 mmole) was added and stirred at room temperature overnight. After diluting with CH2C12 and washing with water, flash chromatography (C-300, 7g, hexane:THF (1:
1)) to give compound (25), 25.8 mg (94,
3%).

Rr value 0.410 Hexane:THF (1:
1) IH-NMR (400MHz, COα3) TMS
) δH5,740 (d, 0.09H.

J3.3Hz, dd, H-1a α), 5.5
86 (d, LH, J = 2.4Hz, H-4c
).

5,411 (dd, LH, J =5.1.53.0
Hz, H-1a β), 2.136 (S.

6H), 2.132(3,3)1), 2.113(
s, 3H), 2.085 (S, 3H).

2,079 (S, 3H), 2.075 (S,
3H), 2.055 (3,6H), 1.994
(S, 3H), ACx 10 Example 8 Ag (JO48,6mg (0,0415mmole)
, 5nce28.2mg (0,04342mmole
), 300 mg of MS4A was dried, and 21 mg (0,02265 mmole) of compound (19) and 14.2 mg (0,01888+r+) of compound (25) were added to it.
+nole) was dissolved in 31 ml of CHα and added under water cooling. Stir overnight at room temperature, dilute with CHα3, wash with saturated sodium bicarbonate water, and purify with flash chromatography (C-300, 5 g, hexane:THF (6:4)) to obtain 9.2 m of compound (a).
g (29.3%).

Claims (14)

[Claims] (1) A compound represented by the general formula [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 is a hydrogen atom or an acetyl group, and R^
2 is a hydroxyl group, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is a hydrogen atom or a benzoyl group ) or fluorine. ) (2) Reacting the compound (16) represented by the general formula [I] (in the formula, R^1 is an acetyl group and R^2 is an acetyloxy group) and H_2N・NH_2・AcOH Compound (17) represented by the general formula [I] consisting of (wherein R^1 is an acetyl group, R^2
is a hydroxyl group. ) manufacturing method. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (3) Claim No. 2 in which the reaction is carried out in DMF
) The manufacturing method described in section 2. (4) General formula [I] consisting of reacting the compound (17) represented by the general formula [I] (in the formula, R^1 is an acetyl group and R^2 is a hydroxyl group) with CCl_3CN and NaH. A method for producing a compound (18) represented by [I] (in the formula, R^1 is an acetyl group, and R^2 is ▲a mathematical formula, a chemical formula, a table, etc.). (5) The manufacturing method according to claim (4), wherein the reaction is carried out in CH_2Cl_2 under an Ar atmosphere. (6) Compound (18) represented by the general formula [I] (in the formula, R^1 is an acetyl group, and R^2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼) and ▲mathematical formula,
There are chemical formulas, tables, etc. ▼ Compound (20) represented by the general formula [I] consisting of reacting with (in the formula, Bz represents a benzoyl group)
In the formula, R^1 is an acetyl group, and R^2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, Bz is a benzoyl group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (7) Claim No. 6 in which the reaction is carried out in the presence of BF_3Et_2O and molecular sieve AW300.
Manufacturing method described in section. (8) Compound (20) represented by the general formula [I] (In the formula, R^1 is an acetyl group, and R^2 has a mathematical formula, chemical formula, table, etc.) (In the formula, Bz is a benzoyl group Compound (21) represented by the general formula [I], which is obtained by reacting NaOCH_3 with NaOCH_3 (in the formula,
R^1 is a hydrogen atom, and R^2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼) Manufacturing method. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (9) Compound (18) represented by the general formula [I] (in the formula, R^1 is an acetyl group, and R^2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼) and ▲mathematical formula, chemical formula There are tables, etc. ▼ (in the formula, Bz represents a benzoyl group) and the general formula [
Compound (23) represented by [I] (in the formula, R^1 is an acetyl group, and R^2 is ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (in the formula, Bz is a benzoyl group)) manufacturing method. ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (10) Claim No. 9 in which the reaction is carried out in the presence of BF_3Et_2O and molecular sieve AW300.
) The manufacturing method described in section 2. (11) Compound (23) represented by general formula [I] (
In the formula, R^1 is an acetyl group, and R^2 is a ▲ mathematical formula, chemical formula, table, etc. ▼ (in the formula, Bz represents a benzoyl group)) and NaOCH_3. Compound (2) represented by formula [I]
4) (In the formula, R^1 is a hydrogen atom, and R^2 is ▲ which has a mathematical formula, chemical formula, table, etc.). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (12) Compound (17) represented by general formula [I] (
Compound (25) represented by the general formula [I] consisting of reacting DAST (diethylaminosulfur trifluoride) with DAST (in the formula, R^1 is an acetyl group and R^2 is a hydroxyl group) (in the formula , R^1 is an acetyl group and R^2 is a fluorine atom). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (13) Compound (25) represented by general formula [I] (
In the formula, R^1 is an acetyl group and R^2 is a fluorine atom) and ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula,
Compound (20) represented by the general formula [I] (wherein R^1 is an acetyl group and R^2 is a ▲ mathematical formula, chemical formula, table, etc.) There is a method for producing ▼ (in the formula, Bz represents a benzoyl group). ▲There are mathematical formulas, chemical formulas, tables, etc.▼〔I〕 (14) The manufacturing method according to claim (13), wherein the reaction is carried out in the presence of AgClO_4, SnCl_2 and molecular sieve 4A.