CA1262131A - Sialyloligosaccharides and preparation thereof - Google Patents
Sialyloligosaccharides and preparation thereofInfo
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- CA1262131A CA1262131A CA000555845A CA555845A CA1262131A CA 1262131 A CA1262131 A CA 1262131A CA 000555845 A CA000555845 A CA 000555845A CA 555845 A CA555845 A CA 555845A CA 1262131 A CA1262131 A CA 1262131A
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention is concerned with new compounds of the formula:
wherein R1 is hydrogen, R2 is hydrogen or acetyl, or R1 and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form isopropylidene, or R5 and R6 together form isopropylidene and Bn is benzyl.
These new compounds are useful as an intermediate in the synthesis of sialoylglycoconjugate, recognition marker on the cell surface, and antagonists.
The invention is concerned with new compounds of the formula:
wherein R1 is hydrogen, R2 is hydrogen or acetyl, or R1 and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form isopropylidene, or R5 and R6 together form isopropylidene and Bn is benzyl.
These new compounds are useful as an intermediate in the synthesis of sialoylglycoconjugate, recognition marker on the cell surface, and antagonists.
Description
l3~
This application is a divisional of Canadian application No. 469,649 filed December 7, 1984.
The invention relates to new sialyloligo-saccharides which correspond to the non-reducing terminal tetrasaccharide unit of N-glycosidic sugar chain of glycoprotein such as borine blood coagulation factor II (see E.G. Berger et al, Experientia 38 (1982) 1129 - 1133), and to the method for producing the same.
NeuAc~ 2 ~6Gal ~ 1~ 4GlcNAc~ 1 ~ 2Man ~1 6Man~ 1~ 4GlcNAc~ 1 NeuAc~ 2 ~6Gal~ 1~ 4GlcNAc~ 1 t2Man~ 1 ~ 3 4GlcNAc R 1~ Asn NeuAc : N-acetyl neuraminic acid Gal : Galactose Glc : Glucose Man ` : Mannose GlcNAc : N-acetyl glucosamine Asn : Asparagine Sialic acid exists in free or combined form with sialoylglycoconjugate such as glycoprotein, glyco-lipid, oligosaccharide, polysaccharide, etc. in the surface oE animal or bacterial cell and much attention is now focused thereon from a medical and pharmacological point of view as a compound involved in immunity, cancer, inflammation, virosis, cytodieresis, hormone receptor, etc.
With increase in use of chemotherapeutics such as adrenocortical hormone or immunosuppressant for the treatment of various diseases such as carcinosis, hypo-immunity and many kinds of side effects are observed and therefore, it is becoming more difficult to treat a subject suffering from such diseases as cancer.
Particular attention has been paid to the importance of sialic acid, which is one of inherent con-stituents of animal living body, as a marker on the cell surface and reactions of sialic acid halide as a glycosy~
donor with various glycosyl acceptors have been conduct-ed. As a result, new sialyloligosaccharides have beensynthesized which are expected to cause no side effect and to possess, many physiological activities such as adaptation of immunoresponse.
The invention of the parent application pro-vides sialyloligosaccharides of the formula described below and the method for producing the same:
-1 ~6~
0~ CooR ~
AcH ~ 0~\ NHAc OR2 ~O--R2 R30~ \
R30--~
or OR2 . .
o ACH~ V
NHAc OR / ~
R 3 0--~ ol R30~
wherein Rl is hydrogen or methyl, R2 is hydrogen or acetyl and R3 is hydrogen or benzyl.
The sialyloligosaccharides of the above formula according to the present invention can be prepared by reacting the glycosyl donor of the formula (12), which can be derived from sialic acid by a conventional method, with the glycosyl acceptor, trisaccharide of the formula (10) to form tetrasaccharide and optionally removing acet~l, methyl or benzyl groups.
H OH NHAc AcO ~ / O
Ac~o~o1 OAc OAc C8n enO~O \
B nO~~--~1 OBn ,:
wherein Ac represents acetyl and Bn represents benzyl, .
OAc OAc ~1 ' X
AcOk\O
ACHN~L7~ COOCH3 OAc : wherein X represents halogen, preferably Cl or Br.
.
The glycosyl donor (12), the starting compo~nd of the~
present invention, can be derived ~rom sialic acid methyl ester peracetate (11) by Xuhn et al method (Chem Ber., 99 611~617 (1966)).
OAc OAc CA~ ' OAC
- OAc The glycosyl acceptor (10), the other st~rting material of the present invention, can be derived ~rom the compQund (6) which can be prepared as follows:
CHzO~n Aco ~ I CH~OAc NPhth BnO ~ AcO~ ~ -OA c Crl 2 OA c 08n RO CH2oR Ni?; R O
RO\~
OR 2 C~55n ¦
anO ~ I
5 nO ~ a OCn (3~ R = Ac, Rl,R2 = Phth (4) R = H, Rl,R2 = Phth (5) R = H, Rl,R2 = H2 ~6) R = Ac, Rl,R2 = H,Ac (Phth represents phthaloyl) The cornpound ~1) is reacted with the disaccharide donor (2) in the presence o~ AgOSO2CE'3 and molecular sieves 4A
powder to give the trisaccharide ~3) which is treated with NaOCH3/C~3O~ to give the compoun~ (4) which is then treated with CH30H-butylamine to give the compound (5) which is subse~u~ntly treated with Ac2O-pyridine to give the compound (6).
The compound (1) can be prepared by, for example, the method described in T. Ogawa, H. Yamamoto, Carbohydr. Res., 104 (1982) 271-283. The compound (2) can be prepared by the method described in M.M. Ponpipom, R.L Buglanesi, T Y. Shen, Tetrahedron. Lett., (1978) 1717-1720; J. Arnarp, J. Lonngren, J. Chem. Commun., (1980) 1000-1002; J. Chem. Soc Perkin Trans. 1, (1981) ~070-2074; T. Ogawa, S. Nakabayashi, Carbohydr. Res., 97 (1981) 81-86; P.U. Lemieux. S.Z. Abbas, B~o Chung, Can. J. Chem., 60 (1982) 58-62.
The glycosyl acceptor (10) can be derived from the resulting compound (6) as shown below.
'.
. .
:
~o OR OR NHAc ~ NHAc o ~ ~ l o~ AcO~
Ro \ - ~\~) ~ / 7~ OAc OA c _ .
08 nO¦ ~nO~ ~1 BnO~ ~ ~ o~OL7~ Oan B nO
Ac ( 6 ) R = Ac BnQ~
(7) R = H ~ OBn The compound (6) is deacetylated by alkaLi metal alkoxide/alcohol, such as NaOC~3/CH30H to obtain the compound (7) which is then reacted with (CH3)2C(OCH3)2 in the presence or catalyst such as p-toluenesulfonic acid (p-TsOH) and subsequently acetylated by, for example, acetic anhydride/pyridine to give 4,6-0-isopropylidene derivative (8) and 3,4-0-isopropylidene derivative (9). The compound (8) is treated with acetic acid/methanol to obtain the glycosyl acceptor (10).
The glycosyl acceptor ~10) is reacted with the glycosyl donor (12) in such solvent as dichloromethane, 1,2-dichloroethane, etc. in the presence of glycosidation catalyst such as Hg(CN)~, HgBr2, molecular sieves, Ag~CO3, AgClO4, AgOSO2 CF3, (C~I3)3COSO2CF3, etc. at -20C to 150C, preferably -5C to 20C, for 1 to 120 hours, preferably 1 to 5 hours to give ~-anomer (13) and ~?-anomer (14) which can optionally be deacetylated, saponified and debenzylated to obtain ~ -anomer (15) and ~ -anomer (16), respectively. Deacetylation, saponification and debenzylation can be performed in conventional systems such as NaOCH3/CH3OH, NaOH/tetrahydrofuran, or paLladium on charcoal/hydrogen system, respectively.
~J COOR t AcHN~ ~O~ NHAc Rt Rz R3 R20~' ~~ O
~3 Mc Ac Bn ORz OR2 OR3 R~O;~
Ac~lN ~ Ac R zO --~ _~ OR~ ¦
R30~--`~ dR3 Rl R2 R3 (14) Me Ac Bn (16) H H H
All the compounds (3), (4), (5), (6), (7), (8), (9), (10), (13), (14), ~15) and (16) thus obtained are new and have never been disclosed in any references.
The invention of the present divisional appli-cation prov.ides new compounds having the general formula:
R50 CH~OR~ ~RlR2 R3~
-- ~ o 4 ~ cn3 cH2osn j BnO ~
BnO ~__~~~
. OBn wherein Rl is hy-drogen, R2 is hydrogen or acetyl, or Rl and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form iso-propylidene, or R5 and R6 together form isopropylidene and Bn is benzyl.
The above compounds are prepared by reacting a compound of the formula:
CH~OBn BnO ~ H
BnO
OBn _ g _ wherein Bn is benzyl, with a compound oE the forrnula:
AcO C~2OAc ~Phth ~ O\ AcO~ ~X
AcO
OAc CH~O~5 wherein X is halogen, Ac is acetyl, Phth is phthaloyl, and optionally performing deacetylation, dephthaloylation and/or acetylation.
The compounds of the invention may be employed as a useful interme~iate for the synthesis of the afore-mentioned sialoylglycoconjugate and they are expected to possess function as recognition marker on the cell surface and ant`agonists.
The inventions or both the parent and division-~al applications will now be illustrated with reference to the following non-limiting examples.
Example 1 Molecular sieves 4A powder (10 g) was vacuum-dried at 190C for 21 hours, to which AgOSO2CF3 (3.4 g, 13.2 mmol) and 1,2-dichloroethane (40 ml) were added and argon was substituted for air in the reaction system.
The compound ~1) (1.6 g, 3.0 mmol~ dissolved in 1,2-di-chloroethane (20 ml) was added and the reaction mixture was cooled to -20C. The compound ~2) ~3.5 g, 4.4 rnmol) dissolved in 1,2-dichloroethane ~50 ml) was added dropwise.
The reaction was performed for 17 hours at -20C to room temperature. After -the reaction was completed, methylene dichloride ~500 ml) was added. The reaction mixture was filtered through Celite ~reyistered trademark), washed with water and sodium bicarbona-te solution, and dried on MgSO~.
After filtration, the filtrate was concentrated in vacuo.
The residue was subjected to column chromatography ~silica gel 300 g), toluene/ethyl acetate = 3/1) to give the compound (3) (3.45 g, 93.2% from the compound (1)) as oily syrup.
~The compound (3~ .
TLC Rf = 0.39 (toluene/ethyl acetate = 2/1) Analysis. Calcd~ for C66H71N23 3/4C6H5CH3 C, 65.06;H,5.90;N,1.06 Found C,6;.15;H,5.95;N,1.06 ~23-5 = ~4.2 (C = 1.03, CHC13) Example 2 The compound ~3)(2.2 g) was dissolved in methanol (40 ml) and lN-NaOCH3 (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 22 hours and concen~rated in vacuo. The residue was dissolved in methanol (lO0 ml), to which n-butylamine (20 ml) was added and refluxed in a bath at 100C for 45 hours. The ~eaction mixtu~e was concentrated in vacuo. The residue was dissolved in pyridine (30 ml)~ to which acetic anhydride (30 ml) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 200 g, toluene/ethyl acetate - l/l) to give the compound (6)(1.9 g, 95.0~) as syrup.
.. . . . . .. . ... .. .
- 12 ~
~The compound (6)~
TLC ~ RE - 0.54 ~CH2C12/acetone = 5/1) AnalySiS: Calcd. for C60H71N2~:
C, 62.22; H, 6.18; N, 1.21 Found C, 62.57; H, 6.31; N, 1.50 ~21 ~ 6 5 (c = 1.15, C~C13) Example 3 Synthesis of the compound (7) The compound (6) (1.9 g) was dissolved in methanol (40 ml), to which 1N-NaOCH3 (1 ml) was added and stirred at room temperature for 19 hours. AMBERLITE (registered trademark) CG-50 TYPE 2 (1 ml) was added to the reaction mixture and stirred for 10 minutes to neutralize it. The reaction mixture was filtered through Celite, concentrated in vacuo to give quantitatively the compound (7) (1.5 g) as crystal.
~1 ` .
[The compound (7)) TLC: Rf= 0.48 (CHC13/CH30~ - 3/1) Analysis: Calcd. for C~HsgNO16.1/2 H~O
C, 63.01; H, 6061; N, 1.53 ~ound C, 63.03: H, 6.73: N, 1.77 PMR: 'H-NMR(CD30D): 7.30 (20H, s, aromatic) 1~93 (3H~ s, COCH3) Example 4 Synthesis of the compounds (8) and (9) The compound (7) (304.9 mg) was dissolved in dimethylformamide (3 ml), to which (CH3)2C(OCH3)2 (0.2 ml, 5 . - 13 -~i2 ~
eq.) and p-toluene sulfonic acid (10 mg) was added and stirred at room temperature for 15 hours. Triethylamine (1 ml) was added to the reaction mixture which was then concentrated in vacuo. The residue was dissolved in pyridine (5 ml), to which acetic anhydride (5 ml) was added and stirred at room tem~erature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 30 g, toluene/ethyl acetate = 2/3 containing 1% triethylamine) to give the compound (8) (256.0 mg, 68u3%) as syrup and the compound (9) (39.4 mg, 10.5%) as syrupO
[The compound (8)~
TLC ~f: 0.40 (toluene/ethyl acetate = 1/3) (The compound (a), Rf = 0.53) Analysis: Calcd. for C59H71NO20 C: 63.60, H: 6~42, N: 1.26 Found C: 63.36, H: 6.48, N: 1.33 ; [~)D23O5~ 23.5 (C - 1.33, CHC13) PMR ~ 7.4 - 7.1 (20H, m, aromatic) (CDCI3) 2.12 (3H, s, Ac~, 2.04 ~6H, s, Ac x 2) 1.97 (3H, Sr Ac), 1.80 (3H, s, Ac), 1.42 and 1.36 ~2 x 3H, s, isopropylidene) CMR 100.84 (C-lc, lJCH159.7Hz), (CDC13) 99.08 5C-lb, lJcH158.7Hz), o~ ~ Me g8.9~ ( ~Ç~ ), o Me 96.74 (C-lar lJCH167.2HZ), Example 5 Synthesis o~ the compound (10) The compound (8) (602.4 mg) was dissolved in 50%
acetic acid/CH30H (30 ml) and stirred in a bath at 80C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 60 g, CHC13~CH30H = 15/1) to give the compound (10) ~456.7 mg, 80.4%) as syrup.
[The compound (lC)) TLC: R~ = 0.54 (CHC13/CH30H = 10/1) Analysis Calcd. for C56H67N20 H2 C, 61.58; H, 6.37; N, 1.28 Found C, 61.56; H, 6.24; N, 1.30 ~)23~5 ~ 12.5 (Cl.18, CHC13) PMR (CDC13): 7.5 - 7.1 (20 H, m, aromatic)
This application is a divisional of Canadian application No. 469,649 filed December 7, 1984.
The invention relates to new sialyloligo-saccharides which correspond to the non-reducing terminal tetrasaccharide unit of N-glycosidic sugar chain of glycoprotein such as borine blood coagulation factor II (see E.G. Berger et al, Experientia 38 (1982) 1129 - 1133), and to the method for producing the same.
NeuAc~ 2 ~6Gal ~ 1~ 4GlcNAc~ 1 ~ 2Man ~1 6Man~ 1~ 4GlcNAc~ 1 NeuAc~ 2 ~6Gal~ 1~ 4GlcNAc~ 1 t2Man~ 1 ~ 3 4GlcNAc R 1~ Asn NeuAc : N-acetyl neuraminic acid Gal : Galactose Glc : Glucose Man ` : Mannose GlcNAc : N-acetyl glucosamine Asn : Asparagine Sialic acid exists in free or combined form with sialoylglycoconjugate such as glycoprotein, glyco-lipid, oligosaccharide, polysaccharide, etc. in the surface oE animal or bacterial cell and much attention is now focused thereon from a medical and pharmacological point of view as a compound involved in immunity, cancer, inflammation, virosis, cytodieresis, hormone receptor, etc.
With increase in use of chemotherapeutics such as adrenocortical hormone or immunosuppressant for the treatment of various diseases such as carcinosis, hypo-immunity and many kinds of side effects are observed and therefore, it is becoming more difficult to treat a subject suffering from such diseases as cancer.
Particular attention has been paid to the importance of sialic acid, which is one of inherent con-stituents of animal living body, as a marker on the cell surface and reactions of sialic acid halide as a glycosy~
donor with various glycosyl acceptors have been conduct-ed. As a result, new sialyloligosaccharides have beensynthesized which are expected to cause no side effect and to possess, many physiological activities such as adaptation of immunoresponse.
The invention of the parent application pro-vides sialyloligosaccharides of the formula described below and the method for producing the same:
-1 ~6~
0~ CooR ~
AcH ~ 0~\ NHAc OR2 ~O--R2 R30~ \
R30--~
or OR2 . .
o ACH~ V
NHAc OR / ~
R 3 0--~ ol R30~
wherein Rl is hydrogen or methyl, R2 is hydrogen or acetyl and R3 is hydrogen or benzyl.
The sialyloligosaccharides of the above formula according to the present invention can be prepared by reacting the glycosyl donor of the formula (12), which can be derived from sialic acid by a conventional method, with the glycosyl acceptor, trisaccharide of the formula (10) to form tetrasaccharide and optionally removing acet~l, methyl or benzyl groups.
H OH NHAc AcO ~ / O
Ac~o~o1 OAc OAc C8n enO~O \
B nO~~--~1 OBn ,:
wherein Ac represents acetyl and Bn represents benzyl, .
OAc OAc ~1 ' X
AcOk\O
ACHN~L7~ COOCH3 OAc : wherein X represents halogen, preferably Cl or Br.
.
The glycosyl donor (12), the starting compo~nd of the~
present invention, can be derived ~rom sialic acid methyl ester peracetate (11) by Xuhn et al method (Chem Ber., 99 611~617 (1966)).
OAc OAc CA~ ' OAC
- OAc The glycosyl acceptor (10), the other st~rting material of the present invention, can be derived ~rom the compQund (6) which can be prepared as follows:
CHzO~n Aco ~ I CH~OAc NPhth BnO ~ AcO~ ~ -OA c Crl 2 OA c 08n RO CH2oR Ni?; R O
RO\~
OR 2 C~55n ¦
anO ~ I
5 nO ~ a OCn (3~ R = Ac, Rl,R2 = Phth (4) R = H, Rl,R2 = Phth (5) R = H, Rl,R2 = H2 ~6) R = Ac, Rl,R2 = H,Ac (Phth represents phthaloyl) The cornpound ~1) is reacted with the disaccharide donor (2) in the presence o~ AgOSO2CE'3 and molecular sieves 4A
powder to give the trisaccharide ~3) which is treated with NaOCH3/C~3O~ to give the compoun~ (4) which is then treated with CH30H-butylamine to give the compound (5) which is subse~u~ntly treated with Ac2O-pyridine to give the compound (6).
The compound (1) can be prepared by, for example, the method described in T. Ogawa, H. Yamamoto, Carbohydr. Res., 104 (1982) 271-283. The compound (2) can be prepared by the method described in M.M. Ponpipom, R.L Buglanesi, T Y. Shen, Tetrahedron. Lett., (1978) 1717-1720; J. Arnarp, J. Lonngren, J. Chem. Commun., (1980) 1000-1002; J. Chem. Soc Perkin Trans. 1, (1981) ~070-2074; T. Ogawa, S. Nakabayashi, Carbohydr. Res., 97 (1981) 81-86; P.U. Lemieux. S.Z. Abbas, B~o Chung, Can. J. Chem., 60 (1982) 58-62.
The glycosyl acceptor (10) can be derived from the resulting compound (6) as shown below.
'.
. .
:
~o OR OR NHAc ~ NHAc o ~ ~ l o~ AcO~
Ro \ - ~\~) ~ / 7~ OAc OA c _ .
08 nO¦ ~nO~ ~1 BnO~ ~ ~ o~OL7~ Oan B nO
Ac ( 6 ) R = Ac BnQ~
(7) R = H ~ OBn The compound (6) is deacetylated by alkaLi metal alkoxide/alcohol, such as NaOC~3/CH30H to obtain the compound (7) which is then reacted with (CH3)2C(OCH3)2 in the presence or catalyst such as p-toluenesulfonic acid (p-TsOH) and subsequently acetylated by, for example, acetic anhydride/pyridine to give 4,6-0-isopropylidene derivative (8) and 3,4-0-isopropylidene derivative (9). The compound (8) is treated with acetic acid/methanol to obtain the glycosyl acceptor (10).
The glycosyl acceptor ~10) is reacted with the glycosyl donor (12) in such solvent as dichloromethane, 1,2-dichloroethane, etc. in the presence of glycosidation catalyst such as Hg(CN)~, HgBr2, molecular sieves, Ag~CO3, AgClO4, AgOSO2 CF3, (C~I3)3COSO2CF3, etc. at -20C to 150C, preferably -5C to 20C, for 1 to 120 hours, preferably 1 to 5 hours to give ~-anomer (13) and ~?-anomer (14) which can optionally be deacetylated, saponified and debenzylated to obtain ~ -anomer (15) and ~ -anomer (16), respectively. Deacetylation, saponification and debenzylation can be performed in conventional systems such as NaOCH3/CH3OH, NaOH/tetrahydrofuran, or paLladium on charcoal/hydrogen system, respectively.
~J COOR t AcHN~ ~O~ NHAc Rt Rz R3 R20~' ~~ O
~3 Mc Ac Bn ORz OR2 OR3 R~O;~
Ac~lN ~ Ac R zO --~ _~ OR~ ¦
R30~--`~ dR3 Rl R2 R3 (14) Me Ac Bn (16) H H H
All the compounds (3), (4), (5), (6), (7), (8), (9), (10), (13), (14), ~15) and (16) thus obtained are new and have never been disclosed in any references.
The invention of the present divisional appli-cation prov.ides new compounds having the general formula:
R50 CH~OR~ ~RlR2 R3~
-- ~ o 4 ~ cn3 cH2osn j BnO ~
BnO ~__~~~
. OBn wherein Rl is hy-drogen, R2 is hydrogen or acetyl, or Rl and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form iso-propylidene, or R5 and R6 together form isopropylidene and Bn is benzyl.
The above compounds are prepared by reacting a compound of the formula:
CH~OBn BnO ~ H
BnO
OBn _ g _ wherein Bn is benzyl, with a compound oE the forrnula:
AcO C~2OAc ~Phth ~ O\ AcO~ ~X
AcO
OAc CH~O~5 wherein X is halogen, Ac is acetyl, Phth is phthaloyl, and optionally performing deacetylation, dephthaloylation and/or acetylation.
The compounds of the invention may be employed as a useful interme~iate for the synthesis of the afore-mentioned sialoylglycoconjugate and they are expected to possess function as recognition marker on the cell surface and ant`agonists.
The inventions or both the parent and division-~al applications will now be illustrated with reference to the following non-limiting examples.
Example 1 Molecular sieves 4A powder (10 g) was vacuum-dried at 190C for 21 hours, to which AgOSO2CF3 (3.4 g, 13.2 mmol) and 1,2-dichloroethane (40 ml) were added and argon was substituted for air in the reaction system.
The compound ~1) (1.6 g, 3.0 mmol~ dissolved in 1,2-di-chloroethane (20 ml) was added and the reaction mixture was cooled to -20C. The compound ~2) ~3.5 g, 4.4 rnmol) dissolved in 1,2-dichloroethane ~50 ml) was added dropwise.
The reaction was performed for 17 hours at -20C to room temperature. After -the reaction was completed, methylene dichloride ~500 ml) was added. The reaction mixture was filtered through Celite ~reyistered trademark), washed with water and sodium bicarbona-te solution, and dried on MgSO~.
After filtration, the filtrate was concentrated in vacuo.
The residue was subjected to column chromatography ~silica gel 300 g), toluene/ethyl acetate = 3/1) to give the compound (3) (3.45 g, 93.2% from the compound (1)) as oily syrup.
~The compound (3~ .
TLC Rf = 0.39 (toluene/ethyl acetate = 2/1) Analysis. Calcd~ for C66H71N23 3/4C6H5CH3 C, 65.06;H,5.90;N,1.06 Found C,6;.15;H,5.95;N,1.06 ~23-5 = ~4.2 (C = 1.03, CHC13) Example 2 The compound ~3)(2.2 g) was dissolved in methanol (40 ml) and lN-NaOCH3 (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 22 hours and concen~rated in vacuo. The residue was dissolved in methanol (lO0 ml), to which n-butylamine (20 ml) was added and refluxed in a bath at 100C for 45 hours. The ~eaction mixtu~e was concentrated in vacuo. The residue was dissolved in pyridine (30 ml)~ to which acetic anhydride (30 ml) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 200 g, toluene/ethyl acetate - l/l) to give the compound (6)(1.9 g, 95.0~) as syrup.
.. . . . . .. . ... .. .
- 12 ~
~The compound (6)~
TLC ~ RE - 0.54 ~CH2C12/acetone = 5/1) AnalySiS: Calcd. for C60H71N2~:
C, 62.22; H, 6.18; N, 1.21 Found C, 62.57; H, 6.31; N, 1.50 ~21 ~ 6 5 (c = 1.15, C~C13) Example 3 Synthesis of the compound (7) The compound (6) (1.9 g) was dissolved in methanol (40 ml), to which 1N-NaOCH3 (1 ml) was added and stirred at room temperature for 19 hours. AMBERLITE (registered trademark) CG-50 TYPE 2 (1 ml) was added to the reaction mixture and stirred for 10 minutes to neutralize it. The reaction mixture was filtered through Celite, concentrated in vacuo to give quantitatively the compound (7) (1.5 g) as crystal.
~1 ` .
[The compound (7)) TLC: Rf= 0.48 (CHC13/CH30~ - 3/1) Analysis: Calcd. for C~HsgNO16.1/2 H~O
C, 63.01; H, 6061; N, 1.53 ~ound C, 63.03: H, 6.73: N, 1.77 PMR: 'H-NMR(CD30D): 7.30 (20H, s, aromatic) 1~93 (3H~ s, COCH3) Example 4 Synthesis of the compounds (8) and (9) The compound (7) (304.9 mg) was dissolved in dimethylformamide (3 ml), to which (CH3)2C(OCH3)2 (0.2 ml, 5 . - 13 -~i2 ~
eq.) and p-toluene sulfonic acid (10 mg) was added and stirred at room temperature for 15 hours. Triethylamine (1 ml) was added to the reaction mixture which was then concentrated in vacuo. The residue was dissolved in pyridine (5 ml), to which acetic anhydride (5 ml) was added and stirred at room tem~erature for 18 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 30 g, toluene/ethyl acetate = 2/3 containing 1% triethylamine) to give the compound (8) (256.0 mg, 68u3%) as syrup and the compound (9) (39.4 mg, 10.5%) as syrupO
[The compound (8)~
TLC ~f: 0.40 (toluene/ethyl acetate = 1/3) (The compound (a), Rf = 0.53) Analysis: Calcd. for C59H71NO20 C: 63.60, H: 6~42, N: 1.26 Found C: 63.36, H: 6.48, N: 1.33 ; [~)D23O5~ 23.5 (C - 1.33, CHC13) PMR ~ 7.4 - 7.1 (20H, m, aromatic) (CDCI3) 2.12 (3H, s, Ac~, 2.04 ~6H, s, Ac x 2) 1.97 (3H, Sr Ac), 1.80 (3H, s, Ac), 1.42 and 1.36 ~2 x 3H, s, isopropylidene) CMR 100.84 (C-lc, lJCH159.7Hz), (CDC13) 99.08 5C-lb, lJcH158.7Hz), o~ ~ Me g8.9~ ( ~Ç~ ), o Me 96.74 (C-lar lJCH167.2HZ), Example 5 Synthesis o~ the compound (10) The compound (8) (602.4 mg) was dissolved in 50%
acetic acid/CH30H (30 ml) and stirred in a bath at 80C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 60 g, CHC13~CH30H = 15/1) to give the compound (10) ~456.7 mg, 80.4%) as syrup.
[The compound (lC)) TLC: R~ = 0.54 (CHC13/CH30H = 10/1) Analysis Calcd. for C56H67N20 H2 C, 61.58; H, 6.37; N, 1.28 Found C, 61.56; H, 6.24; N, 1.30 ~)23~5 ~ 12.5 (Cl.18, CHC13) PMR (CDC13): 7.5 - 7.1 (20 H, m, aromatic)
2.08 (3H, s, Ac), 2.04 (6H, s, Ac x 2), 1.98 (3H, s, Ac), 1~80 (3H, s, Ac) CMR (CDC13): 101.76 (C-lc, lJCH159.9Hz) 97.62 (C-lb, lJcH159.9Hz) 96.50 (C-la, lJCH167.2HZ) 3l3~
Example 6 Synthesis of the compounds ~13) and tl4) Molecular sieves 4A powder ~0.5 g) was vacuum-dried at 190C for 20 hours, to which Hg (CN)2 I101.1 mg, 0 40 mmol), HgBr2 (144.2 mg, 0.40 mmol) and 1,2-dichloroethane (2 ml) were added. Argon was substituted for air in the reaction system, to which the glycosyl acceptor (10) (111.3 mg, 0.10 mmol) dissolved in 1,2-dichloroethane (1 ml) was added and stirred at room temperature. The glycosyl donor (12)(?01.9 mg, 0.20 mmol) dissolved in 1,2-dichloroethane (1 ml) was dropwise added to the reaction mixture and stirred at room temperature for 43 hours. The glycosyl donor (12) (101.9 mg, 0.20 mmol) dissolved in 1,2-dichloroethane (1 ml) was further added to the reaction mixture and stirred for 68 hours. After the reaction was completed, 50 ml of CH2C12 was added to the reaction mixture which was then filtered through Celite, washed with water and sodium bicarbonate solution, and dried on MgSO~. A~ter filtration, the reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 30 g, ethyl acetate) to separate the compounds derived from the compound (12), which were further subjected to column chromatography (silica gel 30 g, CHC13/CH30H = 40~1) to give a -anomer (13) (54.2 mg, 33.8%) and ~ -anomer ~14) (46.6 mg, 29.1~), as syrup, respectively.
LThe compound (13) (~ -anomer)~
TLC: Rf = 0.19 (CHC13/MeOH = 20/1) Analysis: Calcd. ~or C76E94N232 2H2 C, 57.64; H, 6.24; N, 1.77 "3~
Found C, 57.52; H, 5.96: N, 1.75 [~Y~ D f 0.5 (C0.94, CHC13) PMR(400 MHZ)(cDcl3): 10 x Ac, s (1~828, 1,88~, 1,986, 2,034, 2,041, 2,048, 2,067, 2,071, 2,128):
Example 6 Synthesis of the compounds ~13) and tl4) Molecular sieves 4A powder ~0.5 g) was vacuum-dried at 190C for 20 hours, to which Hg (CN)2 I101.1 mg, 0 40 mmol), HgBr2 (144.2 mg, 0.40 mmol) and 1,2-dichloroethane (2 ml) were added. Argon was substituted for air in the reaction system, to which the glycosyl acceptor (10) (111.3 mg, 0.10 mmol) dissolved in 1,2-dichloroethane (1 ml) was added and stirred at room temperature. The glycosyl donor (12)(?01.9 mg, 0.20 mmol) dissolved in 1,2-dichloroethane (1 ml) was dropwise added to the reaction mixture and stirred at room temperature for 43 hours. The glycosyl donor (12) (101.9 mg, 0.20 mmol) dissolved in 1,2-dichloroethane (1 ml) was further added to the reaction mixture and stirred for 68 hours. After the reaction was completed, 50 ml of CH2C12 was added to the reaction mixture which was then filtered through Celite, washed with water and sodium bicarbonate solution, and dried on MgSO~. A~ter filtration, the reaction mixture was concentrated in vacuo. The residue was subjected to column chromatography (silica gel 30 g, ethyl acetate) to separate the compounds derived from the compound (12), which were further subjected to column chromatography (silica gel 30 g, CHC13/CH30H = 40~1) to give a -anomer (13) (54.2 mg, 33.8%) and ~ -anomer ~14) (46.6 mg, 29.1~), as syrup, respectively.
LThe compound (13) (~ -anomer)~
TLC: Rf = 0.19 (CHC13/MeOH = 20/1) Analysis: Calcd. ~or C76E94N232 2H2 C, 57.64; H, 6.24; N, 1.77 "3~
Found C, 57.52; H, 5.96: N, 1.75 [~Y~ D f 0.5 (C0.94, CHC13) PMR(400 MHZ)(cDcl3): 10 x Ac, s (1~828, 1,88~, 1,986, 2,034, 2,041, 2,048, 2,067, 2,071, 2,128):
3,821, (OMe, 3H, s); 2,591 (H-3d, eq, lH, q, j, ~.39, 12.6) [The compound (1~ anomer)~
TCL: Rf = 0.24 (CHC13/MeOH - 20/1) Analysis: Calcd. for C76~94N232 3/2H2 C, 57.97; H, 6.21; N, 1.78 Found C, 58.00, H, 6.04; N, 1.79 [a~9 + 4.0 (C0.50, CHC13) PMR (400 MHz)i (CDC13): 10 x Ac, s (1,789, 1,892, 1,998, 2,006, 2,0~3, 2,039, 2,051, 2,078~ 2,120, 2,154; 3,830 (3H, s, OMe), 2,464 (lH, q, J, 4.88, 12.94 Hæ) .
Example 7 Synthesis of the compound (15) The compound (13) (17.7 mg) was dissolved in methanol (2 ml) and lN - NaOCH3 (0.1 ml) was added thereto. The reaction mixture was stirred at room temperature for 20 hours and concentrated in vacuo. The residue was dissolved in methanol tl ml), and tetrahydrofuran (1 ml) and H2O (one drop) were added thereto. The reaction mixture was stirred at room temperature for 13 hours. AMBERLYST (registered trademark) 15 (0.4 ml~ was added and stirred for 10 minutes to neutralize the reaction mixture which was then ~iltered through Celite and concentrated in vacuo. The residue was dissolved in ethanol (2.7 ml), to which 10% palladium on charcoal ~20 my) suspended in water (0.3 ml) was added and hydrogen gas was introduced. The reaction mixture was stirred at room temperature for 18 hours and fuLther at 60C for 4 hours.
After Celite filt ation, the reaction mixture was concen.rated ln v2cuo. The residue was subjected to gel permeation chromatography (SEPHADEX G-25 (registered trademark), 20 ml, H2O). The eluate was freeze-dried to give the compound (15) (7.6 mg, 79.2%) as crystal.
(The compound ~15)) TLC: Rf = 0.20 (n-BuOH: C2HsOH: H2O = 2 6~5 _ 20.0 ~C0.30, H2O) PMR (400 MHz) (D20) 5,223 (H - la, d, J = 0.5 Hz)~
~ ,634 (H - lb, d, J 8.31 Hz), 4,458 (H - lc, d, J 7082 Hz), 2~679 (H - 3d, eq, q, J 4.63, 12.69 Hz), 2,073 (3H, s, Ac), 2,037 (3H, s, Ac), 1,731 (H-3d, ax, t, J 11.74 Hz) Example 8 Synthesis o~ the compound (16) The compound (14) (19.0 mg) was dissolved in methanol (2 ml) and lN - NaOCH3 ~0.1 ml) was added thereto. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in methanol (1 ml), and tetrahydrofurân ~1 ml) and H2O (one drop) were added thereto. The reaction mixture was stirred at room temperature for 19 hours. AMBERLYST 15 (O .4 ml) was added and stirred for 10 minutes to neutralize the rea~.tion mixture . - 18 -which was then filtered through Celite and concentrated in vacuo. The residue was dissolved in 75% aqueous acetic acid (~ ml), to which 10% palladium on charcoal (20 mg) was added and hydxogen gas was introduced.. The reaction mixture was s~irred at 80C for 30 minutes. After Celite filtration, the reaction mixture was concentrated in vacuuo. The residue was subjected to gel permeation chromatography (SEPHADEX G-25 (registered trademark~, 20 ml, H2O). The eluate was freeze-dried to yive the compound (16) (9.1 mg, 88.3%) as crystal~
[The compound (16)~
T~C: Rf = 0017 (n-BuOH : EtOH : H2O = 2:1:1) [~)D5 5 ~ 21.4(C0.36, H2O) PMR (400 MHz) (D20)0 5,218 (~ - la, d, J = 0O5 ~z), 4,623 (H
--lbl d, J 8005 Hz), 4,474 (H - lc, d, J 7.81 Hz), 2,395 (H -3d, eq, q, J 4088, 12.7), 2,055 (6 Hr s, Ac x 2)f 1,635 (~ -3d, ax, t, J 12.70 Hz) n 1 ~
TCL: Rf = 0.24 (CHC13/MeOH - 20/1) Analysis: Calcd. for C76~94N232 3/2H2 C, 57.97; H, 6.21; N, 1.78 Found C, 58.00, H, 6.04; N, 1.79 [a~9 + 4.0 (C0.50, CHC13) PMR (400 MHz)i (CDC13): 10 x Ac, s (1,789, 1,892, 1,998, 2,006, 2,0~3, 2,039, 2,051, 2,078~ 2,120, 2,154; 3,830 (3H, s, OMe), 2,464 (lH, q, J, 4.88, 12.94 Hæ) .
Example 7 Synthesis of the compound (15) The compound (13) (17.7 mg) was dissolved in methanol (2 ml) and lN - NaOCH3 (0.1 ml) was added thereto. The reaction mixture was stirred at room temperature for 20 hours and concentrated in vacuo. The residue was dissolved in methanol tl ml), and tetrahydrofuran (1 ml) and H2O (one drop) were added thereto. The reaction mixture was stirred at room temperature for 13 hours. AMBERLYST (registered trademark) 15 (0.4 ml~ was added and stirred for 10 minutes to neutralize the reaction mixture which was then ~iltered through Celite and concentrated in vacuo. The residue was dissolved in ethanol (2.7 ml), to which 10% palladium on charcoal ~20 my) suspended in water (0.3 ml) was added and hydrogen gas was introduced. The reaction mixture was stirred at room temperature for 18 hours and fuLther at 60C for 4 hours.
After Celite filt ation, the reaction mixture was concen.rated ln v2cuo. The residue was subjected to gel permeation chromatography (SEPHADEX G-25 (registered trademark), 20 ml, H2O). The eluate was freeze-dried to give the compound (15) (7.6 mg, 79.2%) as crystal.
(The compound ~15)) TLC: Rf = 0.20 (n-BuOH: C2HsOH: H2O = 2 6~5 _ 20.0 ~C0.30, H2O) PMR (400 MHz) (D20) 5,223 (H - la, d, J = 0.5 Hz)~
~ ,634 (H - lb, d, J 8.31 Hz), 4,458 (H - lc, d, J 7082 Hz), 2~679 (H - 3d, eq, q, J 4.63, 12.69 Hz), 2,073 (3H, s, Ac), 2,037 (3H, s, Ac), 1,731 (H-3d, ax, t, J 11.74 Hz) Example 8 Synthesis o~ the compound (16) The compound (14) (19.0 mg) was dissolved in methanol (2 ml) and lN - NaOCH3 ~0.1 ml) was added thereto. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was dissolved in methanol (1 ml), and tetrahydrofurân ~1 ml) and H2O (one drop) were added thereto. The reaction mixture was stirred at room temperature for 19 hours. AMBERLYST 15 (O .4 ml) was added and stirred for 10 minutes to neutralize the rea~.tion mixture . - 18 -which was then filtered through Celite and concentrated in vacuo. The residue was dissolved in 75% aqueous acetic acid (~ ml), to which 10% palladium on charcoal (20 mg) was added and hydxogen gas was introduced.. The reaction mixture was s~irred at 80C for 30 minutes. After Celite filtration, the reaction mixture was concentrated in vacuuo. The residue was subjected to gel permeation chromatography (SEPHADEX G-25 (registered trademark~, 20 ml, H2O). The eluate was freeze-dried to yive the compound (16) (9.1 mg, 88.3%) as crystal~
[The compound (16)~
T~C: Rf = 0017 (n-BuOH : EtOH : H2O = 2:1:1) [~)D5 5 ~ 21.4(C0.36, H2O) PMR (400 MHz) (D20)0 5,218 (~ - la, d, J = 0O5 ~z), 4,623 (H
--lbl d, J 8005 Hz), 4,474 (H - lc, d, J 7.81 Hz), 2,395 (H -3d, eq, q, J 4088, 12.7), 2,055 (6 Hr s, Ac x 2)f 1,635 (~ -3d, ax, t, J 12.70 Hz) n 1 ~
Claims (10)
1. A method of preparing a compound of the formula:
wherein R1 is hydrogen, R2 is hydrogen or acetyl, or R1 and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form iso-propylidene, or R5 and R6 together form isopropylidene and Bn is benzyl, which comprises reacting a compound of the formula:
wherein Bn is benzyl, with a compound of the formula:
wherein X is halogen, Ac is acetyl, phth is phthaloyl, and optionally performing deacetylation, dephthaloylation and/or acetylation.
wherein R1 is hydrogen, R2 is hydrogen or acetyl, or R1 and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form iso-propylidene, or R5 and R6 together form isopropylidene and Bn is benzyl, which comprises reacting a compound of the formula:
wherein Bn is benzyl, with a compound of the formula:
wherein X is halogen, Ac is acetyl, phth is phthaloyl, and optionally performing deacetylation, dephthaloylation and/or acetylation.
2. The compounds having the formula:
wherein R1 is hydrogen, R2 is hydrogen or acetyl, or R1 and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form iso-propylidene, or R5 and R6 together form isopropylidene and Bn is benzyl.
wherein R1 is hydrogen, R2 is hydrogen or acetyl, or R1 and R2 together form phthaloyl, R3, R4, R5 and R6 are hydrogen or acetyl, or R4 and R5 together form iso-propylidene, or R5 and R6 together form isopropylidene and Bn is benzyl.
3. A compound according to claim 2, wherein R1 and R2 together form phthaloyl, and R3, R4, R5 and R6 are acetyl.
4. A compound according to claim 2, wherein R1 and R2 together form phthaloyl, and R3, R4, R5 and R6 are hydrogen.
5. A compound according to claim 2, wherein R1, R2, R3, R4, R5 and R6 are hydrogen.
6. A compound according to claim 2, wherein R1 is hydrogen, and R2, R3, R4, R5 and R6 are acetyl.
7. A compound according to claim 2, wherein R1, R3, R4, R5 and R6 are hydrogen, and R2 is acetyl.
8. A compound of claim 2, wherein R1 is hydrogen, R2, R3 and R4 are acetyl, and R5 and R6 together form isopropylidene.
9. A compound according to claim 2, wherein R1 is hydrogen, R2, R3 and R6 are acetyl, and R4 and R5 together form isopropylidene.
10. A compound according to claim 2, wherein R1 is hydrogen, R2, R3 and R4 are acetyl, and R5 and R6 are hydrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000555845A CA1262131A (en) | 1983-12-08 | 1988-01-05 | Sialyloligosaccharides and preparation thereof |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP23204383A JPS60123494A (en) | 1983-12-08 | 1983-12-08 | Sialic acid-containing oligosaccharide and its preparation |
| JP232043/1983 | 1983-12-08 | ||
| CA000469649A CA1244014A (en) | 1983-12-08 | 1984-12-07 | Sialyloligosaccharides and method for producing the same |
| CA000555845A CA1262131A (en) | 1983-12-08 | 1988-01-05 | Sialyloligosaccharides and preparation thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1262131A true CA1262131A (en) | 1989-10-03 |
Family
ID=25670543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000555845A Expired CA1262131A (en) | 1983-12-08 | 1988-01-05 | Sialyloligosaccharides and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1262131A (en) |
-
1988
- 1988-01-05 CA CA000555845A patent/CA1262131A/en not_active Expired
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