JPS58170797A - Oligosaccharide, derivatives and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] Furthermore, the present invention relates to the synthesis of derivatives of these oligosaccharides.

The present invention further relates to novel oligosaccharides and derivatives thereof of the above-mentioned type having biological properties of particular interest as drugs and/or useful, for example, as experimental reagents.

Furthermore, the present invention refers to their uses, especially the derivatives called biological saminoglyclonoglycans 4. This includes, for example, heparin, heparan sulfate →/
- In oligosaccharides and natural metals particularly found in the chain of biologically active conductors, such as derivatives of sulfate, sulfates are essentially alternating amino sugar-uron units, Nine consists of the opposite. In these units, the amino sugars shown below in Mulberry are more specifically D-gelcosamine-
Has a structure. The uronic acid called uronic acid has a more detailed JIKFiD-glucuron Wk or L-izumeron structure.

The basic structure for Δ corresponds to Se Shichibon Shimoki 1 耘↓ and p, and! ! (α)D-7 corresponding to the following formula and C
'Rukosumiγ (C) L-'1χ°ron- (M1 wrinkles natural sitting child, these various units LQll
/ 1→4.1→4 Three-dimensional %J by combining 4 Ichibanchi + Sakaki!
! ! are connected to each other.

For example, in heparin, the connections between l→4 (the connection between C and a, a and b, and a and C) β and the lid of l - q 4 (the connection between G and a) are Can be seen.

4 V and half a table one ↓ and one and a half 4-44 W-- hand 16←(1 et al.) Furthermore, it is noted that, with reference to natural biomass, the above units include certain substituents, namely the following types of substituents at certain positions. For example, the natural biosac chain is 10-substituted unit, 2-0-sulfate-L-izmeronic acid, 3-0-sulfate-D-glucosamine, 3,6-di-0-sal7-ether-D-gelcosaone, 6-0-sulfate)-D -glucosamine and non-〇-substituted units, for example D-glucuronic acid, L-isomeron, D-glucosamine
° − Contains units. Furthermore, the unit a-substituent is substituted with N-acetyl and /l or -N-sulfate groups at the 2-position.

The importance of the therapeutic use of the above acidic mucopolysaccharides is that 4IK
It is known for the prevention and treatment of blood clots and disorders of blood vessel walls, and has been used for the prevention and treatment of 4IK thrombosis and atherosclerosis and arteriosclerosis.

Furthermore, many studies by the applicant to obtain fragments with high affinity for All and biologically active fragments from heparin chains are known. The nine inventions developed on the basis of these studies are the subject of various patent applications, among them European Patent Application No. 80401425.6 (1
October 6, 980) and French Patent Application No. 81
No. 08604 (April 29, 1981).

In European patent applications, the term "ε F5i" which is of particular interest is used in this formula to denote a Rij80g-group or a hydrogen atom.

This also has unusual anti-thrombotic properties. This structure is represented by the formula: [In the formula, R represents the S axis and the group 9 represents a hydrogen atom].

The methods proposed to date for obtaining products of this type are extraction techniques or chemical fractionation techniques from heparin or from the products obtained during heparin imitation.

The applicant's research in this field has led to new means of obtaining products of this kind and, more particularly, has made it possible to pursue the possibility of obtaining them synthetically [1,].

In this respect, it is appropriate to address the many problems that arise with this type of synthesis. In fact, on the one hand, these products contain in their chains several types of mu and da units, and on the other hand, the bonds between these units conform to the given stereochemistry and are of the 1.4 type; Production is known to be particularly difficult. Furthermore, each unit may have one or several specific substitutions, namely N-acetyl group and -N
- The inclusion of sulfate groups should also be considered.

As a result, this type of synthesis, especially for L-isotrons, has to date practically not been described in the chemical literature.

All of these factors emphasize the critical requirements involved in the development of general and synthetic methods and the limited requirements to readily evaluate KfF.

By examining conditions for acid synthesis suitable for developing this type of compound, the applicant has developed a method by selecting specific Class 11 protection for the substances used. It has been shown that if this type of well-preserved substance is used, it is possible to generate a stereoisomer chain [2. An interesting aspect of its importance is that the developed method has an inherent flexibility. For example, many oligosaccharide III conductors can be arrived at, particularly with the specificity of the synthesis method KII and even units of structure similar to pure fKIIIL.

By this method, the applicant has discovered that the oligosaccharide 5t has extremely valuable medical properties, more specifically high antithrombotic activity.
tl-gain and mourning. Furthermore, the method of the invention makes it possible to obtain a large number of oligosaccharides which are particularly useful as biological reagents and/or comparison compounds for structural studies.

Therefore, the object of the present invention is to
It is an object of the present invention to provide a method for synthetically producing a small group III containing a single piece or a derivative thereof, and the like.

A further object of the present invention is to provide means by which a glycosidic bond can be established between the Mu and V units in a desired stereospecificity.

(Left below) A further object of the present invention is to provide a predetermined functional group in the unit of the glycoside chain, in particular a chain of nine biologically active molecules,
% Niheno (phosphorus, heparan)
Sulfet's! 41j l: The purpose is to provide a means that can be used as described by Tun et al.@b.

A further object of the present invention is that the substituents and/or are different;
The object of the present invention is to provide a means that enables the production of oligosaccharides as described above.

According to another aspect, it is an object of the present invention to preserve these functional groups themselves according to the needs of the synthesis method.

According to a further aspect, the present invention aims to provide novel oligosaccharides having the structure of the above-mentioned natural axes as well as oligosaccharides corresponding to fragments of these products.

A further object of the present invention is to provide oligosaccharides having specific substituents of natural tooth poisons.

A further object of the present invention is to provide a novel oligosaccharide having a substituent different from the specific substituent and/or containing a unit different from the above-mentioned natural tooth poison.

The invention is particularly suitable for the study of active pharmaceutical substances, experimental trials or compounds containing structures of this type! It concerns the biological use of these oligosaccharides as substances.

The synthesis method of the present invention is characterized by carrying out the reaction of the following two compounds, each consisting of or terminating with the A unit of the nigercosamine structure, and a D-glucosamine complex.
- one unit of the quiquip and glucuronic acid structure, especially D-glucuronic acid or isuronic acid, especially L-isturonic acid; one of the unit tables or figures is an alcohol, and the OH group of this alcohol is occupies either position 3°4 or 6 in case t'#:, e or 2 in case of unit.
. The various groups are compatible with each other and with the precursors mentioned above, and the conditions of their use are chosen so as not to change the structure of the units of these substances and the nature of the various substituents present, The establishment of connections between
(2-N-sulfate or (2-N-a) Due to the above prefix, there is a
It's a illusion of τ-t>az.

By means of the present invention, desired chain formations can be formed in a defined 1v1 order and/or with a defined stereospecificity.

Therefore, the measures proposed by the invention are particularly suitable for D-
lj between glucosamine units and D-glucuronic acid or L-isuronic acid! -+ type 4 bond, IJL between D-glucuronic acid unit and D-glucosamine unit, 4
fj1 binding and the establishment of 1 & 4 type binding between the L-isolune unit and the D-glucosamine unit.

The 1+ activated in its final carbon is said to be half open at the layer pressure. The expression "half-open compound on the left" refers to a compound that has a single free or falsely free OH group, making it capable of specific glycomolization.
It means lLIIIs or oligosaccharides. As an example, the following formula l shows an example of an improved hardware whose left side is half open, and the formula;
t-4 (θ11 7, sheep closed p-i 0 Maro grip positive 11 to 1
1: Finally, a derivative is said to be interleaved if both the right and left sides in the above definition are half-open derivatives, and this type of derivative allows chain extension in both directions.

This camphor derivative corresponds, for example, to F composition 3: Closed-derivatives are substances whose units cannot undergo chain extension due to the nature of their substituents.

The group formed in the above step must contain a group that can selectively block the position of the target group or group that participates in the new glycosylation reaction. , these groups can be removed while forming the alcohol in the presence of other groups in the starting polymeric units. Therefore, the present invention is particularly useful for Based on the synthesis method of lea, which has different derogations in terms of order of n1lo combination of a-kai 4 arrogance → n1lo combination with b and/or C, Kancho in cc I can't help but feel like Kf4.

Furthermore, according to another qiIIlkK of the method by Honnobu#,
Generated guru 7 fIAf:ldan or IN! The chemical reaction of the L-dan is applied to one 4-straddle of a given rod, and then several kinds of 41 to 4 people are produced, and then depending on the location, these blind*pts are
The whole group and/or precursor group is removed, a predetermined type of substituent group or a different substituent group is introduced at that site, and then the OH that is combined depending on the location It depends on whether you do it with -s4 of the group or with the whole seam.

It is understood that the various groups present in the continuous unit are compatible with the substituents introduced at each step.

The chemical reactions in one or more vessels used during the α-enablement step are carried out in such a way that the chain structure and groups desired to be maintained and/or groups already introduced are not changed. Also, according to a preferred embodiment of the present invention for obtaining the oligomer group having the above-mentioned specific substituents,
Starting fibers are preferably used which have several carrier groups, namely (1) one or more semi-permanent groups and (2) one or more permanent groups.

Semi-permanent groups are those that can be removed during a glycosylation reaction when the glucide backbone contains a large number of desired units, without removal or change of other components present, and then replace Pfrl in their occupied nine positions. It means a group into which a functional group can be introduced.

What is a permanent group? 'iir+]@ group is introduced instead of a semi-permanent group. These groups are selected from those that are compatible with the functional group introduced after removal of the semi-permanent group. Furthermore, these are groups that are inert with respect to the reaction carried out to determine the position of these functional groups and can be removed without changing the functional group i.

Advantageously, the performance of these steps allows the production of glucide chains in which the mu and m units are selectively substituted.

In particular, it is possible to use the biologically active molecules mentioned above. This nitrogen group is preferably, for example, -N5 or -1iHooo-oa2zoC6H3 (DJuna group), in particular -NH8OS- or -N
Composed of H-acyl, especially K-NH-000H5.

The carboxyl group of the U unit is blocked by a group that is inert with respect to the reaction used in the substitution of the carrier group and that can be removed at the end of the synthesis to free the carboxyl group for the purpose of salt formation. . These supporting groups for the carphofluor function are preferably selected from Kri alkyl groups and aryl groups.

The structure of the compound used during the glycosylation reaction is selected depending on the desired glucide backbone units as well as the desired substituents.

For example, to generate two ms of -U-A-m, one uronic acid structure and one amino acid structure are used, and two ellipsoidal compounds corresponding to the above definition are used.

To extend the chain Jdi, K, which generates and converts the two shields, has this temporary group present in the dan unit, and in order to extend it to the right 11, it is present in the ri 8 position.

Thus, in particular, we can obtain the chain U, AxUyA, where the index combination 1 is 2 to 12 and I, `` and y are not O at the same time.Usually the chain is ``('')ns(muU) n
m, (Um)n or (AU)n, where n is a number from 1 to 6.

According to a variant of the method of the invention, the A-U or rim type change found in the structure of the natural ramus → proboscis is equivalent to a man or μ unit instead of a woodcutter or several units or m units. Sugars that constitute a structure, such as lidφ! Ill or desoxy sugars, or other uronic acid units, can be modified using amine structures or structures with different configurations.

In a preferred embodiment of the process of the invention, the alcohol is reacted with a reactive conductor such as a halogen, an idate, or an orthoester. These combinations are carried out under anhydrous conditions.

In the combined reaction between a halide and an alcohol, the halide is advantageously composed of a beautifying compound or a chloride for reasons of ease of manufacture.

The operation is carried out in a solvent, especially in a bridged medium, preferably dichloromethane or dichloroethane.

A catalyst is advantageously used, generally silver or water. Furthermore, 1 such as -ym collidine, for example
Studies have shown that the extractive IPJ reaction to the water present and the hydrohalic acid produced is likely to be at room temperature or at low temperatures that can be as low as 0°C or even lower. Therefore, it is suitable to operate in an atmosphere of an inert gas, such as nitrogen or argon.

These conditions allow units of structure a and shi or C (and vice versa) + lacquer holder → 豐 → to condense in the desired stereochemistry. In addition, a variant method using a second/or heavy chain to establish a covalent bond with a neutral Akebono or desoxygen is an alcohol of various structures and an x,-l idose precursor of the C structural unit (L-idose (9) found to be suitable for forming covalent bonds with In this variant also 4 ml of leek sheep is used. The organic solvent is selected depending on the reactivity of the alcohol. For example, it is advantageous to have a temperature higher than 100°C.
If a high degree of oxidation is required, a nitrobenzene solvent is used. For lower temperatures, e.g.
Alternatively, a solution such as dichloromethane is used. A mixture of solvents is also suitable for K to carry out the combined reaction.

For the TLtJ& units, especially the KO units, orthoesters are preferably used as reactive groups. The reaction is then preferably carried out at a temperature above 100°C.

The solvent is chlorobenzene or any other solvent with a boiling point above 100°C, preferably 100°C.
It has a boiling point of ~150°C.

K, which promotes the reaction, uses a catalyst such as 2,6-dimethylpyridinium perchlorate.

An example of this type of condensation is the unit of structure C,/(L-isomeron beak) and the structure a/(D-glucosamine)! 1i←Y1''-'-''-''<-e=Galatsu 1 tosa (→-It was found that it is extremely useful for forming interglycosidic bonds with the 11-group unit.

The use of orthoester groups has particularly two advantages.

On the one hand, this can endow the ano 1-carbon of the C unit with the reactivity necessary for the glycosylation reaction. On the other hand, cleavage of this group can place a selectively removable carrier group at the 2-position of the 0 unit, and can then introduce a specific substituent at that position.

0 units of 1,2-0-methoxy-ethylidene group and a4-
← ÷ Tangential method 4 If it is possible to establish an interglycosidic bond between the compounds used in the two bridges > qj! rK An AQ group (AC represents an acetyl group) which can be selectively removed for the purpose of introducing a predetermined functional group, for example -805-, can be provided at the 2-position of the C unit. This percentage ridge can provide a full rounding opportunity to handle the 4 positions of C units.

A sometimes advantageous advantage of these is that they provide 2-0-sulfate-L-iduronic acid units, such as those present in heparin tetramer.

When an imidoyl group is used as a reactive group, it has been found suitable to prepare 4A at low temperatures, particularly at temperatures below or equal to about 0° C., in a solvent such as dichloromethane.

In the starting alcohol, the free oa,l occupies the position where it is desirable to participate in the glyco/lysis bond.

By appropriately selecting the alcohol, 1-2, l-
It is also possible to form a 3, 1-4 or 1-6tJIi settlement.

From the sequence formed at the end of the conjugation reaction, a chain containing units of the F9r desired ridge is generated by repeating the glycosylation reaction step.

It is advantageous if the alcohol function of one of the units A or y contained in the glucide sequence already constituted is then released from its temporary holding group.

The choice of this group is easily established by one skilled in the art depending on the nature of the other groups present in the glucide chain.

Among the various radicals that can be used, mention may be made of the allyl group, which can be used, for example, first of all with isomerizing agents such as Pa, ah and hydrogen conductors, in particular Trio-)riphenylphosphine, rhodium(1) chloride or potassium t - Butoki can easily regenerate alcohol into the position it occupied.

As an isomer, uH4 can be obtained by saponification from a -0-acyl group and a 10-acetyl or 0-chloroacetyl group.

These groups can be removed by using thiourea at high temperature (preferably Fi, 80°C) in medium, preferably at a temperature of 100°C to liberate the OH function. .

The upper ml can be selectively treated with A-U or ali-A unit r.
This enables the production of gluside containing

This method involves the formation of an irregular structure that incorporates the toughness of the glycosylation reaction into U or U-
It depends on what you get by adding it between the A structural units.

It has been demonstrated that the treatment of each component of the present invention with respect to the A and U units can be similarly applied to neutral shields or other units that may contain lucidic compounds, such as desoxysugars. Good morning.

As described above, the base line of each wing present in A and Dan units is selected so as to impart sufficient reactivity to these groups to generate the glycosidic bond.

The line-holding group of the OH group other than the above-mentioned temporary groups is generally selected from the group consisting of acyl groups (C, in particular acetyl, alkyl, substituted alkyl, e.g. benzyl), and for two adjacent positions an acetal group or a ketyl group. Among them, for example, benzylidene, which is advantageously used in the glycosylation reaction, contains several line-holding groups, and these groups are used in the process of functional chemical engineering. Sequential introduction of one functional group and, if desired, one or several OH
Enables the fundamental movement 1Iiii.

Furthermore, these can also be introduced from other groups after death when the glucide skeleton is constructed. This modified normal, for example, OH groups in the 2nd and 3rd positions and OH groups in the 1st and 6th positions.
and 2,3-epoxytoph and 1,6-
The use of sealed anhydro-containing anhydrous forms in glycosylation has led to the use of nanocrystals. This m1lli
Therefore, it is possible to use a gk element which forms a hexafluoride unit in a warm manner, but which does not inhibit the 7X reaction used in the synthesis, since the formation of a glucide skeleton is eliminated. This process has the advantage of giving wide freedom in the reaction rfT of other units.

Furthermore, in this case, one example of the rudder for evobase/de+1 due to gold sodium de' is the introduction of N1 group at the 2 position tgj
As a rudder, this constitutes a precursor of the amine function. 6. Preferably, in the course of the functionalization process, one or more substituents, particularly the above-mentioned specific substituents, can be introduced sequentially to obtain a glucide chain. For this purpose, several types of protecting groups are used, namely semi-permanent groups and compounds containing permanent groups as defined above.

As mentioned above, apart from the *m group in natural plants, Salfue research has shown that the glC Europeanization reaction can be carried out in the presence of a benzyl group. It is possible and even advantageous. Removal of the benzyl permanent group in the presence of the -0-l luer 11-to group can be carried out in accordance with the principles known in the art.

Preferably, the starting OH group intended to be sulfated is then capacitated with an acyl group, in particular an acetyl group, and the OH group intended to be liberated at the end of the synthesis is protected by a permanent group, such as, for example, a benzyl group. 0, l of the method of the invention
Due to the 111 degree melting property, all of the produced glucide chains can be subjected to a predetermined chemical reaction to introduce the [k] group.

The treatment of C is, for example, nisfurization using an appropriate reagent,
Alternatively, the buttocks are sulfated, which is Oside 41.
This is done under conditions that do not change the structure.

Although not specified, this cationic oxidation may be carried out on cricosides protected by gold if necessary.

In a preferred embodiment of Mokku%Ai, 1-Yokakoki sequentially introduces several 111114 units for Rentai, and then the OH
Play the base! What can be done selectively to make this happen?

According to specific conditions, the nalphate group is added to the position of one unit, and the Oa group is released to the other position. composed of groups.

occupied by

A unit 2be tateginrei t is even ijN or NH
rt by a group such as -000-0H1-0,H, and the 6 position of the W unit is occupied by a carboxyl group retained by an alkyl group, especially a methyl group.

A combination of these conditions is, for example, the following:
can be realized.

First, the 10-acetyl capping group is removed so as not to affect the sil group.

In this direction it is advantageous to use strong bases such as sorter tm
A saponification reaction takes place.

This reaction is preferable! It is carried out at a temperature of 1 temperature or less, especially at a temperature close to 0°C.

The product resulting from the hydrolysis is subjected to the action of an alkylating reagent to introduce an image layer alkyl group into a carboxyl group, which has been found to be free of 1 IAh of hydrolysis.

By the reaction with the chemical compound W acid group is released at the position of tLl which is liberated by hydrolysis and by the action of the alkylating reagent.

Satisfactory reaction conditions for reducing oxidation are the use of benign oxidizing reagents, such as trimethylamine/soi complex. This reaction is advantageously carried out in a solvent, in particular a medium such as dimethylformamide. Preferably, the operation is carried out at a lower temperature, generally around 50°C, which corresponds to a reaction time of 4'712 hours.

What happens to the free OH group removed by the ben/nor group that introduces the sulfate group for the alcohol function?

Removal of the benzyl group is advantageously carried out in an alcoholic medium containing the sulfate group and the conversion of the containing group to the amino group.

Water bulking of the precursor group and retention from 0HiIII, l
To obtain Ii+ and t-, it is advantageous to carry out the reaction for about 3 to 4 days.

As mentioned above, the amine-blinding group is the N-acetyl group in the biologically active molecule.
Ruru stick noodles.

To generate M-acetyl groups, 1ml of the product resulting from the water bulking reaction is subjected to an acetylation test. In this regard, anhydrous vinegar is particularly important in VC.

This selective acetylation of F51. It is of great interest to add more VClN-sulfate groups, and this can be done using the woodcutter oxidation test described above. For sulfation, pH% higher than 9 is advantageously 9.
A pH of ~1O is used.

The carboxyl group can be liberated by the agitation reaction and the addition of a strong enemy group.

The product produced can be readily salted with excess cations by means of an exchange resin. In natural filters, the cation is especially 1 thorium.

Therefore, exchange resins containing sodium cations are used in the market.

Zara VCl Potassium, lithium, magnesium, cal/rum salts can also be formed.

A two-tone mixed resin is used, and the resulting vinegar is then neutralized with a cationic base.

'% L:) This book is also directed to Sho 5lJi4, which constitutes the intermediate body in the Yadoki of the above-mentioned synthetic history.

In one s1 class, these oligosaccharides contain less OH
Base 1! In the case of units, the 3.4 square occupies the 6th position, and in the case of y units, it occupies the 2nd, 3rd or 4th position.

In other Class 11IIIi, the minor s#4 is composed of nine fully imaged units, such as those obtained at the end of the glycosylated root. Other plants w4 are 1 piece or a
It consists of a product in which 2 OH groups have been liberated.

The minor S class of these camphor trees has the structure (A-U) or (
It is composed of a chain based on binary units of [U-A)nC in the formula, nril to 6].

These minor 1s classes correspond to the slow - of a-b, e-C-byounenhon 1 and heavyweight ←-←1.

In 1% of the intermediate oligosaccharides of the present invention, the glycosides are constituted by a single species of these binary slow components.

In the group of songs, these types of e-cutter are present.

The corresponding minor S groups have a-b and a-C in their slow chains.
” and 1-4 units.

According to the present invention, the above-mentioned vague order of the linked rings in a two-component unit of one cypress or several buildings is reversed and solved.

According to one variant, the above-mentioned intermediate class S can be formed by one or several types of I! Call the units of L or b or C+4 11 times or several times / maku is ÷ -40 → number of years -
We have an eggplant oxyyari meeting. In these cases, the constituent units are 1-2.1-3.1-4 or 1-6
Depending on the nature of the alcohol used in the cyglycosylation step, the molds are aligned with each other.

The circle for heparin means heparan-sulfate fragment β. It includes the a1→4α and ibl→4aojlji combinations.

The l# of the a-group a contains at least one binary unit with the b1→4a O structure, i.e. β [D-glucuron U ] l −+ 4 [: D−
Glucosamine], this is the formula! = ↓ - A is removed, T is a temporary group tl or a permanent group p or a water atom, y is a containing group, an amine or an amine brocade precursor, and R is an aliphatic or aliphatic group. Chichimoto Hokai,
In particular, it is made of aluminum that contains 1 to 4 carbon atoms,
Here, OR represents a reactive group such as a halide, and furthermore, it is a group that controls Rfi alkyl and MFi, and these -? ! The symbol for the r product has the meaning given above.
Indicates p group.

In another group, the radicals R1 are different from one another, at least one representing a 5pffi radical, possibly together with R one or more other radicals, R1 representing a p group.

The general meaning of the formula IO ship number can be found in the solutions below.

Suitable oligosaccharides correspond to the formula (...), (button or QV): In the above formula, %r has the above dignity.

Preferably, in formulas (M) to (2), each of the symbols listed above has the following combination: M is an alkyl group, or an alkyl group; methyl, p represents a substituted alkyl group, especially benzyl, an acyl group, especially an acetyl group, in R11g or -, an alkyl group, especially methyl or a substituted alkyl, especially benzyl, or OR halogen, especially an odorous IA group or M#i indicates an azido group, T#i an acyl group, especially acetyl, a halogenated acyl group,
A group tl or t** alkyl group, in particular a benzyl group, in particular a benzyl group, optionally a paramethoxy group or a hydrogen atom, ν.

(Left blank) Another suitable group of oligosaccharides is ηl→4bl! containing at least one unit of [D-glucosamine]l
→4[D-glucuronic acid], which corresponds to 2M: Preferred minor IIs have the following formula (vIlt9 corresponds to (2): In these formulas and (2), the symbol M $II
L 5pap is a preferred ILea. The specific meanings mentioned above regarding formulas (1) to (2) more specifically represent an -NH-acetyl group.

This is probably because we are reminded that the order of unit chain formation can be reversed.

α In another preferred review, the oligosaccharide is c1→4a! Preferred oligosaccharides are those of formula (2) containing at least one binary unit of j1, i.e. (L-izumeronic acid) 1→4(D-glucosamine) corresponding to and (1); in preferred embodiments, the symbols shown in these formulas (1) and (1) have the following meanings: The various ID5p and p groups may be the same, and in 1% of the acyl groups an acetyl group or a different one selected from acetyl or benzoyl and aryl or substituted alkyl groups with 5% acyl groups;

N is a precursor nitrogen group, preferably different from that present in the compounds of formulas (1) to M, in particular NHCOO-
(fit-substituted alkyl group), especially -NH-COO-CHs
-C@L group, which allows the nitrogen-containing group to be subjected to different treatments and to form different aZ derivatives at the 2-position of the A unit, T is acetyl,
Halogenated acyl group, 41 represents monochloro or trichloroacetyl, p-methoxybenzoyl, symbol p
1M and R advantageously have the preferred meanings given above for formulas (El) to .

Another type of binary unit of a preferred oligosaccharide has the structure αl→4c, i.e. [D-glucosamine]lα →4[L-iduronic acid], which corresponds to the following formula αD: In particular, oligosaccharides correspond to formula (b) and book): [in the formula,
Preferred meanings of the symbols have the meanings given above for formulas (1) to (1).

(Hereinafter in the margin) Other suitable types of intermediate oligosaccharides falling within the scope of the present invention are:
It corresponds to a product whose protecting groups have been partially removed during the synthesis process. 41, this product of s has − instead of the 8p group.
Contains an OH group.

Suitable intermediate products include the above-mentioned complete hesaccharide-loving mechanisms, such as two-wheeled 1111AB, BC, CD, etc., trisaccharides ABC, BCD, etc., four-wheeled 111ABCD.

Upper shelf such as CDEF @ABCDEFG or BCDE
FGH't or the hesaccharide itself.

Among these minor II classes, structures BC, DE, and DEF are particularly important.

Mention may be made of EF, GH, FGH, EFG, EFGH, DIFGH and CDEFGH.

]1 The preferred intermediate trisaccharide@ corresponds to the binary unit of the ~α curve in the formula.

A preferred group of intermediate trisaccharides has the structure DEF and the formula α
(Stings one of the swords.

Constructed by structure DEFGH.

(XXff) [In the formula, each symbol has the above-mentioned preferred meaning, N1゜Ns
+Ns are the same or different and are selected from the above meanings. ) As described above for each binary unit, the present invention further provides OH
It also relates to the oligosaccharides mentioned above, in which one, several or optionally all of the groups are liberated during the synthesis.

Furthermore, the present invention is directed to oligosaccharides as novel compounds, each corresponding to the above definitions but having one or several functional groups, -acetyl)-6-0-nal7-ether D-glucamine]-methyl-〇-dalcuronic acid is excluded.

These O functional groups are preferably constituted by esters and are more particularly present in the form of inorganic anions.

2. A particularly preferred ester line, composed of sulfate esters, is present in biologically active molecules.

Other advantageous ester lines include phosphoric esters.

These functional groups are supported by one or more primary alcohols and/or secondary alcohols and/or primary alcohols.

Preferred types of oligosaccharides of the present invention include anions such as those described above;
.

In general, it includes a position that has 11 points.

A particularly preferred type contains a units in the ester 41 with -W'' ruaate groups in the 6 and 3 positions.

This type O-S* has a 9-aryenyl function substituted in the 2-position of the unit a-null-011, preferably by other substituents similar to sulfate.

In the oligosaccharides of the invention containing at least two units a , the amine function at the 2-position can be replaced by the same group.

A preferred group of oligosaccharides of this type includes dicarboxylic alcohols, especially units containing a 7-ate group on a primary alcohol.

Preferred oligosaccharides of this description have -NH at the 2-position of these units.
It has an 80s group. Other oligosaccharides have -NH-acyl groups, especially -NH-aryl groups.

Preferably, the esters described below are present as salts with inorganic or organic cations, especially metal cations, especially alkali cations or cations originating from nitrogen-containing bulk organic bases, such as triethylammonium.

The cation used is constituted by sodium.

Other cations such as potassium, madanesium and calcium cations are also suitable.

In another preferred type of the present invention, the carboxyl group of the unit is free, or
or preferably in the form of a salt with an organic or inorganic cation such as those mentioned above. These may be protected as described above.

Preferred compounds contain a unit C containing a sulfate group in the 2-position.

Other preferred compounds - contain sulfate on the Fia unit.

In these type 1IIIO oligosaccharides, the hydroxyl group of the bilane ring is either free or retained by a permanent group of the alkyl type, especially a methyl group.

These 111 kC) 1 mm (t) suitable compounds are
Contains a combination of units ^ and V that correspond to gender.

Corresponding to the biologically active molecules mentioned above, in particular the hesaccharide@ABcDE products, where the p group is replaced by an anion. Suitable compounds correspond to the salts of the above-mentioned compounds.

Other suitable oligosaccharides include N groups in addition to the N group of the ash writing unit.
H-acyl group, especially -NHCOCHm, -NH80s-
Contains 7.

□ This type of preferred trisaccharide 111FiBC, DE, EF or GW type structure, respectively, has the following O formula (XXV) ~
(2) Other suitable oligosaccharides of the invention have the following formulas (XX[X) and (XXX): Other suitable small I
II type is the following formula 00QQ) K corresponding structure: 1kgFG
(XXXI) Other particularly preferred oligosaccharides include, or are constituted by, the following pentasaccharides of formula (4) (2):

Cxxxsr,) Particularly suitable oligosaccharides of the invention@ have the following formula 00CXI)
Contains or is constituted by Class 6II of 6CDEFGH, which is flanked by a structure 6CDEFGH.

Other oligosaccharides are - of the above formulas (xxv) to (XXXI)
corresponding to the above, but with a free OH group instead of the -Op group. These compound lines were then completely lifted.

In 1 ml of other oligosaccharides, the -0SOs- group is OH
J! It will be slow if you replace it by .

Preferably, the oligosaccharide of the present invention constitutes an anionic synthetic intermediate as described above, allowing for the lateral transfer of a derivative of a given fragment of a biologically active molecule.

These constitute comparison compounds for structural studies in 41.

Pharmacological research power of oligosaccharide III of WA IIIIK
Therefore, it is a derivative of 41IK Example ISA.

The bone recorder has been deprotected from sulfated livestock and has been treated with Type 9 (xxx
I) Derivative 50 of pentasaccharide chain 41 is particularly endowed with a high degree of Il affinity for ATIK, and further exhibits extremely high selective inhibitory activity of blood activation X factor or Xa 7 actor.

Therefore, the present invention also provides useful biological biological research in experiments 1i1, particularly as a comparative element for studying other substances in which it is desirable to test anticoagulant activity at a constant level of Xa mizacter inhibition and antithrombin levels. This relates to the composition and use of target reagents.

Trisaccharides of formula (XX I
Adjusted by essl@r test? It has the structure of i/we@hen.

The pentasaccharide 50 of Example 9 is characterized by a significantly lower titer (Yin-Ws+nl@r). In particular, this pentasaccharide is 2000 sulfur/cape*L or greater. Anti-Musical @ (Yin -Mssl@r) and A
It has an affinity of 1116 degrees for 'l'llll.

In tests using chromogenic substrates, this activity was 400
0 unit of action/cape (TE I ENA) Ii
, method and LIE variant: Thrambosis &amp;
5earch No. 10, 1977, pp. 388-410) This test uses the factor commercially available as a solution of 8LL/IIJ in physiological serum by STGMA Kannoqney. The concentration of substrate is 1.
It is 33mM.

To perform this test, do the following300^
j (pH 5).

Incubate it for 1 minute at 37°C.

Add 100 pL of the above OXa 7 Acta (8L/11J) and after 1 minute inject the resulting solution into the substrate.

The total anticoagulant activity of this product is very low (~4 vL/~) in the human PTT test.

This property makes it possible to identify 411 the stages involved in blood coagulation.

Examination of this compound shows that it may exhibit strong anti-blood circulation activity. Furthermore, the derivatives according to the invention are of great interest in overcoming disorders of the blood vessel wall (atherocele pressure and arteriosclerosis).

Furthermore, they have the advantage of not having an active effect on red blood cell aggregation and () not causing thrombocytopenia. Furthermore, it also has the advantage of virtually no effect on bleeding time, thereby eliminating the risk of bleeding. These two properties are highly overlapping in medical applications.

Additionally, long-term 1″:ψh pharmacological responses were observed by the subcutaneous route, which further indicates renewed interest in this compound.

The oligosaccharides of the invention are furthermore advantageous because they are non-toxic.

These compounds are therefore particularly useful in developing particularly useful agents for preventing and treating blood clots.

Therefore, the present invention also provides a pharmaceutical composition containing the aforementioned oligosaccharides, particularly the above-mentioned pentasaccharides, which have even higher anti-Xa activity.

41. The present invention relates to pyrogen-free pharmaceutical compositions containing an effective amount of an active ingredient together with ml adjuvants.

The invention further relates to drug vehicle compositions suitable for oral administration. Dosage forms of the invention suitable for oral administration may advantageously be gastroresistant capsules, pellets or tablets, pills, or may be provided in a liposomal cap.

Other am compositions are constructed by combining these small amounts with supplementary steels suitable for enteral administration. A corresponding dosage form is a suppository.

Other dosage forms of the invention are aerosols or pomades.

The invention further relates to sterile or sterile injectable pharmaceutical compositions suitable for intravenous, intramuscular or subcutaneous administration.

These solutions advantageously contain oligosaccharides (1114 mJ) 100
0~100000 it (Yln -Wsssl@r
), preferably soo.

~50000 e.g. 25000 u/su, in which case these solutions are intended for subcutaneous injection. Furthermore, if these are intended for intravenous injection or perfusion, for example, 50 to 10000 U%
0(l).

Advantageously, the 0@0 medical composition is provided in a form that can be used in a disposable syringe.

Furthermore, the present invention has also incorporated other active ingredients particularly useful for the prevention and treatment of blood clots, such as the oligosaccharide IIIt, such as vasoregulators such as dihydroergotamine, nicotinate, or hemolytic agents such as urokinase. It also relates to pharmaceutical compositions containing the combination.

The medical substance of the present invention inhibits (preventive or natural?2) the stage of blood clotting in humans and animals.
! 411K from blood clots caused by K, such as F-active substances, etc.
411 is suitable when exposed to the risk of excessive coagulability occurring.

To illustrate the present W14Vt, an example of a pharmacology that can be used in humans is given below, which may be administered by administering 1000 to 250G(1(Yin-W
As Hatake1@r) can be administered subcutaneously to patients with 11K,
Or it consists of discontinuous intravenous administration at 1000 to 2 S 000μ724 hour intervals, or continuous administration by perfusion, or 1000 to 25
00044 (three times weekly) administered intramuscularly or subcutaneously (these titers are Yin
−Wsssl@r units).

These doses can, of course, be adjusted for each patient depending on the results obtained and the blood analysis previously performed, the nature of the disorder from which the patient is suffering, and the general state of health.

In addition to pharmaceutical compositions containing oligosaccharides, the present invention further provides at least one oligosaccharide as described above by covalent bonding.
IIT soluble supports are more advantageous than non-soluble supports.
It is an oligosaccharide that is linked to an AT-bond by a terminal sugar.

Conjugates of this type involving pentasaccharides 49 are particularly preferred. Products of this type represent drugs of particular interest in the prevention of hemophilia in cases of ATI deficiency.

Suitable conjugates with soluble supports are produced from proteins, particularly nonaseosaccharides, which are immobilized in vehicles such as polylysine or oxalmonol.

These products are useful as immunogens for persistent antibodies produced in vivo or clonal antibodies that are cloned in vitro using suitable techniques.

In other preferred conjugates, the oligosaccharides of the present invention are attached to an insoluble support. Advantageously, conventional supports are used.
It will be done.

These conjugates can be used as immunoabsorbent agents, for example, for the highly specific purification of muTl and its estimation, or for the development of novel blood I&L hemocompatible polymers by immobilization on biocompatible polymers. It is useful as

Furthermore, the present invention also relates to the use of the low sugar steel as a radiological medical product in nuclear medicine. These products are tracers selected from those currently used in the field of biotechnology.
Therefore, it is labeled.

For this purpose, nine-chiku palmate tium-9 is obtained from a commercially available generator.
9m is a non-reactive heptavalent bertechnetic acid, which is also likely to be highly reactive.
It is carried out by reducing systems obtained from salts such as tin), iron salts (rattan-iron sulfate) and titanic acid (titanium trichloride).

K, which fixes technetium to the scissors molecule, is sufficient in most cases to carry out this simple reduction of technetium under the given p)1 conditions.

On the one hand, the Honya Mei O raw material B 1 that constitutes the support body
It can be used in dosages of degrees S from 00 to I''IA (Ylm -%Vsssl@r).

μν K to obtain these O radiation lI drugs are P, V, KULKA
RNI Setonbayashi/) [Th@Jourml of mc
lear Medklm J Volume 21, No. 2, No. 11
Round according to the method on pages 7 to 121, and mark I like this.
The Il9 product is advantageously used in in vivo tests.

In addition, the oligosaccharides of the present invention can also be used to evaluate the specificity of many enzymes involved in the production of glycosaminoglucuronolycans.

The advantageous properties of the present invention-O-411110 will become clear from the examples below, with reference to Nos. 1 to 32g, which illustrate the compounds used in the above synthesis.

Example 1 The synthesis is carried out from dulcose according to the following steps a).

a) Production step of allyl derivative; b) Preservation step with pe/zolidene groups at 4- and 6-positions of allyl derivative; e) Introducing benzyl group into 2- and 3-positions; d
) removal of the benzylidene group to remove protecting groups at positions 4 and 6; ・) introduction of a trityl group at position 6, followed by acetylation & reaction at position 4; g) primary alcohol at position 6 Gruzo oxidation stage; k)
Methylation step of the car-xyl group at the 6-position; 1) step of introducing the f-lovenyl group into the 1-position; j) step of removing the acetyl group at the 4-position; these 0 steps are ζ as follows: Ta(
(See Ki 1 ■ and counting pigeon).

O produces gaseous hydrochloric acid (18,9) with allyl alcohol (60
0-) is heated to 70°C.

Next, add anhydrous dalcose (300g) and leave it for 3 hours.
Maintain at S degree.

The reaction can be followed by thin layer chromatography (t, t, e,) in methanol/lyroform (1/4.mah) solvent. The brown solution obtained after 3 hours is dried in vacuo, neutralized with an aqueous solution (5olIj) and dried again. The resulting nine residues were treated with acetone (500
+wj), bring to a boil and maintain this state until the entire amount is dissolved. After cooling, the wire rod is canted. What should I do with the residue again? The extract is analyzed to ensure that there are no traces of residual matter, or that the extract is contaminated with impurities to a high degree.

A portion (1211) of the extracted first fraction is subjected to silica chromatography. Recover the derivative l which can crystallize in an acetone/ether mixture (6.!i g;
M, P, 95-99°C). The remainder of the product is the same compound 1
(37Ii) was dissolved in dimethylformua (200ar), then dimethoxytoluene (41g) was added, followed by hydrated balatoluenesulfonic acid (130WI).
Add Ii).

After heating (in water bath) for 2 hours under vacuum and ml flow, the reaction is complete (t, L, e, methanol/chloroform, V2
5. (ma/ma) and evaporate the solvent. Dissolve Chiron I in methanol (minimal amount). A solution of the kernels was dropped into an aqueous solution of sodium tritium diate (6.3 Jil in 320 d of water), and the resulting washed precipitate was recrystallized in ethanol (2
1 #: M, P, 120-121°C). The mother liquor also gives product 2. Total yield (37 g; 71.4 tatami).

Compound 2 (45N) was dissolved in anhydrous DMF (s o o #l
l). Sodium hydride (50% in oil)
28 g of dispersion) are added.

After 30 minutes, the mixture was cooled to 0°C before adding pencil bromide (
52d) was added dropwise. The zero reaction was t, L, c, (
Ether/hexane, 1/1. I'll follow up with Ma/Ma).

Methanol (150+7) is then slowly added, evaporated to dryness and taken up again with chloroform. The chloroform phase is washed with water 1 and dried over sodium sulfate. After evaporation of lIm, the residue is crystallized in an ether/hexane mixture (36.5 g; M, P, 83-8
4℃).

This product is t, t, @, (ether/hexane, l
/l, v/ma) is slightly contaminated by higher migrating impurities.

Removal of Cancer Group A solution of compound 3 (56 g) in methanol (1 t) was added with water (4 t).
50117), and after 2 hours had passed by adding tihoc acid (17jl),
The mixture is allowed to cool, the bath medium is evaporated, and the residue is taken up again with chloroform (IL). The chloroform solution is washed with water until the pH becomes neutral, and then dried over sodium sulfate.

In this way, pale yellow Shirolag (4811) is obtained.

This syrup is used in the next step (synthesis of compound 5).

The obtained derivative 4 (48,?) was converted into pyrinone (25 (Foundation)
) Dissolve K and add trityl chloride (38.5 g).

The reaction is terminated after 1 hour at 100 °C (t, L, c
.

Ether/hexane, 1/1. Ma/,). Add acetic anhydride (200d) to the previous solution. ! Complete the reaction in the morning (t, L, @, ether/hexane, 1/2.ma/
,).

Evaporate to dryness, filter the residue with chloroform (500 d), wash the chloroform phase with lO-predominant potassium sulphate solution, water and then dry over sodium sulphate.

Evaporate the chloroform. In this way, compound 6a
get. This is used in the reaction to prepare the 11 compounds for $7 m.

The obtained derivative 6& is dissolved in chloroform (500 m5). The solution was cooled to 0°C and added with a methanol solution of boron trifluoride (20%).

120 tAf) was added dropwise with stirring. This reaction is t, ic, () luene/aryuton, 10/2,
v/v).

The reaction mixture is decanated in a separatory funnel. The chloroform phase is washed with water (2 x 100 m), with a saturated solution of sodium bicarbonate, and then with water until pH 25 is reached. After drying and evaporation, the resulting good residue is applied to a silica glu (500 g) Q column equilibrated in toluene. After bathing most of the impurities with pure toluene, the product was dissolved in a toluene/acetone mixture (10/2.v/
v). In this way, compound 7a was converted into 4
Obtain 8g. This [W! , used in the synthesis of compound 8a.

A portion of compound 71 is obtained in pure form.

The structure is confirmed by N, M, R spectra as well as by elemental analysis.

A solution of compound 7a (48Ji') in acetone (800g) is cooled to -5°C. Next, a bath solution of chromium trioxide (30 g) in sulfuric acid (3.5 M; 125 d) was added to the pot for 7 JII. Leave the mixture to come to room temperature. The reactants are t, t, c,
(Methanol/chloroform, 1/10.

At the end of the 0 reaction, the water (5
00rra) Open inside. The product is extracted with chloroform (3 times, 250 tj). Chloroform phase'lpH
Wash with water until neutral, dry and concentrate with sodium sulfate.

Shirolag (83N) obtained from Samurai is used as it is in the production of compound 9a.

Chiron obtained in the manufacturing stage of compound 8a! ether (3o
oak). An ether shadow of diazomethane is added until compound 8a disappears (t, t, c, ether/bequin, 1/1, v/v). After ζ) acid hydration with acetic acid, the IIIs are evaporated.

The resulting residue (253 g) is dissolved in hot ethanol. II conductor 9a crystallizes during cooling. ^ After crystallization, pure this compound-9a (18,4g) M, P, 85-8
6° C., [α]=+12° (l, 2 chloroform) is obtained. The product is characterized by its IR spectrum, N, M, R, spectrum and its elemental analysis.

Compound 91 was also obtained in an amount of 7.61 from the crystalline P solution.

The overall yield of compound 9a from compound 2 is 38%.

9m (4g) of the collar conductor is dissolved in a mixture of ethanol (119d), benzene (51+aJ) and water (17m). Next, Zoadebicyclooctane (170N9) is added and refluxed. Tris(triphenylphosphine)-rhodium(I) chloride (No. 55α) is added to the boiling solution.

Continue boiling for 4 hours (t, 1.c,, ether, /
Hexane, 1/1. v/v).

During the reaction period T, the solution is treated to remove the common edge.

The residue was chromatographed on silica gel (1501) in a mixture of ethyl acetate/chloroform (C1150, V/m) to give compound 10m (3.25y; s
zri. This compound 10ati M, P, 90 in ethanol
℃. am by man elemental analysis and N, M, R, and tg spectra.

Removal of adipose tissue 10a (350”1TI) with methanol (5d)
Add 1% inside. Sodium metal-) (0,2aJ.

Add 2M). After 1 hour at Penghou temperature, Mewek x
5 G -H'/Resin (d@v@x r@sin 50
-H''/ ) is added to stop the reaction. After filtration, product 13 is obtained. Product 13 is contaminated by a small amount of product resulting from α-β elimination.

By modifying step e) to perform a benzoylation reaction instead of the acetylation reaction, allyl-4-0-benzoyl-2,3-no-benzoyl-6-〇-)lyl-α
-D-glucopyrano 7d (compound 6b) is derived. Then, the trityl group was removed and allyl-4-0-benzoyl-2
, 3-di-0-benzo-alpha-loglucopyranoside (
Compound 7b) is obtained.

These reactions are carried out as follows.

A solution of compound 5 in pyridine was then added with benzoyl chloride (1,
5 equivalents) and the reaction is followed at t, L, c, (ethyl acetate/benzene, 1/20.m/m). Excess benzoyl chloride is destroyed by adding excess methanol. After evaporation to dryness, the residue is taken up again with chloroform, quenched with a solution of 1 (1) KHSO3, washed with water, dried and dried. This silone 7'' (105[, obtained using 3011 of compound 3)
Dissolve the solution in sodium chloride (300d).・Ladruene sulfone @ (monohydrate 76 in methanol 100-
Add g). The next morning, terminate the reaction (t, io,
e Ether acetate/chloroform, 1/20. Ma/Ma). The chloroform phase is washed with water until the pH is neutral, dried and evaporated. Obtained syrup (9111)
was subjected to chromatography on a column of silica glue (#1,2), eluted with chloroform (0,64), and then separated with a mixture of ethyl acetate/chloroform (1/20 mm). . In this way pure derivative 7b (30j
i) obtain. This derivative 7b is used in the preparation step of the t1 compound 8b. From compound 7b, -CI20 at position 6
11 groups, then introduce a methyl group into the obtained carxyl group, and continuously convert (Ajj /L-4-0-benzoyl-2,3-)-〇-benzyl-α-D-darkopi 2nocy→chloric acid (compound 8k) and the corresponding methyl ester (compound 9b) are obtained.

These derivatives are produced as follows.

The syrup obtained contains compound 8b methylated with diazomethane as described for compound 81.

The residue obtained at the end of methylation was treated with silica glu (20
0j; ether/hexane, l/l). Compound 9b is thus obtained (21#: 77.51
). The structure is confirmed by the 1B and N8 spectra.

From compound 9b, compound 10b was added to the handling method for lO &
obtained from.

Other changes include (allyl-2,3-)-〇-pentrue α-D-glucopyrano7do)uronic acid and [2,3-
Methyl (0-benzyl-α-D-glucopyranoside) uronic acid (compounds 11 and 12) is prepared.

Compound s b (1,9,9) was dissolved in methanol (4Qiu
) to dissolve W4 in 0-order soda (5N) to soda's I
# of M! The zero reaction that is added in sufficient quantity to have a change is t
, L, a, (methanol/lialoform, 1/4 °m/m) When terminating the reaction, water (100 *
Add t). Wash with ether, acidify and extract the product with ether. The etheric phase of clarity is defined as pi (
Wash with water until it becomes neutral.

Derivative 11 was not cleaved, and methylation of derivative 11 with an ethereal solution of diazomethane gave compound 12 (900IQ; 56%). Kono compound 12
The structure is confirmed by a 1 to 7 liter column (ether/power (1,3, chloroform)), its IR and N, M, R, chromatography and elemental analysis.

In the same manner, derivative 1 was obtained from compounds 9 to 9b.
1, t! 1; It is possible to obtain derivative 12.

Compound 13 can be obtained from compound 12 by the following method.

II derivative 2 is treated with a complex salt of rhodium as described for compound-91. Compound 13 in yield 90
Get it with 'S. This compound 13 has seven IR and N0M, R
, characterized by a spectrum. Treatment with acetic anhydride (1aJ to 180wIg of compound 9aK) gives compound 10m.

Sea conductor 13I/'i compound 9a or 9b with other modifications
Compound 10% can be obtained from 10b using the method described for compound 11.

Practical 9112 This synthesis is carried out in steps 0 and 1 below: Preparation of (1-noromo2.3-di-0-benzyl-4-o-chloroacetyl-α-D-glucopyranoside) uron-fused methylnacetate; Nest II that guides the illusion 21118! Condensation of 117 and compound 16;
Bromo version that gives 20 mittens.

This synthesis consists of 13% monosaccharide (7"af-1'-
2.3-C0-benzyl-α-D-glucopyranoside) uronic acid methy★ is carried out in three steps: 1: Chloroacetylation of compound 13; 2: Anomeric carbon limb “Dη(ui+bl・・king).

3: Anomeric carbon bromination compound 1 B (2, sg) with viridiy 30 m (
6,56 mm@l). After cooling to 0° C., a solution of chlorine acetyl 2-chloride in ditalolomethane (20 aJ) is added dropwise. After 30 minutes, it was evaporated to dryness, the residue was extracted with chloroform 20011j, and KH11
04 l〇-bath solution, wash with a fistful of water, dry, and shrink. The resulting syrup was mixed with silica gel (20011: Bath #I
Apply to the chromatograph of l enemy M*01t/Hekinan: 1/3; M/M). In this way, 2.79 pure compound 14 is obtained in the form of syrup (yield: 80 hers).
; [α) = +2 (・Gourd 1.5; taloloform).

The desired structure (by elemental analysis and N, M, R, spectrum) is determined in the pupil 1.

2.7. ! Derivative of i' (5,3maiol) 14
was dissolved in a 70% acetate/water (5/1) mixture, mercuric oxide (3,1 g) was added, followed by mercuric chloride (3,9,9). Acetone (27d) solution is added. After 5 minutes, the salt is filtered off. After the embroidery is dried, the residue is removed again with chloroform. The chloroform phase is washed with 10% Kl solution, water 0Ji1N. After evaporation, the product is crystallized in a methyl acetate/hexane mixture. M, P, 105-107℃; [α几-J
F 4.7 (equivalent, l chloroform) isomer 29t
4 Ru. The structure is confirmed by principal analysis and NMR spectrum (yield: 80%).

211 (43,3mrnol) compound-15
a Dissolve in methane 501. aytn-collidine4.
After adding 8-(34.4 mmol) at 0°C, HEPBUR
N D, R, and HUD8ON H, R,, J, Ck@
m, 8oa, P@rkin I (1976) 754-7
Manufactured in accordance with 57! Add romomethylene dimethyl ammonium bromide (17111!II (II)).

After 4 hours of reaction, the mixture is diluted with nochloromethane lO-, then poured into ice water and evaporated to 191 L #i with ice water. When chromatographed on silica dal (209; dissolved in hexane/ethyl acetate% a/'1: ma/ma), the compound 82.5 (
・-1,5:chloroform) 6 elemental analysis and N, M, R
, the structure is confirmed by analysis.

This synthesis consists of monosaccharides 16 and 8701'9 (3,8 mmo
Based on 17 combinations of l).

Trierite (dri/rtt/X1N) in 870# (3.8mm@l) compound 17 di-aa methane bath solution
and powdered 41 molecular sheet (o, sg) and freshly prepared silver carbonate (0,5259).

After stirring for 2 hours, 670 il (1,
3s + mol)fi and add. After 6 days, the solids are removed by filtration. *The syrup obtained after condensation was mixed with silica (50j:
1. Mah)'s taromad graph. Trisaccharide 18 is obtained in the form of toam (42 lWkg; 5
0-). [α] Me 17° (e = 1.chloroform).

Elemental analysis confirms the structure. NMR analysis confirms the steric pupils of the cylindrical bond.

C) Preparation of trisaccharide of structure 19 by acetic acid fractionation of trisaccharide 18. Trisaccharide 19 is produced by aging acid decomposition/lv such as less than 1 fl of two wheels.

Dissolve 300 Wv of compound 18 in a mixture of anhydrous vinegar #4d and freshly distilled trifluoroacetic acid xd.
The reaction mixture is stirred for 10 hours at 18° C. and then evaporated to dryness and co-evaporated with toluene. Apply the IA@ product to a cuff chromatograph using silica dal (15N). Tsuku g
Dissection with a mixture of lomethane and ethyl acetate (19:1.ma/ma) gives a mixture of anomeric ivy acetates of structure 19 282IIQ in the form of a colorless syrup (yield 86-). The type-to-type trams determined by NMR analysis are 4/1.

NMR spectrum confirms the desired structure.

D) trisaccharide 19! Manufactured beak of 2 If20 by lomo conversion! 1
Mixture of acetates of 9 - Let K T I Bra act. Mixture of 19 acetates in a mixture of nochloromethane 3d and ethyl acetate 0.3117-1409, 17-18
TiBr140# (T
h2 equivalents) for 20 hours. After cooling to 0°C and diluting with nochloromethane 30117, the mixture was poured into ice water,
It is then washed with aqueous potassium bromide 511 solution, water, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on a silica glu column (10, li'). t￥1: By elution of ethyl acid/dichloromethane (19/1, v/v) mixture,
It is recovered during the next elution.

- Bromide 20 (74 da; yield 50 da), unstable (ready for subsequent reaction) in the form of a colorless syrup.

The desired structure is confirmed by the cooperation spectrum.

- one minute corresponding to unreacted starting material (28 da; yield 20
h) The almost immobile fraction corresponding to the partially pendylated compound is carried out 9113 (the derivative with 22 is benzyl-3-0-benzol-2-benzyloxy-cal; Oki7-α-D
- Produced from glucopyranoside (#conductor 21) by the following method (see Figure 5).

P, C, WY8B, J, KI8B, H*1v, Ckim
, Mu@taJfi11833-1847 (1975)K
Compound 21 (98711 kg, 2 m-・
l) in anhydrous 1.2 dichloroethane (1 s
d) In the presence of N-acetyl-i/sol (2.5 mmol freshly prepared) F, reflux for 30 hours. After cooling and diluting with chloroform (50 iu), the organic phase was washed with IM solution, water, a saturated aqueous solution of limestone, and water.
Dry (sodium sulfate), filter and distill.
The residue is chromatographed using a column of silica glu (50,9). Decomposition using a zochloromethane/aryl chloride mixture (15/1.mer) gives the derivative 22 in the form of a syrup, which is crystallized in a mixture of ethyl acetate/hexane (759 ml; 71 capsules). M.P.
114-115°C; [α] win = +88° (-1, chloroform).

Example 4 (33) The synthesis is carried out in the following steps starting from compound 23 (see Figure 6).

1) Step of introducing benzoyl group at the 5th position 2) Methylation step of the cal-xyl group at the 6th position 3) Isomerization step of the OH group at the 5th position 4) Step of forming a pyran ring 1) Benzoylation reaction 3-0 -benzyl-1,2-0-ingropyrine-α
=D-darcofuranoside (compound 23) 63p is dissolved in 500aJ of anhydrous pyridine.

Add 85 jl of trityl chloride and heat at SOt: for 1 hour. Compound 24 is thus obtained.

Optical rotation #Ii: (α) = -34,7°, chloroform.

The structure of this compound is shown in infrared and N, M, R,
Confirmed by elemental analysis.

The hardware is then cooled to 0° C. and 45 mB of benzoyl chloride is added. The next morning, methanol 30014 is added to decompose the residual reagent. The resulting mixture is evaporated and taken up with chloroform. The chloroform phase is washed with water and quenched with sodium sulfate to tlp% $71. Compound 23 is thus obtained.

The resulting syrup is tallowform 4QQaJ! Dissolve in 4C. After adding 100 atm of a methanol solution of 5M) radruene sulfone, the solution is left at 4°C until the next morning. After washing the organic phase with water, 215 g of a mixture are obtained.

This mixture was mixed with silica glu (ether/hexane, 2/
1 (Ma/V) solvent). Thus compound 26 lum. The structure of compound 26 was confirmed by infrared and N, M, R, spectra.

2) Methylated compound 26 (
1,887? ) in 3.5 M H2B of e cros (1s 11 ) dissolved in 20 aj
Add 3.5 l of O3(29i1) solution dropwise at f50°C. The temperature is allowed to rise and the mixture is allowed to stand in this state for 1 hour.Then, the reaction mixture is poured into water and the product is extracted with chloroform. After washing with water, drying and mulching, and evaporating to dryness,
Compound 27 is obtained.

Next, 10iJ of 1N soda was added, and the reaction mixture was kept at mold temperature until the next morning.
The product is destroyed by linear movement of the pumping liquid. Compound 28 is thus obtained.

This compound is dissolved in ether and methylated with noadimethane in a conventional manner. After evaporation, compound 29
(1,08,9 nia 0.4 rice cake) is obtained. Compound 29 by optical rotation elemental analysis, infrared and N, M, R,
I recognize the sadism of

Isomerized anhydrous trifle (trIMia ankydrlde) based on 3+ 5th position 10) (
A solution of dichloromethane (16d) containing pyridine (0,811j) was cooled to -20°C, and a solution of pyridine (0,8aj) in dichloromethane (8g11) was added thereto.Next, at -10°C, dichloromethane ( After 1 h, the reaction mixture was diluted with sodium bicarbonate, 1 h
Mixture of water and ice containing 601119'g (8aJ)
The organic phase is washed with 311HCA, H2O, and NaCtlla solution, dried, and set aside. Compound 30 is thus obtained.

Remove the syrup again with DMF (10y). Add sodium trifluoroacetate (1.6 g) and stir at 80°C for 3 hours.
Heat to ℃. Compound 31 is thus obtained. # After extraction, extract again with dichloromethane, wash with water, dry,
The residue is taken up with methanol and the solvent is then evaporated after 1 hour. Application of a column with ether/hequinane (2'υ) as solvent gives compound 32 (450 roform).

The structure of compound 32 is shown in infrared and N0M, R, S(cutol,
Perform FIM using 7C system analysis.

4) ``72'' (10,000 IL +1 -n) This synthetic compound 32 is made by force, compound 321oo=w
) tl Refluoro #I - Dissolve in a mixture of trifluoride/water (9/1). After 15 minutes, the solvent is evaporated. The cooked material is crystallized in ethyl acetate/hexane. In this way, 110 μ of compound $33 are obtained.

The characteristics of this conductor are as follows.

Infrared spectrum: CHCL, r of medium 5' unit: 345
0 (OH), 3080.3060.3030 (CH,
:pennol) and 1740 (,C00CH,)NJi
, R, x vector: δ in ppm with TM8 as standard: , 3.75 (8, 3H”, C00M・), 4.9
8 (1m (”).

7.30 (S, 5H, C6)1. ) Elemental analysis C14111807 Uraronki +'j! #I value C
・－・・・・・・ 56.37 56.1
7H・・・・・・・・・ 6.08
5.85M, P, 125-
126°C (see 1/margin) Example 5 Synthesis of nate (38) From derivative 33 and the iduronic acid structure, it was synthesized according to the following Stellar Ill (see 7IiJ).

α) Acetylate derivative 33; β) Add pro-A to the mixture of ano v-11 acetates 34 and 35.
ent) to introduce a bromine atom onto the 7-carbon bulk; y) to form an orthoester at the - and 2-positions; a
) Carry out monochloroacetylation at the 4-position of the orthoester.

A mixed solution of compound $83<311) of anhydrous pyridine (20d) and -glacial acetic acid (1011t) was heated to 0 while blocking moisture.
Stir the reaction for 5 h at 0° C., evaporate the mixture to dryness, evaporate on a torzy (4×2Qd) and dry in vacuo. W
The A residue is chromatographed on a silica Dull column (15ON). Elution with a mixture of toluene:ethyl acetate (4:l by volume) gives the following substances in sequence:

A first fraction consisting of one furan derivative, - Compound 34 (α anomer), Chiron 7'' (170 drops,
4th grade)% [α]. z-43; (5: l, chloroform, N, M, 11. (CDC13): 's6
．． 23 (1@1, Hl)* Compound 35 (β anomer), crystallized in ether-hetPt mixture, (2688p, 63 arrogant), M, P.

: 112-113°C, [α)6-+9 (!:ichloroform), N, M, R, (CDCl,): J:
6.0 g (d, IH, H-1, Jl, 2:1.5-
).

The α-anomer 34 and β-anomer 35 treated with the E-period synthesis monomer are not separated, and the mixture is used as it is in the form of syrup for subsequent reactions.

Mixture of acetates 34 and 35 (21211 g.

0.5mM) is dissolved with anhydrous dichloromethane (5"lj) and anhydrous ethyl acetate (0.517m). Titanium tetrabromide (250ml 9.0.7raM) is added in one portion and the reaction mixture is evaporated. Trim and stir at room temperature for 24 hours. After cooling to 0°C and diluting with dichloromethane, the organic phase is washed with ice water (3 times), dried (over sodium sulfate), filtered and evaporated to give a light colored silolag. derivative 36 (21
7#, 96*) to obtain 6 N, M, R.

(CDCl3): ': 6.4) (1, I H
, H1). This compound is extremely unstable and is used immediately for subsequent reactions.

(2.122 g of a mixture of acetate 3tI and 3d).

9) bromide 36 anhydrous dichloromethane (20jlJ) 1! The solution is stirred at room temperature under an atmosphere of dry alzine. -ytn-colicin (265aj
, 20 mM) and anhydrous tertiary-butanol (3#Il
, 30 wM) are added sequentially and the reaction mixture is stirred for 15 hours under ambient conditions. After dilution with dichloromethane (50 aJ), the organic phase was washed successively with saturated aqueous sodium hydrogen sulfate solution and water, dried (over sodium sulfate) and -
evaporates and evaporates. The residue was filtered onto a silica column (12(1)
chromatograph.

(in a volume ratio of 2:l containing triethylamine in 05q6)
-・Kisan:! rliII! Elution with an ethyl mixture yields compound 37 in the form of pure siloso7' (1,5421, 70 capsules of compound 34 + 35).

[α]. Knee 23° (!:l, chloroform), N, M
,R.

(CDCl, ): J: 5.48 (d, IH, H-1, J
,,2:2.5i(s).

a) Monochloroacetylated orthoester 37 (220Q, 0.5 mM
) in anhydrous methanol (10 g) is cooled to -20°C under pressure in an atmosphere of dry arunone. Anhydrous potassium chloride (40 ~) was added and the reaction mixture was heated to 5
Stir at +llI. Drain the solids, evaporate the P solution and place +J4 in chloroform (50m).

Wash the crab in ice water (three times) and dry (over sodium sulfate), filter and evaporate. The residue ★ is immediately dissolved in anhydrous birinone <4@t) and anhydrous dichloromethane (2 tl). Dry Al! After cooling to -20 υ under / atmosphere (freshly distilled 90, 1 pal).

A solution of chloroacetyl chloride (1,2 tf J waM) in anhydrous dichloromethane (1-) is added dropwise. The reaction mixture was stirred for 30 minutes under the above conditions and then a water-water mixture (1
00mj) Pour K. After stirring for 15 minutes, the mixture is extracted with chloroform (3×20d). ice water.

The organic phase is washed successively with an aqueous sodium dihydrogen dihydrogen solution and water, dried (over IJ sulfate), filtered and evaporated. Immediately transfer the residue to a silica dull column (12I
Chromatograph I). Hexane (containing 0,2-triethylamine in a volume/weight ratio of 5:2): # When eluted with an ethyl acid mixture, the following substances were obtained in sequence.

Monounsaturated compound 39 (15 Da, 8 excellent).

- orthoester 38 sulfate f (145 Mg, compound 1
2 sl*), (α), = +19 (!: 1 + chloroform), N0M, R, (CDCt,): J
: 5.45 (d.

IH, H-1, J, 2:2.5Hs), 5.
24 (a, d,.

IH, H-4, J, 4:2.1HssJ4.5:1.
5Ha) 14.00 (a * 2Hr CL-CH
2-Coo L Example 6 Synthesis of nosides Stella lα) Condensation of Hua sugar 38 and 22C) Vζ↓
Then, the monochloroacetyl group at the 4th position is removed using Stella lβ to obtain the desired bishaft 41 (8th
(see figure).

3 g (284'IIv, 0.6
22 (2141?, 0.4)
A solution of anhydrous chloropenzene (121F7) with 14 mM) of
Heat to 0°C.

After 101 LI of solvent has slowly distilled off, a solution of (freshly prepared 0,006 mM) 2,6-nomethylpyrinonium perchlorate in coulobenzene (4d) is diluted with 30
Add KM dropwise for 0 minutes and simultaneously distill the K(47140) solvent. The reaction mixture is then stirred for 1 hour with simultaneous cooling and distillation of fresh solvent (10#Ij) so that a constant reaction volume equal to K 4 ml is maintained. After cooling and diluting with chloroform, the organic phase is washed successively with saturated hydrogen hydroxide solution and water, dried (over sodium sulfate) and filtered. Apply the residue to a silica Dull column (401 glue p-madograph. (volume ratio 4
Elution with a :3→hexa/:ethyl acetate mixture yields the following proboscises in sequence.

Single proboscis 22 (120 Da, 51 G) - Biaxial 40. Crystallized in an ether-methane mixture (112
~, 30 h), MP: 144-145°C.

[α),”=+35°(・:1.Chloroform), NM
R(CDCj5): Matches the desired structure.

Step β: Removal of monochloroacetyl group Biaxial 40 (
9 at 56', 0.06'mM) and thiourea (7I
Pyrinone (2,5a
j) and absolute ethanol (0.5ij) at 10
The reaction mixture was evaporated to dryness in a cold MJ tube for 40 minutes at 0°C and the residue was taken up in a water-chloroform mixture (40d, volume ratio 1:1). The organic phase is washed with water, dried (over sodium sulphate), filtered and evaporated.

The residue was applied to Chromatograph K using a silica Dull column (2 g). Elution with an ethyl acetate-hexane mixture (volume/weight ratio 2:1) gives 21141.

Crystallized into ether (46 da, 30 min), M, P,:
146-147°C, [α]. =44 (c:1.chloroform), NMR (CDCj,): consistent with mo structure Example 7 &! Synthesis of WI143 41143 is produced by the following Stellal (see Figure 9)
.

a) Condensation of the biaxes 2o and 41 synthesized in Examples 2 and 6.

b) Selective -〇-r formed at position 4204 of the 94-saccharide
Monochloroacetylation.

a) Anhydrous nochloroethane (1,5a+7) prepared in a complex reaction with a compound of good bromide 20 (64ap, 80.sM) + l (slda, 60 μM) and Nilla Sheep 4X (powder, 80.sM) in a molten mixture. solution in a dry ant Al F7 atmosphere)
-5 Stir for 30 min. Cool the reaction mixture to -20°C and add gym-=tlysine (20aj, 150xM)
and mackerel triflate (3xq, 120 nM) are added sequentially. The reaction mixture was stirred for 1 h at -20'O
Allow time to warm up to room temperature. Nochloromethane (50lal
), the solid was dehydrated and the fIt was diluted with IM HCtl+
Lit water column, washed with water (twice), dried (over sodium sulfate) and evaporated.

The residue is chromatographed on a dtt silica dull column (8,@, 230-400 mesh dull). Elution with a mixture of H-41 and ethyl acetate (volume ratio 4:3) yielded H-41.
1142 is colorless plus (391) shape - 1' times 1jL
Ill. ('')g'=+ss'(a=o, 6;CHC
j,), the NMR spectrum is consistent with the desired structure.

Fill the column with ethyl acetate-hexane mixture (volume ratio 2:l)
When eluted with
Containing birinone 1.25- and anhydrous 7-tanol 0.25-
Mixed solution with m and thiourea (7 drops).

Heat at 100"0 for 20 minutes in the presence of 10100JI. After cooling and evaporation to dryness, the solid residue is dissolved in water 201111:
and extract with chloroform (5X5a+j). The organic phase is washed successively with an aqueous sodium sulfate solution and water, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on a silica Dull column (31).

When eluted with an ethyl acetate-to-molecular mixture (3:2 shell ratio), derivative 43 was obtained in the form of a colorless glass (27J
1.80n).

Example 8 (See Figure 10) Synthesis of pentasaccharide 45 with wood (45)
get.

lf, PAVL8] CN and W, 8TgNZEL
, ffk@m, B@r.

111 (1978) 2334-2347, 54 μML Tetrasaccharide 43 (26
9, 18sM) and U mole + s-5-7-f41 (powder,
5 oap) o gil o o x p y (0,8 gj
) After stirring the #I liquid for 30 minutes under an atmosphere of * temperature, -2
Cool to 0°C @ lym-corino/(16!j.

120JM) and silver triflate (26afi, 100
, sM) are added sequentially. The reaction mixture is stirred for 18 hours, and the temperature gradually rises to room temperature. Dichloromethane (
59aj) to dehydrate the solid, and the P solution was first washed with a cold aqueous IM HCt solution and water (twice), subjected to JE imaging (with sodium sulfate, passed through, and evaporated).

The residue is filtered through a silica gel column (819, 230-400 Messier). When eluted with a mixture of sodium chloride and ethyl acetate (4:3 by volume), the pentasaccharide 45 can be recovered in the form of a colorless saccharide (30 da, 901 g). [α]. =+67 (@-/l: CHCA
s); The NMR spectrum is ``1'cm from the desired structure''
It turns out that the protons are I, F, DKII (respectively).

Example 9 Pentasaccharide 50 (Dll production (see Figure 1θ and Figure 111A) This production is carried out in the following step.

(a) Removal of acetyl group (51146).

(b) Sulfation of the -OH group thus liberated (Gotate 47).

(c) 1OH hydrogenated and protected with benol group
All bases! L and -N, 1& are converted to -Nu2 groups (pentasaccharide 48).

td) NH, the pentasaccharide by sulfurizing the group 49), then 6
Saponification of the -COOM group at position (5m150) is carried out as shown below in step fl-4.

a) Removal of the acetyl group of derivative 45 of #II45 (2811 g) in 1,2-nomethane (2,5,*/) and methanol (0,81!j)
Stir the solution while cooling. 1M soda solution 1
Add aJ dropwise over 10 minutes. The reaction mixture is stirred at 0° C. for 1 hour and then at room temperature for 12 hours. After cooling to 0.degree. C., 1 portion of IM sulfuric acid (3i/) is added and the milky mixture is immediately extracted with chloroform (5.times.5.it).

The horizontal phase is washed with water, dried over sodium sulfate, treated with P and evaporated. The residue is taken up in methanol (21 Ll) and treated with an ethereal solution of cyanomethane for 30 minutes (perfllI
O Noah! (At the platform where the yellow color persists due to the presence of methane).

After evaporation to dryness, the residue/E silica gel column (21230-
Chromatograph K (400 Metsiel) was applied. Dichloromethane-methanol mixture (volume ratio 15: l)
Upon elution, five shelves 46 are collected in a colorless glass bottle (18 das, 72-).

(α):08+5de(@:z,l;Chlorophor J-
).

m spectrum confirms the desired structure.

Compound 46(22~)O diethylformamide (0,5
IIIj) Triethylamine/80. Complex (2
Add 2M9, 2.5 eq. 10 H) and heat the reaction mixture to 50° C. for #14 hours. Then triethylamine/80. The complex (10 mg) is added and the reaction is carried out for 24 hours. 6 Methanol (0,5 zs/) and Riophor* (0,5R1) are added to the reaction mixture. CHCl,
The solution is introduced into the top of a Tiger Sephadex LH2° column equilibrated with /CH,OH (volume ratio l:1). Collect the fraction containing the sulfated product and evaporate the solvent. In this way, a plus-like substance is obtained (30w9). This substance was chromatographed on silica glu (109) as a 0m eluate (ethyl acetate/male lysine/acetic acid/water (
A solvent consisting of 3 parts of a mixture (6:2:0.6:1 by volume) and 2 parts of a mixture of ethyl acetate/viridi//acetic acid/water (5:5:1:3 by volume) is introduced.

Fractions containing the desired product are collected and concentrated.

After evaporating the solvent, the resulting residue was dissolved in water-containing methanol and equilibrated with a methanol/water mixture (50:50 by volume). 50W x 4.

Sound the Na+ column. Thus, the nato-
) Hydrogenation The product obtained above is dissolved in water (methanol (3,7j17) containing 0,3 shoulder).

This molten WIK catalyst (pa/c, s excellent, 4ov) km +L, water volume 11II! Stir under 1 atmosphere for 5 days. After the catalyst was temporarily removed, the U;V spectrum analysis of the resulting S liquid revealed that the absorption peak derived from the pennol group had disappeared. Further evaporation of the solvent leaves a residue, compound 48.

Compound 48 is dissolved in water (4-). pH 9.5
K #, add trimethylaine/SO5 complex (5
Add 4 da). 0. The pH is maintained at 9.5 during the reaction by addition of IN soda.

-After the evening, add more sulfated sulfate (27 Da). The final addition is made after 24 hours.

After 48 hours, soda (3M #34 R1) is added to the formed compound. When the solution is stirred at room temperature for 3 hours, the methyl esters of the uronic acid type units are hydrolyzed.

The reaction mixture is then neutralized and concentrated to a volume of approximately 2Ial. The solution thus obtained was added to Sephadex G25.
Introduce the color A (100-
let Analysis of one minute collected by UV absorption (206 nm)
and polarometry (265 nm). The fractions exhibiting optical activity were collected, the solvent was removed, and the residue was
ml of water and lyophilize.

In this way, a cast conductor 50 is obtained in the form of a white powder (5.6 Da, 25 pieces of product 45).

The desired structure is confirmed by NMR spectroscopy. In particular, for the anomie proton of the darcosamite unit, 536,
It is observed that 5.45 and 5.52 ppm of dislocations (δ, TM8) are found for protons in i(, F and D, respectively).

Example 10 (51) Synthesis of one (see Figure 12) Monosaccharide 13 (0,215,f, 0.5 m rnut
Monosaccharide 44 (0
, 49g, 1mmoA・) in dichloromethane (3d) solution and leaking error sheet 41. (powder) are added sequentially.

After cooling the mixed zone to 0°C, sym-corrinone (0,16d
) and silver triflate (0,3, @ ) are added.

1aIrIJIi&, mixture ttsuk op methane (50a
dilute with j). The solid was dehydrated, and the solution was washed with 5% sodium carbonate, 1% sodium carbonate, 1% potassium hydrogen, and 1% water.In this way, the S-IpA residue was reduced to 4%.
It will be done. Toluene/acetone mixture (volume ratio 30:l)
When 411 is prepared on silica using

This product is confirmed by elemental analysis.

Example 11 MuNWA6 0811 (54) Acetiminoru 2.3-Noropen True 4-0- [
1
--Ranoku! Synthesis of - and 2-benzene (see Figure 12) Two $1,151 (180 da) of a-7//water (volume ratio 1 s: 1.61 J) solution contains water steel pentoxide (z3zv) and chloride. Solution of mercury in acetone/water mixture (z9zap/hv
) are added sequentially.

- After filtration and evaporation, it is taken up in chloroform and washed sequentially with 10% potassium chloride S solution and water to obtain 2 types of 52 (1
40■).

Dissolve Type 52 (too much) in 0.6 lll of methanol. Add ammonium formate (160 da) to this solution.
and 10 pieces of P4/C catalyst (100 Da) were added. 5
After minutes, remove the catalyst and add acetic anhydride (10 drops).

After evaporation, the product obtained is purified on silica using a toluene/acetone mixture (4:l by volume). In this way, two kinds of 53 (61WR9) are obtained.
It can be confirmed by Rf of @r@, r@f@r@nc* 5719). The solvents are chloroform/ethyl acetate (volume ratio 3:2)) tf=0.40 and toluene/acetate/(volume 1 ratio 4:1) Rf=0.20.

Derivative 53 (60#) was dissolved in dichloromethane (1,5111
7) [12 then 0 then trichloroacetonitrile (7
5 μL) and water bulking sodium (1,5#). After 15 minutes, the -conductor 53 disappears and the -conductor 54 becomes predominant. After filtration and evaporation 54 is obtained (67 da), chloroform/ethyl acetate (volume ratio 2:1; Rf=
0.59) using silica grate (lII%*rc
1 from RfK of k4of@r*n** 5719)
Derivative 54 is confirmed (Rf of compound #I53 = 0.3
7).

Example 12 stem (57) synthesis of.

This is done from these synthetic RI cast conductors 55 and 56 (see Figure @13).

a) Methyl (promo 2,3-di-0-benzo-4-
0-A7-D-glucopyranoside) Production of uronate compound 55- ('4) / P-compound 1 m
(32L 85.5 mmote) of pyrinone (25
0aJ) solution to trityl chloride (2L6g).

1.21) and heat to 80°C. Furthermore, trityl chloride (4.6N, 0.2s) was added after 3 hours of reaction.

1b was completely formed 41k (t, t, @, fusilica; methanol chloroform, volume ratio 1:20), solution t
Cool to oC and add pendiyl chloride (15-11,5 mB)
Add. - After the evening, 1c is formed quantitatively. Add methanol (1,5d) dropwise to the reaction mixture #IK and concentrate to dryness. The obtained residue was converted to radruenesulfonic acid (9
After 2 hours of reaction, the reaction mixture is transferred to a separatory funnel containing ice water (/2 t). The product ldi after extraction with chloroform is used in Stellal below.

A portion of this product was purified and 11
Check the 1I supernatant. The product is colorless after one fall. [α
0 = -61° (chloroform).

The product (95 g) obtained in Stella f was mixed with acetone (
After cooling this solution to 0° C., a solution of chromium nitrite (52 g) in 3.5 M sulfuric acid (220 ml) was added dropwise. After 2 hours of reaction, pour the reaction mixture onto ice water (lt). The product 1. is extracted with chloroform (5 x 200 ml). The chloroform phase is washed to pi neutrality, dried and concentrated to dryness.

The obtained residue is dissolved in methanol (650jtj), soda water (20g 15.0aj) is added dropwise, and the mixture is heated to 50°C. - After the evening, the resulting solution is partially concentrated and poured into water (1, sg. The aqueous phase is washed with ether and after acidification with #L# the product 1f is extracted with ether. Drying over sodium sulfate and concentration to dryness yields a yellow mass containing 1 (5(1)).

This residue (50II) was mixed with a butyric acid/trifluoroacetic acid mixture (
Volume ratio 15:1.615d) Dissolve K.

This solution is stirred at 100° C. and water (1so, y) is added.

After one night, evaporate to dryness to remove trace amounts of acetic acid and evaporate toluene. A good residue, partially formed from unhydrolyzed 11 and 1 g, is dissolved in ether (400 a/k).

An ethereal solution of diazomethane is added to this solution at 0 °C until complete methylation (t, 1.o.).

Silica, ether/hypersanate, volume 1 m ratio z:l).

Excess diazomethane is then destroyed with acetic acid and the reaction mixture is concentrated to dryness.

What’s left? K is purified using a silica powder ram (200II).

The cafe is first flushed with pure loloform and then with a chloroform/ether mixture (3:l by volume). In this way, lk is obtained (8.6, @, 22.2mm
ot*, (2611 of la).

Crystallize derivative 1k. m, p, 122123℃
, elemental analysis, NMR spectrum) its structure is confirmed.

1 k (3.9 g, 10 m + m@js) in bilysin (50 mj), acetic anhydride (44! J, 42 mm
oje). After 2 hours, the reaction mixture is evaporated to dryness. In this way, 1t is obtained (4.62g, ss*
).

Titanium tetrabromide (1.5 L) is added to a solution of 1/, (x, B) in dichloromethane (3Qmj) and ethyl acetate (3d). Stir the solution overnight at room temperature. After dilution with dichloromethane, the reaction mixture is poured into ice water, the organic phase is washed with aqueous 5-sodium bicarbonate solution, evaporated and concentrated. The remaining ★ is silica (5011, ether/hexane, volume ratio 1
:Apply to chromatograph in step 1).

In this way, compound 55 is obtained in the form of a colorless white monomer (9
20H9s62-)e (α]2'=+97.5(c=
1. The structure is confirmed by elemental analysis (chloroform) and m spectrum.

b> A solution of ts conductor 56 (432M 0.3 mmot*) in dichloromethane (10aj) was added to a chive solution in 4X
Sheep (0,51ri, Vitririte (drierit@
.

1II) and freshly prepared silver carbonate (0.42 g) at 0°C. After cooling to 0υ, compound 55 (
49G! , 1mmots) of nochloromethane (@d)
The solution is added dropwise and the reaction is continued for 2 hours, after which the reaction mixture is filtered. After evaporation to dryness, the residue was chromatographed on silica dal (-medium: ethyl acetate/chloroform, volume ratio 1:6) to obtain derivative 57 (285 mites 5jll) 114 The structure of 57 was determined by elemental analysis. and NMR
Confirmed by spectrum. [α): 0x39 (chloroform); MP=1!56-1! $9℃.

Example 13 Synthesis of derivative 59 represented by (59) Trisaccharide 5'l was prepared as follows (obtained by removing the acetyl group at position 4 of compound 57 of Example 12 f+fc) Trisaccharide 58 and monosaccharide 44 (see Figure 13).

Methanol (2517) of trisaccharide 57 (260111g)
To the solution, add IN Noda solution (25 wLl) at 0°C. After 1 hour, the mixture is acidified by addition of IN hydrochloric acid (30d). The resulting product is extracted with chloroform. After evaporation, the residue is crystallized in an ethyl acetate/hexane mixture. Derivative 5B is obtained (167, 7011i).

[α]20--311 (chlorophor A), MP=169
-170℃.

The structure of derivative 58 is further confirmed by K NMR spectra.

Condensation of two $1158 and monosaccharide 44: In a dichloromethane (5-) solution of compounds $44 (300 da) and 58 (155 da), 4X sheets (powder, 5004)
, corrinone (100 μt) and silver triflate are added sequentially. After 15 minutes, the solution was dissolved in dichloromethane (501Lt
) and washed with water, 10% potassium hydrogen sulfate solution, and water sequentially.

After drying, the residue was applied to a Silica Dull column chromatograph K and mixed with an ethyl acetate/chloroform mixture (4 to 1 ratio).
:10), thus obtaining derivative 59 in the form of a Japanese-French foam.

NMR analysis of the structure of Kinjindai 59.

Confirm with photorotation electric power ((α)o'=+2;:ri■form).

Example 13A Trisaccharide 20 can be reacted with methanol under the same conditions as for the synthesis of 4 g EFGH described above, thus yielding the β-methyl glycoside. The MCA group is conveniently removed and the trisaccharide is treated with 1144 ml under the same conditions as for the preparation of the stave.

The obtained trisaccharide is subjected to a conventional reaction for the purpose of film retention and functionalization, and its structure is confirmed by m-spectrum.

Example 14 Formula (62) Conversion of the N3 group at the 2-position of the glucosamite unit to the -M-C group.

b) Opening of the 2.3-E/+C bridge of the unit at the end of the f group.

--) Opening of the anhydro-1,6 bridge of the same unit.

Manufactured from Metet fK (see Figure 14).

Derivative 59 (10■) in DMIP/ethanol mixture (
1/1. lx/) 1 catalyst Pd/Ca CO5 in solution
(51,5 Da) is added. Add the suspension to 1#4. Stir under high hydrogen pressure for 96 hours.

After passing through and evaporating the catalyst, the residue is dissolved in methanol and acetylated by adding one drop of acetic anhydride.

Derivative 60 is obtained quantitatively.

The structure of derivative 60 was determined by elemental analysis.

Optical rotation f ((α), = +3), 5; chloroform)
It will be confirmed. Transcript = 147-149°C.

b) Cleavage of the epoxy bridge; Similar to the synthesis of derivative 58, derivative 6o was saponified to form an acyl group at the 6-position of the non-reducing end unit and an intermediate 5-
The methyl ester group in the position is removed.

After extraction, the residue is dissolved in millet and heated to 120° C. for 48 hours in the presence of sodium chloride. After evaporation, extract with chloroform and 0. Washing sequentially with 1N HCl and water, drying and evaporation of the solvent gives compound 61 after acetylation with (pyrisine-acetic anhydride).

-) Anhydrocarbon: Compound 61 is oxidized and decomposed at -20°C under normal conditions (sulfuric acid) and treated with a 0 reaction mixture '41J1 to form the derivative laQ.

11 Example 15 Synthesis of the flea conductor 63 shown in (63) (see Figure 141) When the derivative 62 obtained in Example 14 was treated with a solution of tin tetrabromide in nochloromethane and ethyl acetate, Lonoide 63 is obtained. Its structure was introduced by Nmils.The elemental analysis value is -17.

Example 16 Formula (68) % Formula % A listed in 1941, pag@s 50-51
.

The following 4 steps are carried out from the unit 64 produced by the method of N@ub.rl.r (see FIG. 15).

1) Pennorization of 3rd place 10H basket.

2) Remove the pennolidef group to release the 10H beats at positions 4 and 6.

3) Tosylation of the 10H group at position 6.

4) I substitution of the 10〒-group at position 6 with benzolate.

Stella/1: Hydroxylation/
#Rium octahydrate (3,6II) and barium oxide (1
66N) was added. After 10 minutes, stir at room temperature and continue the IFIA reaction with 6 dropwise additions of pencil bromide C4, 5 ml).

let A white residue is thus obtained. When this residue was analyzed by thin layer chromatography, it was found that it contained a base substance, ie, derivative 65. The dielectric 65 is used as is in the following stende.

Step f2: Removal of benzylidene groups The residue obtained in the previous step is dissolved in a mixture of methanol (370d) and water (130rLI). To this solution, add Druene Sulfone #1 Hydrate (31) and reflux the mixture overnight. After cooling, most of the methanol is evaporated and water (259d) is added. Wash the filter with a small amount of chloroform (100 il) and treat the aqueous phase as follows.

l) Precipitation of the 1lium salt with sulfuric acid, 2) F1 of the barium sulfate formed! ! 4.3) H
4A resin 45 (OH-)K! Filtration! 111(D
ll(D removed.

Removal of the resin and concentration leaves a pale yellow residue, derivative 66.
is obtained (5.7 g). This derivative is used directly for the preparation of compound 67.

Sten f3 nidosylation reaction This derivative 66 was treated with dichloromethane (150m) and DM
F (10 m/). This solution V(,
Add tosyl chloride (5,61,30mM), trimethylaminopyrinone (121) & enalamine (5aJ) sequentially. The reaction is carried out under a flow of dry M1 while excluding moisture.

After 18 hours of reaction, ice water is added and the mixture is stirred for about 14 hours.

The reaction mixture was diluted with dichloroethane, and the nochloromethane phase was washed with 2M hydrochloric acid and saturated sodium carbonate in this order.
Then, wash with water until the pH becomes neutral.

After drying with sodium sulfate and evaporation of the solvent. The obtained residue ★ was applied to a silica gel column (200 g).

Dissolved in ethyl acetate-hexane mixture* (Taniro ratio 4:1) 11
111).

- Collect the AL portion containing the conductor 67. Removal of the solvent gives a solid residue (4.6 g), which is
Used for synthesis of trench compound proboscis 68.

Sten f4: Before the pensolization reaction, dissolve the li4 conductor 67 obtained in Stellal in anhydrous dimethylforma (P(50a7). To this solution, add 1 molar solution of sodium hensylate in pencil alcohol (3011). Add the mixture. Heat to 90υ for 1 hour.

After cooling to room temperature, the mixture is concentrated to dryness. Chloroform (
4001Lt) K.J), the chloroform phase is washed with water and saturated sodium chloride, dried and evaporated to dryness.

The residue is chromatographed on a silica gel column (201, chloroform/#ethyl acid, volume ratio l:1).

The derivative 68 is thus obtained (12.3.9).

The yield is compound 64027.6-, 'Compound 6
8tj crystalline. MP=149-150℃, [α)
(s'' = 87 (a = 11 oo form). Infrared spectroscopy and elemental analysis confirm that product-68 has the desired structure.

Run 91117 Synthesis of Trisaccharide 73 (See Figure 15) This synthesis consists of the following steps: 1) condensation of derivatives 68 and 69 to yield trisaccharide 70; 2) removal of the benzyl group to yield derivative 71; ) sulfating the -OH group of derivative 71 to obtain I conductor 72, chlorinating the anionic group and removing the acetyl group;

This synthesis takes place from monosaccharides 68 and 69.

/%g) f7 compound Journal of Atn@r
iean Ck@m-1@a18e*i@ty, 77(
195B), p, 3312. Listed in OG, N, l1ol
l@nba@k's method of manufacturing monosaccharide 68 (4
50! , 1.1mM) of dichloroethane (30ILl)
Add mercury monobromide (400 μ, 1.ltaM) to the solution. After dilution with approx. 1 (17 g) of dichloroethane, 4x (powder) of Molecule Cisol is added to the reaction mixture.

Hg) f fluoride 69 (1,11,2,75mM)
Add more dichloroethane (IM) II solution. After dilution with 10i1j of dichloroethane, the reaction mixture was diluted with 90-
Reflux for about 14 hours at a temperature of 100°C. After cooling, the reaction mixture is diluted with dichloroethane (100 rILl) and the solids are removed by passing through a piece of fluted paper. The organic phase is washed successively with a 10-potassium thiiodide solution (2 x 25jlLj), a 5-element sodium bicarbonate solution (2 x 25d), and then with water until the pH becomes neutral. Dry with sodium sulfate, filter,
The residue is purified using a silica column (1sOg). The column was sequentially filled with three kinds of acetate-ether mixtures (volume ratio: 1:5.1:4.1:2).

The trisaccharide 70 is thus obtained in pure crystalline form (39
0■). MP=189-190℃, [α]20=+60
(.=0.4.chloroform). Infrared spectrum, N
MR spectra and elemental analysis confirm the desired structure.

Add derivative 70 (100~) of methanol (20i+j) bath gvc, catalyst (pa/l, 5110011). The suspension thus obtained is stirred for 3 days under a stream of hydrogen.

Collect the catalyst from the temporary trap. Evaporation gives a residue consisting of trisaccharide 71 (73 m 97-).

The NMR spectrum confirms the desired structure of the compound.

It is noted that the trisaccharide 71 is the precursor of the basic unit of helan-sulfate;
In the ninth stage of producing Kamo derivative 73, it is sufficiently de-infested to carry out the saponification reaction as described below.

Dimethylformamide (211 da) of compound 71 (70 da)
7) Add sulfating agent (sulfur-trioxide complex in trimethyla, 75 Da) to the solution.

-After the evening, further complex (35 .mu.) is added. After 6 hours, the reaction is stopped and the mixture is evaporated to dryness, taken up in chloroform, neutralized with triethylamine and evaporated.

Chromatography on a silica Dull column (20,9, methanol/chloroform, volume ratio l:2) isolates the pure sulfated derivative F2 in the form of a white powder. This derivative is unchained and used directly for the synthesis of Kuuniyari 73.

(Left below) Water (4-) was added to a methanol (9-) solution of derivative 72 (71MII), and then 1M soda solution (1-
). After stirring at room temperature for 4 hours, the reaction mixture was
・Pass through rlit・lR120H catem.

The IL solution thus obtained is neutralized, the salts are diluted with water and removed through a 98 Had.x G25 column 1. Fractions containing sulfated dillt are collected.

When freeze-dried, the -conductor 73 is obtained in the form of a white powder (a6M9). [α];. =st; (c gourd 1° water).

As a result of the conductivity analysis method for the derivative, the sulfate/calhokyfur ratio is 2. Elemental analysis, (11ONl
iiR analysis confirms the desired structure of the product.

Length Example 18 Compounds containing D-glucosamine 75.76 and 7
Synthesis of 7 (see Figure 16): Methyl-3-〇-benzyl-4,6-〇-
Benzylidene-2-benzyloxycarbonyl annot-2-deoxy-α-D-glucopyranoside (ZU YONG KY (, Sei 5iniea (P
@klng),! I (19511) 461-487. c.
A52 (1G581) 3694) solution of compound 74 (41SI9.l+sM) in anhydrous N,N-dimethylformamide (1 osv) t1 anhydrous bary) (6
13IQ), barium hydroxide octahydrate (1s 5m9)
and Hensyl bromide (O, 15 mg) were stirred at room temperature in the presence of O, protected from moisture, for 5 h. The reaction mixture was then diluted with chloroform (50 mg) and mixed with 50% ice-cold acetic acid, water. Wash sequentially with (sulfuric acid) IJum)
Dry, filter and evaporate. The solid residue is recrystallized with ethanol (461 Da, 91 X): Mp: 202-2
03℃; [α]. =+46 (C: 1.chloroform) Compound 76: Methyl-3-0-benzyl-2-benzyloxycarbonylamino-2-deoxyalpha-D-glucopyranoside Compound 75 (300 Iv), monoacetic acid (10 mg)
S suspension [stir for no minutes at 100°C. The solution is then cooled and dried 11 times, water (+xlo-) is added and evaporated. solid! 1IIIE was dried under vacuum and recrystallized in a 2-g straw panol to give compound 7 II (22G!,
l1lX)tl! , 6°MP: 151~is! ℃.

[α], w+e4° (C: 1. methanol).

11 conimethyl 6-Q-benzoyl-3-〇-benzyl-2-benzyloxy-benzyl-benzoyl-2-deoxy-α-D-gelcopidenoside anhydrous pyridine (Hd) and dichloromethane (12d)
) Compound 76 (8359, 2nhM) in O1m1 compound
The turbid solution dissolved in tS was evaporated with moisture and benzoyl cyanide (40 o q, 8 sM) O? F in K1
m+llll' Stir for 5 hours. Excess of reagent is destroyed by addition of methanol (S-) and stirred for 30 minutes. The reaction mixture is evaporated to dryness, toluene is added and evaporated and dried under vacuum. solid! Compound 77 (938 da.

90%), MP: 154-155°C, [α), = x+7
4 (C: 1.chloroform) Example 19 Compounds 711 and 7-9- having the structure
Synthesis (see Figure 16)
Bromide 36 (i
A solution of 0.425 of a mixture of n-acid salts 34 and 35 (freshly prepared from 1.degree. 1 mM) in anhydrous dichloromethane (10 mg) is stirred at room temperature under an atmosphere of argon. mym-
Collidine (0,68sd, 5y+aM) and anhydrous methanol (0,4(ld, 10mm) are successively added and the reaction mixture is stirred under the above conditions for 20 hours. After dilution with dichloromethane (sob), saturated carbonic acid Wash the organic phase successively with an aqueous sodium hydroxide solution and water, dry (over sodium sulfate), evaporate with P, and evaporate with S. The residue is applied to a chromatograph on a silica gel column (209). Hexene:ethyl acetate mixture. (Capacity ratio 31.) jj engineering fk7<
7 g of the compound in the form of pure syrup (802 Da, 76X of acetate 34 and 35)
is obtained. [α]. =-21° (g: 1, /
oOholA), NMRCCDC4m)'δ:
8.8! (d, IH, H-1, Jl, :3Hi).

Compound 79-V-benzyl-1,2-Q-t@rt
-butoxyethylidene-β-L-methylidoviranuronate vl orthoester obtained in step r of Example 5 37
(484III?, 1.1 gM) in anhydrous methanol (15 m
Cool to ℃. Anhydrous potassium carbonate (60 ap) km is added and the reaction mixture is stirred under the above conditions for 5 hours. The solid is dried, evaporated with Fl[tJI and the remaining dILt treated again with chloroform (so-). The organic phase is washed with ice water (3 times), dried (sodium sulfate), filtered and evaporated. The residue is serially chromatographed on a silica gel column (25 g).

(2:1 volume ratio with 0.5% triethylamine)
Elution with a hexane:ethyl acetate mixture yields the following materials in sequence:

Monounsaturated compound 3G (31 Da, 7%) syrup.

[α)Da+103 ((1: 1 * 10o$lum) e NMa(CDCta): δ: 6.27 (
d, d,, IH,1(-4, J, 0.:5H
1lJ,,,'iHm)-5,67(d+IHeH-L
J,,,:4kin).

One minute of life (271tIg, 12%). This - minute is dP
Crystallizes in the nan-ether mixture to form compound 79 (
120188%), MP: lll-69°C; [α] D to 1G (older brother: 1. Chloroform).

NMI (CDCjm): II: ! 1.41 Pmatog 27 1 and Compound 7 by silica gel column
During the crystallization process of 9, a new compound with lll slightly higher than compound 79 is generated.

After chromatography on silica gel, some pure fractions of this new compound 8o can be isolated (41 Da, 11N).

Syrup, [α]. Shoe +21 (See: 1. Kroholm).

NMR (CDCjs): a:s, 5s(d, IH
, kI 1 .

Jl, : 4. IHm).

In the synthetic globulin of the present invention, in order to prevent the formation of compound 80, the crude syrup 81 is not subjected to t-chromatography and used directly in the subsequent reactions.

! Agricultural flu 2111g 1, I2 and 830 [m (approximately 171
14': Methyl-6-0-benzoyl-3-〇-benzyl-dicarbonylamino-2-deoxy-4-0-(2,4-di-0-acetyl-3-0- Benzyl-α-L-methylidovilanuronyl)-α-D-glucopyranoside Orthoester 78 (8GiQ
, 0.2WLM) and alcohol 7 obtained in Example 18.
7 (529,0,tmM) and anhydrous chlorobenzene (8
-) The solution is heated to 140° C. with stirring in the presence of some dry argon flow. After slow distillation of the 6-nucleus tst-(N, to, KI)C'wv.

A, F, BOC)tKOV, T, A, 5OK
OLOVSKA-IAand V, J.

8NIATKOVA, Carbonhdr, R@s,,
1g (1971) 17-27/0,002mM) of 2,6-dimethylpyridinium perchlorate in chlorobenzene (2sd) JJii15
0 drops and simultaneous KC2-) I medium added over a period of minutes
JIllllI. Then under the above conditions, fresh solvent (10 m
) and the distillation at the same time, the reaction mixture is stirred for t1 hour. After cooling and dilution with chloroform, the organic phase is washed successively with saturated sodium hydrogen phosphate solution and water, dried (over sodium sulfate), treated with P and evaporated.

The residue was chromatographed on a silica gel column (15 g). Elution with a hexane:ethyl acetate mixture (4:8 by volume) gives the following materials in sequence:

one starting material 77 (20 Da, 38%), - Homogeneous minute in thin layer chromatography (549).

According to the NMR spectrum, this fraction contains multiple 0-)
fk/f)k(a: 3.3!-3,50) and their signal is the orthoester
This is due to methyl glycosides produced by rearrangement. This fraction was crystallized in an ethanol-water mixture and recrystallized in an ethyl acetate-hequinane mixture to form compound 81 (44a
p, s OX).

MP: 120-121°C, [α]D-+17 (a:L chloroform), NMR (CDC15) '1& to desired structure.

Compound +111!182: Methyl 5-o-benzoyl-
3-〇-benzoyl-2-benzyloxycarbonylamino-2-deoxy-4-0-(!-0-acetyl-3-0-benzyl-4-0-chloroacetyl-α-L-methylidopyranuronyl)- α-D-glucopyranoside Nine orthoesters obtained in Example 5 38 (120 da·
0,25 M) and Arco, - Lua 7 (66 Da.

Anhydrous chlorobenzene (8-) with 0.125 m) is heated to 140° C. with stirring under a slight stream of dry argon. Solvent 6sgt - After slow distillation L7'L, &
@-dimethylpyridinium perchlorate (o, ooxs
Chlorobenzene #1 liquid tube of Hino M), soybean (1 mg) t-
Add dropwise over 15 minutes while distilling at the same time. After stirring the reaction mixture for 1 hour, it is processed under the conditions described for the preparation of 81. Remaining IIEe silica gel column (15L)
Apply Chromato Club K. Hexane: Ethyl acetate (m
mfIIA with a mixture with a ratio of 7:4) gives the following substances in sequence: Product 77 (40J11,6ON) -211ila8, crystallized in an ether-hexane mixture (2184+, 30%), Mp :tna~144C
, Cα]e vomit (See: 1. Chloroform).

NMR (CDCjl): Matches desired structure / 1 serving 11
': O-decrop acetylation and acetylation of 2s82 and acetylation of 2@52 (xzap) and thiourea (IsIv) with tpyridine (12mg) and absolute ethanol (0.3mg)
The mixture is stirred at 100° C. for 30 minutes.

After cooling, the reaction mixture was evaporated to dryness, leaving a residue [water-chloroform mixture (:fil! quantitative ratio 1:1.20 mg) i'
:, AI): Take. The entire organic phase is washed with water, dried (over sodium sulfate), treated with P, and exposed to IA. Wash the residue on a silica gel column (1 g). Ethyl acetate (not analyzed) was immediately acetylated (2:1 volume ratio of pyridine:acetic anhydride, 1.tad). After 15 hours, the reaction mixture was evaporated to dryness at ambient temperature and the residue was purified on a silica gel column (0.
5g). 6# ethyl:hexane (volume ratio 1:1
) gives trisaccharide 81 (7119). Crystallizes in an ether-hexane mixture, MP: 1
20-120.5℃, MP of 81 busy mixture is 120
~121°C.

Example 1 Series 21 Synthesis of 35ins (see Figure 18) Bromide compound 4 (H, PAULggN & W, 8TE
NZICL, C,hem.

ji! 111 (1978), 2334-2347, 110 iy, 0.25% M) and alcohol 41 (prepared according to Example 6, 113 da, 0.1 g Vortex M
) and anhydrous dichloromethane (λs ad ) lag are stirred for 30 minutes in the presence of 4 μm of molecular sheep (11 ends 1001 p) under a dry argon atmosphere with the light turned off. After cooling to 200℃, sym-collidine (70nj,
0.5! lsM) and silver tri72) (789°0.3
0% M) t- are added sequentially and stirring is continued under the above conditions for 2 hours. Next, dichloromemene (50 mg
), dehydrate the solid, and dilute Fllll to 0, 1 M (
Ice-cold LIJ [1llIl% water, aqueous sodium bicarbonate solution S, washed with water, dried (sodium sulfate), filtered and evaporated.

Transfer the residue to a silica gel column (xsL).
I can do it. When triturated with a mixture of hequinane:#ethyl (1! quantitative ratio 4:3), 31111811 (189 mg, 88%) in the form of a colorless glass, which cannot be crystallized, is obtained. [
α)p''+83 (3-: 1*chloroform): NMR spectrum (90MHz, CDCLm
): J: 7.26 (m=2sH, BPh,): 5
．． 44 (d, d,, l H,f(/, Jl'
/: 1 G, 5Hs I Jr, /: 9Hi)
; &, 26 (d, ILHs-J, t, / /'↓1.
5Hz): 359 (* + NLCOOh1); 3-06 (d, d-+ IH+ Ha *
J/+/: 18 Hs+J//: 10
．． 5Hm)”, 2.1!, Loll, 101 and JjJ
? (41st, 12th, 40th day).

Example 22: Synthesis of trisaccharide 89 1 Synthesis HHs (See diagram) This synthesis involves the following 4 steps.

a) Removal of acetyl group, b) Sulfation, C) Water Xtl & addition 1 d) Sulfation of anno functional group a) yi-ft5 vague! ! Three @s by leaving 90-
A solution of 85 (1221v) il of Kojihada Ichiyari dissolved in a mixture of 2-dimethoxyethane (6-) and methanol (2-) is stirred at t-O<0>C. 1M aqueous solution of soda (
2-) was added dropwise over 10 minutes, and the reaction mixture f
Stir at 0° C. for 6 hours. Next, 1M hydrochloric acid is added dropwise at a time when the pH reaches -0 (a white precipitate appears). The mixture was poured into ice water (100d) and extracted with chloroform (100d).
- 5 times). Wash the organic phase with ice water and add C@acid) IJ
dry), dry and evaporate. The syrupy residue is dissolved in methanol (2-) and treated with an ethereal solution of azomethane until a persistent yellow color appears.

After 30 minutes, the reaction mixture is evaporated to dryness. The residue is chromatographed on a silica gel column (IOg). Trisaccharide 86 (85Q, 8
1X) is obtained.

[α]. ±+77 (a:1.chloroform), NMI'
L spectrum (90MHz, CDC4): OA
until J = 2 ppm without c signal). Elemental analysis: consistent with desired structure.

b) Production of 3@at by sulfation 84 bodies 86 (41#) ODMF (1id) I@ solution,
Trimester/sulfur trioxide complex (TM/80n:
601v:050℃ adding 15 equivalents per 0Hji
Leave overnight to complete the reaction. Methanol (0,1
After addition to S-)', the solution is introduced into a Sephadex LH-20 column (X, 5X251) equilibrated in a chloroform/methanol mixture (1:1 by volume). SS on the same mixture can separate the reaction product from the reagent excess and reaction port medium. The resulting residue was chromatographed on a silica gel column (10 g) and ethyl acetate/pyridine/vinegar/water (volume ratio 98:5 @:1
3:32). After dissolving the obtained trace product in methanol, Dov@x50*X4, N
a (5m) Pass through a resin column. After S irradiation and drying, the derivative at (ss da, 100%) is obtained. This derivative is *La (volume ratio!i, i, 1 3 ethyl acetate/pyridine/vinegar soap/water and volume ratio v:s:o,x
(ethyl acetate/methanol/acetic acid) to ensure homogeneity. [α) 2”=+s; <methanol)
.

NMR spectrum matches the desired structure.

C) Preparation of 3988 by hydrogenation Compound ay (201v) t methanol (2-) and water (0
，! 1 sd) and 5% P dissolved in a mixture of
The catalyst is removed by a second pass through stirring for 96 hours at a hydrogen pressure of 0.2 bar in the presence of a/Q; (20M9). Ultraviolet analysis confirms the absence of aromatic rings. J[After that, the product is used for the synthesis of 3$1189.

d) Derivative 88 obtained in the pre-preparation step of 3489 by sulfation with 1 water (2-) (14
5.q, /NHkai). - After the evening, add the same amount of complex. After 48 hours, using 2M soda-
is set to 12, and this value is maintained for t8 hours. After neutralization with hydrochloric acid, the reaction mixture was transferred to a Sephadex G-25 column glue O
V) Multiply the graph and chew with water. Compound 8 was formed by a color reaction with carbazole, which is characteristic of uronic acids.
Detect 9 (BittIr & Muirs Aa1
1aj Yama U-Crow, 4 (191S2), 330-334)
. The fractions containing 89 are pooled together, treated with Dowex resin 2 ms OW X 4 *Na t4A and sm with water. After lyophilization, as(4,15w9) is obtained.

According to colorimetric analysis of carbohydrate components, glucose amine 5.1
There are 2.55 moles of uronic acid per 5 moles (ratio A).

The NMR spectrum of the product confirms the structure (slow, anomeric bond, value - substitution by salt).

Trap Farming 1 No. 1 (= Synthesis of Zeng's Nitana 9! (see Figure 19) Product 91 (dissolved in dichloromethane (50d))
19) Stir in an argon atmosphere for 1 hour in the presence of t-trielite (6 g) and freshly prepared nine-charcoal silver (4, sg). Next, 9G(Zn2)k of halide dissolved in dichloromethane (10M4) is added, and after 1.5 hours 28g of halide 904 are added again. - After the evening, it is removed with solid tF hot water and the resulting residue is purified in a silica gel column (1/3 g by volume) of ethyl/chloroform (volume ratio 1/3 G). , product 92 (886Iv, yield 42%
). This product crystallizes out in a hequinane/ethyl acetate mixture. MP: 104-106C; [α]′D@
z Q (@=l; chloroform).

Elemental analysis and NMR spectra are consistent with the desired structure.

1 Agricultural Crab" Complete Set 1: #4 Fresh Snoring Of Stalks (See Figures 19 and 20) Derivative 9z(t,s9)'t, Mixture of Chloroform and Methanol (Volume Ratio 1/1) K111% do.

Then 2-sodium memenolate (2-sodium memenolate in methanol)
M) t-Add. After 20 minutes, dissolve the solution 1
Neutralization by the addition of o＠驕, thereby obtaining a single i-conductor 93t-2, and after evaporation the fraction of carboxylic acids which can be hydrolyzed by conventional methylation with diazomethane in ether. Can be esterified again. The residue after evaporation t1 is treated with a mixture of pyridine (20 mg) and anhydrous vinegar* (2 m) overnight. The evaporated uk residue was crystallized in ethyl acetate/hequinane to give product 94 (1,12!
$9: yield 81.6X). MP: 1 G 3
~105°C; [α]H−+ Lm (−1S chloroform).

Elemental analysis and NMR spectra are consistent with the desired structure.

In addition, the m4 body 94 has a derivative 9! instead of the derivative 91!
It is produced using the same procedure as described above.

! 111111 Fang 11 (see Figure 20) In the first step, the anhydride bridge is opened, and in the next step, the bromination reaction is carried out.a) 1.
8-Anhydro bridge opening ft&*941g)
was dissolved in anhydrous rh iron (10 mg) and heated under argon.
Cool to 0°C. Add concentrated #R (5005L) to the cold solution.
Added. After 30 minutes, the reaction mixture was diluted with chloroform (150
mg) and then diluted with an aqueous sodium bicarbonate solution (4 mg).
00mgK26.5g). After gas evolution, the chloroform phase is washed twice with a saturated solution of Na 2 Cl and dried. Chromatography on silica gel (509) using a mixture of ethyl acetate and chloroform (s ratio 1/20) yielded compound 96 (995 Da; yield 86.
7%) is obtained.

This compound is a white foam.

Spectral and elemental analysis confirms the production of the desired structure.

b) Brominated interferon 96 (0.2 g) in dichloromethane/hgl (
213jf). - the eel, stirred overnight and then diluted with dichlorotetramethane, a mixture of water and ice (5
0 m) and washed twice with 50-ml ice water. The syrup obtained after drying and evaporation is chromatographed on silica gel in ethyl chloride/chloroform (volume ratio 1720). In this way the derivative 97t1 yields 25~sO
Get it at

NMR spectrum (CppmlCDC45): 2.
04:111, m proton! -0A- singlet; 3.7:1, proton C00M5 OV bullet; &33: proton ■, doublet; J, 9. -t
3.5 Hl.

Synthesis of 4-98 (see Figure 20) Bromide ey (solv, sonM) and alcohol 41 (4; 11v, 50 gM) prepared according to Example 6
) with Molecular Sheep 4λ (
powder, 1001 v) for 111 minutes. −
After cooling for 10CK, -Fllk-collidine (11 μt, a
0 μM) and silver trifluoromethanesulfonate (~triflate, 189°70 μM) were added sequentially,
Continue stirring under the above conditions for 3 hours. The reaction mixture was then diluted with dichloromethane (30 m), the solids were dried and
Washed sequentially with 0.1 M water-cooled hydrochloric acid solution, water, saturated aqueous sodium bicarbonate solution, and water.
Dry (over sodium R), pass through once.

The remaining it-silica gel column (7 g) is chromatographed with hequinane-ethyl acetate (quantity ratio 4:3).
cm&compound r##fruto crystal mar@tx, four axes 98 are obtained in the form of colorless glass (56 da.

Yield 470X).

(J+VR spectrum (270 Mkls, CD
Cta) characteristic 2S near, 25(ms3!if(+7P
h):L3! I(d, d, + tn, n, r: I:
: Hl * JB m 40 kin): S, 27
(a, * iH * I J: e 2”.

LSI (s, 3H, cO bit ID0): 3.59 (a, 3
) I-Cqgli1@o ): 3.37 (d-
d−+ IHeHl Jl* * ' 7.5Hz
@ Jm”eg-: 9.5H1): 3.18(d
, d, e IH+< * J1# * ll#: 3.
5Is * Jf l/ : 11 as ) S 1
0 g and 1.97 (2s+' and lH, 40bJ).

This spectrum is shown in Figure t-@33.

Example 27 &! Synthesis of g@ee (see Figure 21) Anhydrous memel (3 mg
) The solution is cooled for -*5 cyc under a dry argon atmosphere. Anhydrous potassium carbonate (12 da) Yr is added and the mixture is stirred under the above conditions for 6 hours. The solid is then dehydrated and FI
Evaporate II and remove the residue with chloroform (I Bad).
Process again. Add 1 m of saturated sodium chloride water to the organic phase.
Wash sequentially with water, dry (over sodium sulfate), oven and evaporate.

The residue is chromatographed on a silica gel column (2 g). When mixed with ethyl acetate/bekifun (volume ratio 3:2), a shelf 19 (22Iv, 85
%) is obtained.

N IVI RX Vector (270MHi, CDC4
): J Near, 30 (m, 35H, 7Ph): 5.37 (
dl 1H1fll:IJ1#, I:R5Hz):
5.29 (d-4, + I He <, Jl l
#': 10Hw * J@' *, #: 8.8H Atsushi): 5.09 (d, IH+H1sJ1.: 3.8 stone);
3.57 (a, 3H, C00jli ldo)
: 3.43 (a, 3H, COO to gluoo): 2.
08(s, 3H, 6Ao).

This compound 99 has 411100, (3 of the second unit)
It is a mono-acetylated chemotactic derivative (at the 3-position of the second unit), and is an intermediate in the synthesis of analogs of the sulfate, which is not sulfated at the 3-position of the second unit.

! Cliff 1ヱ”!瑺↓See lΩ Imperial Ward (see Figure 21) This synthesis is based on the following steps.

a) Removal of acetyl group, b) Sulfation, ・) Hydrogenation, 4) Sulfation of amino group a) Production of derivative 100 by removal of acetyl group! 4@98 (40 Da) to 1,2-dimethoxyethane (3
-) and methanol (1+wg) and cooled to 11C. 1M water bath solution of soda (1
-) was added dropwise over 10 minutes and the reaction mixture t-
Stir for S hours at 0°C. Then IM salt 5ltpif-o
Add dropwise until , and pour the mixture into ice water (50 m). After extraction with chloroform (5×5), the organic phase is washed with water, dried (over sodium sulfate), purified with P, 4, and evaporated with S.

The residue g1 is dissolved in methanol (l-) and treated with an ethereal solution of diazomethane until a persistent yellow color appears. 3
After G+, the reaction mixture is evaporated to dryness. The residue is chromatographed on a silica gel column (ag). A mixture of ethyl acetate/hequinane (volume ratio 2=l) is mixed with 4 1'OOC21y.

75cX) 2>146fl, 66 MP: 1!
6~1! 7℃ (ethanol); [α)D”+JS5
(a: 11 chloroform): NMR spectrum (
90 degrees, CDC4): (! No. 1 OΔC does not exist as a whole (heading to J-2).

Elemental analysis 2. DMF (1 mg) of derivative 1010 (λ41f) produced by attracting and b conversion into the desired structure 11! !
TMA/80m 1I11 body (244) is added to the solution. If left overnight at 50°C, the sulfation reaction will produce photons.

Methanol (0.5 mg) was added to the reaction mixture, and the mixture was then diluted with chloroform methanol (1:1 ratio).
1) into a Setadex LH-20 chamber equilibrated in step 1). Collect 1 minute meal containing 101. After evaporation to dryness, the residue is chromatographed on silica gel (10 g) using a mixture of ethyl acetate/pyridine/acetic acid/water (180 nia 7:19:42 by volume). One pure molecule: Collect. Dowex 80W to concentrated dry VK residue
Pass 2 μm of Na and elute with water.

The product obtained (30IIP) is homogeneous in thin layer chromatograph with primary m#&. The structure is confirmed by 100 NMR spectra. [α type 0 + 39° (Cw
l, methanol).

A backing tsuba conductor 101 (10 Da) of 10 derivatives by C-addition was dissolved in a mixture of methanol (1.8 sd) and water (O4s+1)** and 5X pi/c (1 (lv) in the presence of 0.2 par ke7)
Stir under hydrogen pressure. After 96 hours, touch by
Remove. After evaporation, the derivative 102 is used directly for the production of the derivative IOs.

; Derivative 102t obtained in the step before manufacturing derivative 103 by LJ conversion is cast in water (2-). 1) HIl of this solution! IKIII and set this value to iin
Maintain it throughout the process. A TMA/801 m body (14 da) is cooled. After 24 hours, the addition (l'4 da) is carried out again. After 48 hours - (-12, then after 2 hours on Jl! 7. The reaction mixture was transferred to Sephadex G-25.
Apply column (sod) chromatography. Derivative 1
One minute containing oal (detected by color reaction of uronic acid)
were collected, passed through a DOWEX 50WX4 Na+ resin column, and then frozen.

In this way, we obtain 4@103 (2 Da).

Freezing of component C colorimetric analysis of derivative 103, 992112.
There are 91.84 moles of glucose amine in every 0.6 moles of glucose amine present.

The structure (chain, anomeric form, ms base position #) of Sakesentai to3 is shown in the NMR spectrum (270jtHi.

TMS), this spectrum 11) is 4.72: 30; 50;
It is 7.

The light presentation may be performed with the synthesis of 1118 (see FIG. 22) or by the following steps 1 to 7-.

Step 1: 1 艷 105 Li Yihuang This compound is a Canadian Journal oblique electronics story Camdiatz Jourml of C
hemistry.

! 11 (1G73), N and L listed on page 3357
, Ho1d@r and B, Fram.y-R@id and prepared from chemotactic compound-104. Compound 1104 (i.

12, sysM) dichloromethane (20 mg) 1! To the solution, tosyl chloride (0,'!15g), dimethylaminopyridine (1@#) and triethylamine (0,7m) 1
Add m order. After stirring for about 14 hours under a stream of nitrogen to remove moisture, the reaction was quenched by the addition of ice and water. The reaction mixture was diluted with dichloromethane (50 mg) and then diluted with dichloromethane (2M hydrochloric acid and saturated bicarbonate). St
Wash the organs with water, and finally wash with water until Kp&( becomes neutral.

IIL- and residue after evaporation ss conductor 1051.49
．． ．． 97%) is used to synthesize the derivative 10[-.

Step 2: Synthetic monosaccharide xos (al, sg) of $ conductor 106 and sodium chloride (39g
) is dissolved in a7tonitrile (1150 m) and the solution is refluxed for 3 hours. After cooling the reaction mixture, a white precipitate is formed. F? Concentrate I and treat the residue again with chloroform, then wash the chloroform phase to neutrality with water, dry over sodium sulfate and concentrate to dryness.

Silica gel column (2001i+, ether-hexidene volume ratio 1/l) glue b mudgraph, syrup t-
obtain.

This resulted in a dilated derivative (14.7g, 71°5X)
is obtained. [α)”=434° (1, chloroform)
.

O The structure of compound 106 is confirmed by infrared spectrum, NMR spectrum and elemental analysis〇Suasob 3:°
To a solution of derivative 107 of 106 in anhydrous pyridine (200 mg) is added anhydrous 6112 (43 m)'. The reaction is complete after about 14 hours of stirring. The reaction mixture was concentrated to dryness, leaving a residue t,
Purify on a silica gel column under pressure using ethyl acetate/hexane (volume ratio 17@) as tfals. Collect multiple pure fractions together.

This results in 1G of product? (1@, 49.70%) is obtained. The product is syrupy. [α];. --)4
．． 5 (1,3, chloroform). The structure is confirmed by elemental analysis and infrared spectral analysis.

Step 4: Eel! The 19th Emperor of Hagami! Derivative 107 (4G+) of pyridine (1
Add silver heptadide (AgF, 6.99) to the 00sgl) solution. After 2 and a half hours, the reaction mixture is poured into a mixture containing lipoform and ether (volume ratio 1/4.IA).・The obtained suspension 111 liter solution was passed through a pleated filter, the F solution was concentrated to dryness, and the residue was again filtered with chloroform (5QO).
m). The chloroform phase is washed with a tio% potassium aqueous solution, and then with water until neutral. Dry with sodium sulfate and dry all together to obtain a running residue (L7
9) Chromatograph on a t-silica gel column (200 g) (I!1: Ethyl acetate in a volume ratio of 1:4.
hexane). A fraction containing product 108 was collected and the solvent was evaporated to yield a crystalline material (1,62q,
54 copies) are obtained. MP: 81-82°C.

[α)', -gQ (1, chloroform). The structure of compound 108 is delineated by infrared spectral analysis, elemental analysis and NMJI spectral analysis.

Step 5:! Dissolve 10 g (fl) of the pressure sensitive 119 product in methanol (20 mg) and tochloroform (20 mg). Add sodium methanolade (zm, z-) to this solution (4 times). After 1.5 hours, the deacyl reaction is completed. The reaction mixture is diluted with chloroform. The chloroform phase Washed with water until neutral, dried, and heated at 10 a.
1,89-10o%) t444o C01lIEt
Immediately dissolve in tetrahydrofuran (50 m) and then add a solution of borohydride (BH, IM) in tetrahydrofuran (10 mg). After 1 hour of reaction, the boron hydride in the thorns is decomposed by adding ethanol. After the end of gas evolution, dilute the reaction mixture by adding 100 s.d. of tetrahydrofuran (120 s.d.) then 8M sodium hydroxide (soda, 12 m) and (120 s.d.) hydrogen peroxide (
8-) are added sequentially. After heating at 50° C. for 2 hours, the reaction is stopped.

Pour into Sat chloroform (500 mg) and wash the resulting organic phase with water, then with 8M hydrochloric acid and finally with water until neutral. This results in an extremely cloudy chloroform phase. This phase becomes transparent upon drying with sodium sulfate. - After that, emit chloroform,
The resulting residue was applied to silica gel (Google) and qMadograph (chloroform-methanol, volume ratio ao2t).
).

In the above process, the idose derivative t o e (t, o
s, 55%). The product is syrupy. [α]fu, -ten ss, (1e chloroform). The desired structure is determined by elemental analysis and NMR analysis.

Step 6: Synthesis of m-conductor 112 This synthesis is carried out in one step from 114 conductors 109 (without intermediate 110 and lll'i).

Derivative 10G (125g, 6mM) in dichloromethane (
50sd) 11mK1 dimethyl ainoviridine (60 da* O-24 Tsuru M), triethylamine (1.7 mg,
12M) and trityl chloride (2,59,9M)t-
Add sequentially. The reaction is complete after about 14 hours. As a result, a derivative of 110 yen is obtained. Here, dimethylaminopyridine (150Q), triethyliso (1,7m) and benzoyl chloride (1,0Q) were added to the reaction mixture.
5m). 6 days later, 1! Dichloromethane was removed through l'JIAR and dimethylformamide (40
-). The reaction mixture was heated to -70°C and kept overnight. Here, benzoyl chloride (1-) and triethyl aban (1.7m) were added again, heated to 70°C, and kept for 8 days. Next, the dimethylformate was evaporated and the turtle residue was treated with chloroform again, and the chloroform phase was mixed with water, saturated sodium bicarbonate solution, 2M salt #111
Wash sequentially with I solution, and finally wash with water in a neutral trench.

After drying, chloroform is evaporated to yield compound 111.

Derivative 1129 is obtained by immediate reaction to remove the trityl group t- from this compound. Residue t2 containing derivative 111
Dissolve the solution in chloroform and add 10 dl of the methanol (IM) solution of the toluene sulfone sapon-hydrated solution until the reaction is complete after 4 hours reaction at room temperature. Now dilute the reaction mixture with chloroform, The resulting residue is washed with water, dried and evaporated.The resulting residue is chromatographed on silica gel (100 g, ter-hexene volume ratio 3:1). In this process, the pure alligator conductor 112 (1,
5g:52X) is obtained. This alligator conductor is syrupy. [α]: * = + 8° (1, chloroform)
.

Analysis of the infrared and NMR spectra confirms the structure of the desired product.

Step 7: Seal 111p This synthesis is performed directly from the resistor 112 without the intermediates 118 and 114Yr alone. Compound 112 (1,
After cooling the a7ton C2,0ml solution of 29) to 0°C,
3.5 of chromium oxide (Cr01 e 1.i 79 )
M[II! (5sd) Drop solution (t9*) at 00°C
After stirring for 30 minutes, return to room temperature. The reaction lasts for 3 hours. The reaction mixture is then poured into a separatory funnel containing ice water (loOsd). The product formed [chloroform (I
Extract with IXISOm). Dry with chlorium, filter and concentrate to dryness. The obtained nine WA residue (compound 11 B
) Ytlfi)-k (100 mg) Kll. Add 3M sodium hydroxide (hoop) ill solution (17
-) t- is added and the mixture is kept under stirring for about 14 hours.

Acidification with sulfuric acid and extraction with ether into compound 1141 followed by immediate methylation with diazomethane by conventional methods affords compound 115. After evaporation of ether, silica gel CBOf, ether-hexane: volume ratio 4/l
) to give pure compound 118. #Conductor 11M1-Collect pure fractions containing solvent t-remove. In this process, Xa7@Taku4
A body L I S (587q, @59X of conductor 112) is obtained. The product is syrupy. [α):,
=+91i (2,65, chloroform).

The desired structure is confirmed by NMR analysis, infrared analysis and elemental analysis.

``See 11'' Synthesis of 2 species 117 (see Figure 82 and #I23) This synthesis is a monosaccharide produced as in Cocoon! ! 5 and ch@rn
ische B@rloh! s 111 (1978) 2
234-2247, PaulsIn and W,
It is produced by the method of 8t@ni@l and carried out using Yutan 1144.

Compound 115 (200 mg, O, 115 M) (D
Dichloro0) pnC10m) #liquid K, compound 44 (0,
4!10';l) *ayrn-collidine (150
m) and silver triflate (260 Iv) are then added.

The reaction mixture is kept under stirring at .theta..degree. C. for 3 hours under a constant stream of moisture and light.

The reaction mixture is then diluted with dichloroethane (100 mg) and filtered through a pleated filter to remove solids. The resulting solution 1-X saturated sodium carbonate solution, water and 2
Wash sequentially with M sulfuric acid, and finally wash with water again until neutral.

The residue obtained after drying with i#IC11 sodium and evaporating the dichloromethane is chromatographed on silica gel (SO2, coloform/ethyl acetate; 15/1 by volume).

Pure derivative 117 (327JIjF.

82X) is obtained. The product is jelly-like.

((11':, ±+!17° (1, chloroform).

NMI analysis and elemental analysis confirm the structure of 2$1117 and the ano i-form.

Example 81 Synthesis of 2@122 (@23 Figure 41) This synthesis follows the following steps.

a) removal of the acetyl group, b) sulfation; Addition of water, d) Sulfation of the primary 7-on group.

2ill 17 (! @ 0q))Ytllll/-k
c 1id) Dissolve K# and add 1M soda (1-) dropwise.

After the completion of the reaction, the effluent of reaction 1 compound [-) ITIw, which is led to the top of the DOWEX 50 resin column (5-), is concentrated to dryness, and then added to methanol again.After the saponification of Ka4 body 117 is completed, The resulting free 1IIfIk product was purified using MjJ, derivative 118 using di/1 ether/hexane).
t-get. The yield of compound 118 is 92 Da. This product is used in the synthesis of direct conductor 119.

b) Preparation of 211119 by sulfation J: The product obtained as described in 1. , I II
(92η)r Dissolve in dimethylformamide (5-) and add trimethylamine/filtrate dioxide (25 da). The solution is brought to SOC in about 14 hours.

After evaporation to dryness, the residue f: Take up again in chloroform, then wash the chloroform with water, dry, and bind to dryness. 4 (methanol/chloroform). After evaporation of the pure fractions, the sulfated bilinear 119 (58IIg
:55.11%).

@) Manufacture of two shafts 120 by adding water 2 m119 (58 mjp) ts methanol-water (15 m
Dissolve in the mixture of g+ 2-). Then the catalyst (5% P
i/C: 60 drops) 1 is added and the suspension is stirred under hydrogen atmosphere for 48 hours. In this step, derivative 11
The benzyl group resulting from 9 completely disappears, and the azide group of derivative 119 is similarly reduced to anno group. The catalyst is C
, and then the reaction mixture is evaporated to dryness.

Thus, 2111120 is obtained, and this disaccharide is the product 1
jl and 122t - processed immediately to obtain.

d) Preparation of 2111122 by sulfurization of the group -NH, dissolved in 24120 water (6 m). To this solution was added trimethylamine/sulfur complex (25 Iv), while - of the solution was reduced to 9 by addition of soda (0, IN).
．． Keep it at 5. After 45 hours of reaction, 1N soda is added to give -f:12. After that, 1 o'clock + ijj % - holds this value. After neutralizing with 121 Hagane 1i 1N hydrochloric acid, add May's Dow, X 50 column (5
-), I'm worried about the rumors from this column. After collecting and shrinking a portion containing the sodium salt-like substance 122, Sephadex G21 was added as a water solution.
The product t-desalts by passing through a 5 column (50 mg). In this way, the two shafts 122 (271v,
68%). Upon lyophilization, the product becomes a white powder bed. [α];. -+9! i, ♂ (t, a: water).

Carbon-13 NMR analysis revealed that product 122 was F9T.
The structure of the haze is established.

! Preparation of 2-0-α-L-idopyranosyl)-o-galactose (compound 188) (see Figure 24) This synthesis is carried out by the following four steps a) to d).

8 g of venter O-acetyl-α-H dopyranose (compound 1!3: p, P HEMLIDE&, T,
08mm.

E, M, DAVIDILON & R, W, JEAM
LOZ, Carboh)rdr, R@s, .

3 (11117), 463) in anhydrous dichloromethane (100 m) at 0° C. is saturated with hydrogen hydrogen gas. 3m after 2 hours with 1ifi? Pour the Ik1 reaction medium onto ice and extract with chloroform. Wash the organic phase with water.
Dry and evaporate (residue 1)
1 in a dichromitane-ether-benmene mixture yields bromide 124 (5 g, 95X). M
P: 126-127°C.

[α]. =-12♂(e;oyys, chloroform).

(Additional blank space) b) Benzyl-3,4, -trilow benzyl-1,4,6-→di-0-benzyru/-D-galactobitunoside (T@trah@dron, vol. 32 , 1 fJ m
J, C, JACQUIN, published on page 8, 1976.
ffiT and P, 1 iINAY chemical food 1 snow 1s) 200111F) m water dichloromethane (100 drift liquid, molekie two sheep 4X (-soo
wIg) and mercuric bromide (s.

wg) at SO 0 C under dry nitrogen in a trench reduced in volume by half. A solution of 124 (300 Da) of bromide in dichlorotetraethane (10-) was added at one Vc for 3 hours and the volume of the reaction mixture was kept constant by continuous distillation of dichloroethane. Time IK
, the reaction medium was cooled to ambient temperature, and the reaction medium (10
011j) Diluted, treated with 10% potassium iodide solution, hydrogen carbonate, washed successively with thin ice solution, water, dried (sodium sulfate) and evaporated. . Ethyl hequinane acetate (1:1, v/'v)
The mixture was used to purify the residue by applying it to a silica gel column (30 g).
Syrup-like two-shaft 1!・(z e oil, 9G11:
(α]%'--ty" (4: 1., s clorogastric form))v was obtained.

The logical value for C,,H,,O,: c, ss, zo;
H*(25;0e27.l5IS+ Actual value: C, @!1.91; H, Ll l;
0, 27.1 filGC) benzyl-3,4,
6-tri〇-benzyl-2-0-(α-L-idovitzyl)-me〇-gatuktoviranoside (compound disaccharide 1
1 Is (200119)' to 'anhydrous methanol (l
A 1M solution of sodium methylate in anhydrous methanol (O6 RoJ) was added. 1 hour later, D
The reaction medium was neutralized with (IW@X 50(H”) resin, filtered and evaporated.

Dichloroethane-acetone (7: 3 * v7/v
) mixture was applied to a silica gel column (1(1)) to purify the 1lIl 127(1fi4, 11i)V pure state ([ αゎ1-43° (cL: 1,4
am holm)).

Theoretical values for C6°H4, O, K: c, ss, as;
H, @, 5olo, 2B, On.

1M! Column value: C, 111 (311;) I, 6,64; 0
, 21S, 2711° charcoal (*har@oal) (
in the presence of 10-palladium on acetic acid (
0,1114) V ethanol (2 wheels 12 in 1 sip 0)
? (200wjIi) Hydrogenated for 148 hours. Using a methanol-chloroform (4:1, V/V) mixture, the product was purified by applying it to a silica gel column (IBg) to form a wet, colored wheel-like free disaccharide. Got (S), 1! all, 10G9
1; (α) “n”-+ 28 @(C: 1.2 *
mefi/-le)+11S@(10 minutes)→+93@(
2 hours) (C: 1.1. Water).

Theoretical value for C,, H engineering 01K: C, 4 snow, 10; H
, @, 48, Actual value: C, 41,71; H, (4119 g.

1 to vaginal case 31:1. l: 3,4-di-0-isoglu first El, 2: 3,4-di-0-isopropylidene-@-0
-(M, 4,486-teto-p-acetel-α-L-
idopyranosyl)-α-D-, fF tutatopitunose (
Compound 130) was prepared.

J, Mm, ch@m, ilo*,, Volume 63, 2!11
Page 6, Year 11 R, C, HOCKITT, H, G
, FLITCHIR and J.B.

Anhydrous dichloroethane (zo
m) 1111, 4X (s o o
IV) and mercuric bromide (soo*) in the presence of 1F at 90°C.
The mixture was stirred under dry nitrogen at t until the volume was reduced by half. bromide 1!4 (flfio■) sitaproethane (1
01+J) solution was added, and after 24 hours, bromide 124 (
111#) Zik vs u z p 7 was treated with the reaction medium. Dichloroethane-acetone (9: 1 mV
/v) mixture tN1, silica gel column (sog)
Purified by chromatography of
1101 disaccharides were obtained. This trisaccharide was recrystallized in a methane/pentane greenhouse (8809.9 g, M, ?,
1110-1@1℃, [α) T −++ B so(
Theoretical value for K: C,! 1! , 88; li.

6.48; 0,40,114° Actual value: C,! 11. a11;)i, 1400.40j
31L Next, the following hand 1 [K Therefore, - conductor 130 to 1
゜2:3,4-di-0-isopropylidene-@-〇-(
Preparation of α-L-idopyranosyl)-α-D-gatsuktoviranose (compound 131) ecll! used.

Two wheels 111 by the technique @ which I described about the production of trisaccharides
3G (100N9) was deacetylated. Methanol-
Using Couform (4:1, V/V) S food, it was purified by chromatography on a silica gel column (1811 g) to obtain an amorphous endothermic-wheel-shaped biaxial 1111 $1. Reached (204 wisdom, ss*;(
α) %@−++@3°l:0.7. methanol)).

Theoretical value for C1i"l@011': C*, 5
"j' g He?, Ill; 0.41.66°1111 value: c, no, ss (24th WJ and 2nd sg
reference).

First, Be/Giroux 2.3.4-) So0-Benzyl-
8-0-(2,8,4,6-teto2〇-acetyl α
-L-idopyranosyl)-7-D-galactopyranoside (compound 133) was produced. Benzyl-2*3
s4-) Ku0-benzyl-β-D-gatsuktovitunoside (K, MIYAT and RoW, JEANL
OZ Carbohydr, Res, Volume 21.

Compound 132 prepared according to p. 45, 1972)
200 WIg of acupuncture water dichloroethane (1 mouthful of 0 solution, 4
X Moreki Two Sheep (SOOda) and ferric bromide water # (8
011) f) In the presence of eo'c, turn! i1 under the height,
Stir until the volume reaches BIIJ. Bromide 1an(x
4o111I) was added and stirred for 24 hours at 1 reaction medium v90'C. Two wheels 1
After preparing 11M IC'), a similar procedure as described above was carried out to obtain a residue. This residue, dichloroethane
1! of a silica gel column (3ojI) using acetone<tz:t, v/v) mixture. (2274; 7011; (α) M--s O@
(C: 1. riroform)) - Theoretical value for CIIH14011: c, @s, 2o;
n.

6.8 violence; o, 17. I I.

Actual measurement value: C;・container, @i;it, @, zs;o, zy,
・@regret.

Next, the following hand JIK11 is benzyl-2,3°4
-trilowbenzyl-a -O-(α-L-idovitzyl)-/-n-ga2tatoviranoside c-metallic compound 134
1m8 of chemical metals were used for the production of ).

The key to the production of the motorcycle 1117 is flltc, so the motorcycle 1 m3 (1 @ @ If) t' group 7 * fk is converted into a carbon dioxide form-methanol (.: 1 a v/v) f
1 compound was purified by chromatography on a silica gel (10#) column, and an amorphous Niwa 111114 was obtained (14719, 1101: [α
]V・-11'(C:0,1.Tallowform))・C4
Theoretical value for @H4@011': c, @s, ss; g
.

・,・o；o、m翫04゜Actual value: C, -Hatake, ? 4;He・, @I;O*11. s
? - (II Yuki @ Sonosan II).

Example 3: 2-acetate 1'-1,S, -tri The preparation of this compound was carried out according to steps 1) to +4) below.

2-acetide-3-0-acetyl-1゜6-anhydro-8-desoxy-/-D-glucopinose (Fj
CIIM11'? and P, 8INAY Carb@h7
Dr.
vx hair 4 y (40-) 11g of powder activated at 50°C for 48 hours with a key (IJF) #) $6 Stirred at 130'C with 2 o'clock open stirring. Dilaw ethane (s Om)ililt' processing of bromide 1 to 4 (1,4!11), HL reaction medium to 13
0'CK was held for 10 hours. Then bromide 1 s 4
(6,71) was further added, and the reaction was continued for 24 hours. Disaccharide 5111! For the manufacture of
Reached @. Ethyl acetate-ether (Is=1.v/v
)I & Shamoni, this compound was purified by applying it to a silica gel column (!00I) glue ■ Matodatsufi, and was purified using a two wheel 11Hzm (t, s1% 85fi;
α〕en-To, @” (C:1.crowol^)) was obtained.

Layer theory values for Cl4H3l'14N: c, it, s*
;H*f5.94eNeLBO*0m40.0B.

Actual value: C51,38;H,8,II;N,! ,+sl
:0.40.0! i-0 ゛ Bilinear 134 (100 kg) was deacetylated by the technique previously carried out for the production of the disaccharide 11117. Ethyl III acid-methanol (z: 1, V
/V) I11 rosette vmh"c, silica gel column (a
O #) By refining the paste w-w toduffy, the trisaccharide IN s t (s o owll, static
-; (a)''; --s s, oo (C: 1j, methanol)) obtained O C, 4H,, O,, N fist @, S II, OKK vs. 611
1kll: C, 44, fist! ;H# 1.4藝;N
, 3,74, l1lIII value: C, 443111; H,
6,61;N,4.2'l@.

Acetic anhydride, acetic acid and sulfuric acid (7:l: Oj, V/V) (r) in the presence of metal (8114) #).

11 g of trisaccharide (1 $0 WIfI) was acetylated for 1 hour at ambient temperature.The reaction medium was then poured into ice water, stirred for 4 hours, and then extracted with chloroform (10 $W). Ww form phase II & acid hydroxide f) AI) 11
I11 dilute aqueous solution, washed with water and dried (-acid sodium)
Then, I walked over to II. 11 Shun ethyl-ether deposits (
The residue III#I was purified using a silica gel column (TOE) using a silica gel column (TOE) to obtain 13s disaccharide, which was recrystallized using ethyl acetate pentane. (120wII, 41
1; M, P, 110'C; (a) between w-4o°
(C: 1, ROW HOLM)).

Elemental analysis: C,, H,, 01, N Synthesis value for K: c, 4s, s
BH,t,80;0,4! ,so;N,2.0? .

mSW value': Cl41. sl;H,i,jl;ot4m
, 1@:N, 2,129G.

To produce the trisaccharide IB, 9, trisaccharide 138 (100&l) was acetylated by locking technique using a silica gel column using a methanol solution (1:2, V/'V). Ctrl) paste was purified by applying it to an ILI matrix to obtain a biaxial 11-unit compound. This trisaccharide ll111# was recrystallized in aqueous ethanol (48 kg; gill1MP143~14I6℃
, [α] Fuu 20@~31” (C: 0.1° water-methano-#(1*:1*V/V), 14 hours bale)
.

Elemental analysis: C14H,,)io,, @ 0,511
．． Radiology value for OK 20, 41, 1・;Ho・, 11
; N, jl t.

Actual measurement: C84 snow, IS; H* @ -6s;
N m 1.1 m lel gold compound s * (o
, x I ) of viridi y(slll) IIm [0, which was cooled in a 70° C. trench, then tosyl chloride (0,07I) dissolved in pyridine (1@I) was added. The reaction was allowed to proceed for 34 hours at room temperature. After adding the Toharu water, add 30% of the food.
I pressed it for a minute, poured it over ice, and poured it over ice again.
* After extraction with 1), KuroOtlskA@1'
1011KHIO4 Mizutokyo, Water.

Washed successively with 1 ml of saturated NaHCOs and water. After drying over sodium chloride and condensation to dryness, the residue was dissolved in an ethyl acetate/methanol mixture (IS/1,
V/V) using silica gel (sol)
I put it on the f-todatsu fee. In this way, the pure metal compound 140 (tso-; 5oft, [α) ”!1-+
74° (C:l, 1.terum)) was obtained.

Elemental analysis: 04@H4@O1,)1m (111!, Reference 13) Theoretical value for K: C1・s, 4d; He・j);)jet,
? S; 0, depth 1,74: ■, s, sy, depth value; C06m, ? ? ;He・, 1m:N, 1jl;
The 0.14J1-;11.41°NMIM spectrum was consistent with the intended structure.

Pyridine (11aJ) of Preparation Hardware 149 (10011IP)
) Solu*g Plow Water Vinegar Solubility (added 0).

After being left overnight in an electric field, the first reaction greenhouse was dried.

Ethyl acetate/to life! (1/1 #v/v) @Food II
- The residue was applied to a silica gel column (!I#) using a silica gel column (!I#). In this way, a syrup-like metal compound 5a1 (!osq, 〇-; [α]"ts-"''' (C: 1 @ta1a@hoxum)) was obtained. Elemental analysis: C4, H,,H80,,(*l4,0!I)
■Logic value for K: C# 61,7@;He 174
:) io ”-';on!!?,41; Isl, 4
8゜夷-value: C1・IJI; II, 1.・1:Nl2,3F;8, Sj 8, NM藱Susubetasil The intended structure and successor.

Aryuton (Smg) @il of Kametal 5at (sso*)
Sodium K iodide? A (18011) was added. This warm, sealed tube was heated to 70'C for 7 hours. After evaporating with dry water, the ascites was removed and extracted with filtrate. Rinse the sides of the WW form with water, and rinse with sodium sulfate.
El! It was dry. 11 dry bales and the residue were re-milled in the WW Kasararu Todoroki/Pentane building (10 srs
76 Reference; m, 9m 121-174℃, (α) I
n−+71.6” (C:IJ, Tallowholm)).

5Jtll! Analysis: C,,H4,Ol,)iI (II ml, 733
) Theoretical value for K: C, $IJi:lij, a4;)
fsl, 1? ;0.1SJ@; 1.14JL Yi-value: c, sa, ・s; II, s, sz; N,
1.41s;0,! LIT: Ie14,1 (1°11 Svetator was pinned to the intended structure.

2) Kogen lj 1 house Ilk ■ dispatch! 1m8 of prepared metals (IJF) and 5ill of N-iodostasis compound (II) in DMF (MolmJ) were mixed at 0℃ for 30 minutes.
After stirring for a minute, tri-7erphosphine (111
) t' Added gradually during 1 hour・1llf at go℃
After heating, vol of methanol (III) was added, and then the reaction mixture was condensed and dried. The product was extracted with tallowform. Water tarorum.

It was washed with sodium thiosulfate at Hirokazu's request, and then washed again with water. After drying and evaporation of the chloroform, the residue was placed on a silica gel column (IOf). Compound 143v ethyl acetate contaminated with triphenylphosphine
Chromatography eluted with a methanol mixture (1!l/1°V/V) After evaporation and drying, the derivative 1'4. ,．． 3 was dissolved in pyridine (10 mg) and then acetylated using acetic anhydride (10 mg). After passing in the usual manner, the derivative 14m was recrystallized in a chloroform/pentane compound. I let it happen. The yield of compound 139 was 8b-, which was
It was similar in all respects to the compound obtained from compound-1311.

Compound 14! (400wI!I) of anhydrous pyridine (1m
) il [K ts 11 l (400 da) 7' was added. The suspension was stirred for 48 hours in the dark and the mixture with 0 was then poured under pressure into ether (200-). After filtration, the ether phase was washed with 1011 NaHIO, a solution of 1
Next, it was washed with 101G NaMC0 solution and finally with water. After drying and crimping in a dry bottle, the residue was recrystallized in a proform/ether mixture (20.
@ '-;-pa-'s'c; (a)%j-+70
"(C:184-18 1.4; Chloroform)), Elemental analysis: Theoretical value for C41H4VNO11 (761,821)K: c, s4.as; III, 6.!2; N
, 1j4, Actual value: c, s, a, s; u, i, meeting i;
N, x, ys.

The NMR spectrum shows the compound ta, which is similar to the expected structure.
Tetrahuman with a new sound of 4 (Ss/If)! 7tsun (・aJ) medium cm was solved. O″CKCK in nitrogen atmosphere
cooling.

Add boron hydride (Fuji 11.I'rl [SI medium IM, 1m) and then KIN! I was raised again in the family. After reacting for 1 hour, it was added to 1 page of hydride (111j). 30
After minutes, ethanol was added dropwise. Gas emission stopped S
A mixture of ? Diluted with HF(1.-). Add soda (SM, 1.HsJ) and then add persurunated water @ (1.HsJ).
10th judgment; o, sm) added, +s.

'CK! When the threshold was maintained *, **1-Pour fe into tallowform, Chlorofumiform Sv salt and water solution (0, I N
) and then water.

Drying (Na, go,) 1. , % - After drying, ethyl acetate/methanol mixture (XS/a; V/V)
The resulting mixture was subjected to climadography on a silica gel column (4sI) using a silica gel column (4sI). Derivative 14s elutes first (@
swe*18 悌), then derivative 13 (2! S da;
II4'll was eluted. - conductor 1i8 & recrystallized in ethyl acetate/methanol mixture (**p-1
1°C; [α)% e=+・4.4° (C: 1. methanol)).

Elemental analysis: C3iH41N011” Theoretical value for HIIO:
C05z, s7; a, s, ys; a, s, os.

msi value: C162,4! ;1. s, II; N, IJI
.

Derivative 141 (301 methanol (1od) 1111 with catalyst (9U'C, II 91;
After stirring, filtration, and evaporation in hydrogen SSa in the presence of a
Acetylation was carried out using a pyridine/-hydroacetic acid mixture (Yuki Iaj/111J). After going to the overcharge treatment 111, the residual snow was transferred to a silica gel column (10I) to obtain a carbide compound 13I (14wIfI, 8111;
m, p, 191℃; [α]〒-+ s @ (C:Ol
・, taroform)).

Example 3 Gold layer of trisaccharide 14- with the following general formula This synthesis is carried out in three steps (Part 8)
First, the orthoester of the L-Ison trout conductor! In the 0th order in which reacylation is carried out, the Minetsuta W loacetyl group is reacted with one of the subsequently formed alules, biax.

Orthoester 38 (118
Misaki%0.11mM) and benzyl alcohol (0.1am
, 115mM, freshly heated. After gradual distillation of iI medium.

2, - dimeter viridiekumpatarore -) (!,
8μV) evening! At the same time as benzene (2@l) was added dropwise during t-no minutes, the solvent (211j) was added. Then, new solvent was added dropwise while the reaction mixture was stirred for approximately 3 minutes per reaction volume. After cooling.

Rim 00 form (placed at 1 mouth 0, organic yam II% hydrogen carbonate) IJ Rim water WI solution, washed with water, dried (sodium sulfate), filtered and ** .

The residue was chromatographed on a silica gel column (Ig). Hequinane-ethyl acetate (2:1, V
/V).

It was difficult to obtain one minute containing the dalicoside mixture 146. This contribution was not divided at this stage [102
Cape, @1-;N-M-R-(9OMBz * CDCI
m)':? , 3 G(m-1ON* 21h
), 8. Meeting 5(sszu*C1-Cl,-
Co), L74 (1, SILeCOOM*).

s, o s and 2.03C2 haze, overall 811°β
β:2 to OA and α:2:1)).

2) Selective 〇- Theory Monokuji 1 A Dragon Chirhi The aforementioned mixture 1
4 prefectures (102111) of pyridine (+swLl)-absolute ethanol (1-) *vf*urea (2b II >
) and heated to 100° C. for 20 minutes. Cooling charge 1 Reaction mixture was dried to 1 km, and the residual material was extracted again with a water-chloroform mixture (1:1.V/V, fi port 0.The organic phase was washed with water and dried (sodium sulfate). It was then filtered and emitted.

The residue was chromatographed on a silica gel column (10I). # Shun ethyl-hekity mixture (4:1*
v/v) and 4T for glycoside 14.

Glycoside 148 (!@ml, 5s-): Colorless solid; [α) %11-+7f''' (Q: 1° chloroform); N, M, l, (il OMHz.

CDCl, ) : a : 7j O(1!
1; 10M, meaning pk3゜Is, Ol (gas
IH*Ml)% 4-140 (d a ZH#)
1. ．． 1. ! J-1111m) #B, 7 fields (@
s 11'[eCOOM@), $, 1! (1m!
D, exchanged with O (Stt OH), 2. Ol(・, pH, 0
deep red).

α-Glycoside 147 (I14QF, compound 3I to F
iO1111m colored silicone.

[α]t■-ss'(standing; 1.ri stomach ■form); N, M
, Ro(110cm(1# CDCl,): δ near, 1G
(ta, 10H, 2ph), fi, 05 (2Hs)!
, and [1# J, , m I extremely weak Noun constant for HsK), 3.71 (m, 3H, cOOM*)
.

! , 10 (1g, D, OH exchanged with 0).

11.015(**3HgOA11)*3)-91 in anhydrous dichloride aSS methane ( The 10-well solution was stirred in the presence of 4x Molecular Sheep (powder, SO cape), protected from light and moisture, and cooled to t'-10'C.
ym +, Collijin (110ak) □ and Silver Tori 7
The reaction mixture to which 2 drops (2 drops, 100 mM) was continuously added was stirred for 2 hours under these conditions, and then diluted with tetratetramethane (300 μL) to gradually dissolve the solid. , P moat ice-cooled 0, 1 MMCI aqueous moat, water, s-*g*sodium hydrogen water lIm.

It was washed with water, filtered dry over sodium sulfate and evaporated.

Residue silica gel column (8I, gel 230-400
Metsushi! L) was subjected to chromatography. Toluene - ≠ * 1,000 l (Is: 1 a V/V)
The trisaccharide 141 (801) was eluted as a colorless syrup.
111,11・-) - N, M, R, spectrum (270MHs eCDCI,
) was in agreement with the intended structure.

Shown in this Spect A-Shichiyo 32 Garden Example 311: Tetrasaccharide Garden on B8 Mums).

Kushi Serum Album Olym: yiy;o, tjpl, e
) and tetrasaccharide (xswI; tomM) phosphate 111
(0,1j1M;ν117.(1;1.mouthJ)lIll
Sodium cyanoborohydride (11m9; Wo.

μM) & ** was left at 37°C for several days.
The autologous-oligosaccharide mixture was eluted with water to resolve the unidentified pentasaccharides and salts. Under these Qin conditions, B8 Mu 14: Ruri 124
We were able to maintain a constant amount of 11 ml of tetrasaccharide.

The same reaction can be carried out on a uniform carrier such as 2-ainoethyl-polyata9ruad or 2-ainoethyllucerine, or any suitable carrier containing a primary amine function a. I decided to do it myself.

Similarly, by operating under already electrophilic conditions in the presence of antithrombin irises (Part 9 of II), oligobran was immobilized directly above antithrombin, and through this, the oligobran was Anti-thrombin irises were obtained (lJOIK#,
FlllL@tt@rl # l 4 II@, e
ll-1 (J 0 p. 114).

;IIsu' Lily and 11 Compound-2 (s, ・I) and mercuric cyanide (3,8I)
f) Shita ww7 Tan (40j)illK.

Solvent approx. 1. - After 1 meeting, 4 * Rekiou Two Sheep (I
I) is added to make it linear *, 6/! /(s, 4aI: turn 11
1aM) was added. After stirring for one night, the first one was removed by passing and the first one was WSX methane. - The latter was combined with turquoise, and the organic 11 obtained was then washed with 1 g saturated potassium hydroxide, and then with water. After being dried and concentrated.

Obtained shizuki (104F) 1 methanol (1Img
) in natricummetano) (IM.

1m). silica gel(
say; chloroform/methanol; 10/1:v/v
) Obtained from a bale of Taroma Gutufi 1.
3 is f/II Tsubu (((E)","--1!"(C:
1,1, /IIm$#A) ), this syrup was added to the acid-containing chemical container. Layered.

1st Emperor! Upper 114 button two-wheeler @1sl (1,71) t'-water DMF (17d)
After understanding this, add trityl chloride (4-4!
IF) *Dimethylacenoviridine (1 drop) was added, and then triethylamine (proverbs: mer) was added. After 3 days at mold temperature, the metal parts were crimped under vacuum. *The hardware was applied to silica gel (sol; hequinane first, then hequinane/vinegar ether; !/first then l/1; v/'v).

In this way, chemical compound 1.4 was obtained (1.II).

Compound 1@4 is a cystic whelk ([α)%”--ts, m.

(C: 1,1, Rita Roholm)).

2. The sheet obtained at the end of the production of compound 114 in 1.6 (2,4
1) Depressed in t'DMF (40 m).

Next, palitum hydroxide octahydrate (1,@4N), barium oxide (7,011), and finally benzyl bromide (211J)
)t-added. After reacting for 4 hours, methanol was added, followed by a2 form (100s+4). The m-isomer was poured out, and then the taroform phase was concentrated to dryness. 16 fl of the biaxes obtained at this stage were directly converted to compound 166. For this purpose, the residual material is
After extracting again in
/) Methanol-6fI111 (sss) was added. After reacting for 4 hours, the reaction mixture was diluted with dichloromethane and diluted with 1
Next, it was washed with sodium hydrogen carbonate water S*. After drying, it was applied to a metal silica gel column (100I; ethyl acetate; 4/1&ec 1/1; V/V), and in this way, the metal compound l. 6 was obtained ([α)%F --so(C:0
．． ? , dichlororum)).

Weight 10j'' Bano 11 Derivative 166v Acetone (0 order dissolved in 200,
Chromium oxide (1) (・yoIf) 1,! iM sulfuric acid (S > **) was added at 0°C. After 1.8 hours, ice and water were added to the reaction mixture and the oxidation products were extracted with a chromium column. Chloroform IIt-water. Washed with water, dried, and shrunk the eel in a dry state★ by adding diazomethane.

After dissolution in ether, the residue was methylated.

Compound 16st-*. This compound was dissolved in silica gel (hexane/ethyl acetate; 4/1 # then 1/1; V/V
) purified above. The purified compound is 7.
7' (((X) ``DI-1+-1,l'' (
C: 1 s/''*lum)) The zero elemental analysis and the phosphor spectrum were consistent with the expected structure for compound 168.

Note: Example 8! By the method described in I (from *g to *1?), metal compound 168 can be converted to a halide by aging acid decomposition.

(Left below) lll! I), the 31st WIA and the 3rd Yukizono line are the gardens showing the compounds of the present invention 43 and 149 ONMI specator, respectively.

Ao...Aryuthyl group, Rei...Methyl group, Bm...
・Benzyl group, lz...benzoyl group, MCCO2・
Minetutar acetyl group, 'rr...fk group, but-/? #Basic, 8...
llOs″baseφ 工 工! C 〇a:) eの＼↑ r O”) - 山 山 １ t Z 訳,, LL+ Continued from page 1 Priority claim @ February 1, 1982 ■ France ( FR)
■82 01575 @ February 16, 1982 ■ France (PR) ■ 82 02526 ■ May 28, 1982 ■ France (PR) ■ 82 09392 @ June 22, 1982 ■ France (FR) ■ 82 10891 ■ 1982 June 22, 1982 ■ France (FR) ■ 82 10892 @ July 2, 1982 ■ France (PR) ■ 82 11679 ■ August 6, 1982 ■ France (PR) ■ 82 13804 ■ September 20, 1982 ■France (FR) ■82 15803 @September 20, 1982 ■France (PR)■82 15804 @October 27, 1982 ΦFrance (FR) 82 18003 0 Inventor Jean Choay France 75007 Paris Rue Saint-Guillaume 21 @ Inventor Jean-Claude Lormo France 76
150 Marom IJI Joseph Delatre 1 0 Inventor Mahmoud Nasr Alexandria, Egypt Alexandria University Faculty of Science is Chemistry Department (No address) Procedural Amendment Form G) 1982 May 13, 2015 Kazuo Wakasugi, Commissioner of the Japan Patent Office 1, Indication of the case Patent Application No. 1178M of 1982
2. Title of the invention Oligosatsu color, to%+r and its production method 3. Relationship with the case of the person making the amendment Patent applicant name: Shorei Nis.A4, agent: Zan, Shinjuku-ku, Tokyo Inn 1 “Eye 1 No. 14
Issue: Yamada Hill 5, Date of amendment order: April 6, 1982 8, Contents of amendment (1) The column for a brief explanation of the drawings in the specification is amended as shown in the attached sheet (no change in content).

(2) In the attached drawings, Figure 13 has been amended to Figure 13a as shown in the attached sheet (no change in content).

(3) In the attached drawings, Figure 13a has been amended to Figure 13b as shown in the attached sheet (no change in content).

(/1) In the specification, ``Figure 13'' on page 166, line 5 to line 6 is corrected to ``Figure 138 J (no change in content).

(5) "Figure 13a" on page 166, line 9 in the specification
The text has been corrected to read "Figure 13b" (no change in content).

(6) In the specification, in the first line from the bottom of page 171, “13th
The text "Figure J" has been corrected to "Figure 13a" (no change in content).

4. Brief explanation of the drawings Figures 1 to 30 are process diagrams of the compounds of the present invention, and Figures 31 and 32 are diagrams of the compounds of the present invention 43 and 1, respectively.
Figure 13 shows the NMR spectrum of No. 49.

AC...Acetyl group, Me...Methyl group, Bn.
...benzyl group, Bz...benzoyl group, MCAO
... Monochloroacetyl group, Tr... trityl group,
but...butyl group, S...5OB- group.

Claims (1)

[Scope of Claims] (A method for the organometallic synthesis of oligonucleotides constituting or corresponding to 11II-type mucoporinuclide fragments, comprising reacting 2@0 compounds. Compound a, *% glucosamine structure OA unit 1%, D-dal-9in, or U of glucuronide structure
Unit 4IKD-Dalcroix 11iiIL
Is it composed of 141KL-iduronic acid?
It is an alcohol having the above-mentioned A unit or U unit at the end, and the above-mentioned A unit or U unit is one OH group, and the OH group having the alcohol function is d3 in the case of the A unit.
The U unit occupies either the 2-13- or Fi4-position, and the other unit is activated and the 9-amer carbon That is, it contains a reactive group, which, together with the alcohol o-on group, is located at 11o in the desired stereochemistry.
/Q Cosillation - May be able to form a conjunction and thereby produce a -M-U or -U-M sequence. The reactivity baseline of the A and U units is compatible with the functional groups and/or groups present in these units. Except for the A and U units in which the amber carbon is activated, all positions of the A and U units have 10H, a) or mineral orboxyl groups or O precursors of these groups. , these groups themselves, if present, are blocked by one or preferably several types of omta groups.9. These various Q groups are compatible with each other and with the precursors, and these O-holding groups and the precursors are inert to the glycosiwarf reaction and, together with the reactive groups, are compatible with the subsequent O-reduction. The conditions for the reaction of the starting materials to occur are these, allowing for the positional determination of the rounding that introduces a given substituent at various positions during the process, and for the subsequent execution of this procedure by the operator. The structure of the unit of the substance and the nature of the various substituents present are selected so as not to change, even if the interglycosidic
-N-acetyl)-6-0-nalphate-D-gluconaine]-[methyl-〇-merta-attack acid] structure. (2) The formed nine-sequence OA unit and U unit contain a temporary protecting group, that is, a group capable of selectively blocking a certain position of the A unit or U unit that participates in the glycosiwarf reaction and is about to be destroyed. 2. A process according to claim 1, characterized in that these groups are present in the starting material O units so that they can be removed in the presence of other groups. (3) Introducing several types of O-type groups in succession into a given type O functional group or group using the generated glucide chain Kl or by some chemical reactions, and then optionally converting these functional groups OII
Conductor 1 Forming 1 - Featured Patent Claim OI 1ml
The method according to item 1 or 2. (4) The blinding step removes only some of the precursor groups and/or protecting groups of the derivative, or
Also, all of the protective groups and /0 precursors are removed, and substituents of the given O type or successively different substituents are introduced into these 0 substitutes, and then optionally decomposed and 9 The @O method according to claim 3, characterized in that it consists of liberating a portion of the 1OH group present in large quantities as well as the hydroxyl moiety. (5) The starting material contains several O-type holding groups. These protecting groups are. (a) one or more semi-permanent groups, i.e.
A reaction I in which the skeleton contains many desired units! , groups that can be removed in the first place without removing or changing other groups present, and (b) the introduction of functional groups into one or more permanent *, m, semi-permanent groups. Claim 11, characterized in that @ holds an -OH group, and pl is a group obtained, for example, an acyl, an optionally substituted alkyl, or an aryl group.
1. The method described in any of Section 4 of III Building. (6) The A unit is a nitrogen-containing group constituted by an advantageous K et -Ns or a HIRO-NHCOO-CHs-O@HsO group, or an A-based simple group at the 2-position. Any other group constituting the precursor of the kenne derivative, especially -NH8
0m- or -NH-acyl, more preferably a-NH-
6. The method according to any one of claims 1 to 5, characterized in that it contains COCHs. (7) The carboxyl functional group of the U unit is inert to the reaction used in the substitution of the protecting group and can be removed at the end of the synthesis to liberate the carbocyl group, often for the purpose of salt formation. Blocked by a group that is 9. 7. Process according to any one of claims 1 to 6, characterized in that these protecting groups for the carbo-enzylic functional groups are preferably selected from Kti alkyl groups and aryl groups. (8) The provisional group is present in the U unit for U-A disaccharide extension 011 in the left direction, while it is present in the IIKaA unit in the fabric direction extension, thereby. Subsequently, a glycocrane reaction is carried out to obtain the desired chain reaction Uw A x U y As C where,
The sum of the subscripts is an integer from 2 to 12, and it is possible to obtain #kai (these values are included in the range where FiW and Y do not result in simultaneous KO), and this enchainment is usually U (AU
)n, (AU)nA. The method according to any one of claims 2 to 7, wherein the t411F mold is of the type (Um)n or (AU)nC, where nFil to 6). (9) sugars constituting structural analogs of the A unit or the U unit, such as neutral sugars or deosucroses, or other uronol units Ui or inosaccharides with different configurations,
9. A method according to claim 8, characterized in that it is used in place of one or several A units or U units. (101) Reacting the alcohols mentioned above with reactive derivatives such as monolides, preferably chlorides or bromides, imidates or orthoesters. The condensation reaction of halide and alcohol is advantageously a Koenlfi-Knorr type reaction, in a solvent medium, especially an organic solvent. j! preferably in an organic solvent of the dichloromethane or dichloroethane type, preferably the catalyst. Generally, silver salts or mercury salts are used, such as silver trifluoromethanesulfonate (commonly referred to as Silper trifluoride F), silver carbonate, and silver oxide. Under a cloth of mercuric bromide or mercuric cyanide, also a proton acceptor such as 11-collidine and water that may be present and/or an extractant of hydrologonic acid such as 4X molecular The reaction may be carried out in the presence of sheep, at room temperature or at temperatures as low as OC or lower, under an atmosphere of an inert gas such as nitrogen or arunone. Or. When forming covalent bonds between alcohols of various structures and L-iduronic acid OL-idose precursor, condensation reaction #
i. Using a mercuric derivative, especially dimercuric cyanide and/or dihydric bromide as a catalyst, and using a molecular sheep, especially 4A molecular sheath, the appropriate value depending on the reactivity of the alcohol. The condensation reaction with the orthoester, e.g. In any other solvent medium where the catalyst is e.g. 2,6-dimethylpyridinicum/? - carried out in the presence of chlorate. Is the condensation reaction with ibadate low temperature 1? Claims 1 to 9 are carried out in the presence of a 4A molecular thief and a catalyst such as boron trifluoride etherate in a solvent medium such as dichloromethane at a temperature of about IK OC or less. The method described in any of the paragraphs. The alcohol function of one A unit or tiU unit comprised of aυ and contained in a nine-gluside sequence is advantageously liberated from its temporary carrier, e.g.
, Rh or! r derivatives, especially rhodium tristotriphenylphosphine (1), or potassium t
using @rt-butoxide and then under acidic conditions, especially with a mixture of mercuric oxide and mercuric chloride. or from 0-chloroacetyl, for example by saponification using thiourea in a solvent medium, advantageously at a temperature above a80C, preferably at a temperature of xoocs degrees. The method according to any one of Items 2 to 1O. 0り What is the OH group protecting group other than the above temporary group? acyl groups (particularly acetyl, alkyl, substituted alkyls such as benzyl);
For the adjacent positions, an acetal group or a ketal is selected from, for example, benzylidene, and another carrier is selected from the epoxide form or the -〇H of 2') at the anhydride bridge.
% characterized by consisting of blocking groups
The method according to any one of items 1 to 11 of the range of 1FFrill search. Q31 The material to be subjected to the glycosylation reaction contains several types of protecting groups, which allow for the successive introduction of one or several functional groups during the functionalization step and, if desired, 91 This makes it possible to release one or several 10H groups. The protecting group may already occupy a position in the substance to be subjected to the glycosillage reaction, or it may be introduced by another group after the glucide skeleton has been constructed;
This modification can be carried out, for example, by the -OH groups at the 2- and 3-positions and the 10H groups at the 1- and 6-positions, respectively.
- A substance blocked in the form of epoxides and 1,6-anhydrides is intended for use in glycosilage carbonates, and by opening the epoxide function with sodium azide, the N1 group is transferred to the 2-position. It is possible to introduce
13. The method according to any one of claims 1 to 12, wherein the N group constitutes an adenine blind group O precursor. -OH of the starting material to be converted into α4 sulfate
The group is protected by a cetyl group on the acyl group 41, while the 10Hfi to be released at the end of the threat is held by a permanent group, e.g. a benzyl group.
A method according to any one of claims 1 to 13, characterized in that: subjecting the whole glucide chain to a given chemical reaction, e.g. esterification carried out under conditions that do not change the side structure, in particular sulfation with suitable reagents,
41 introduces a different type of substituent and shows that this sulfation can be carried out in a specialized or non-specific manner depending on the packaging for well-preserved glycosides.
The method according to claim 1mK, wherein the method is an I image. (161) The functionalization step can be carried out selectively by introducing several types of substituents into the chain in succession, and especially by introducing sulfate groups at predetermined positions of the Ic unit.
A derivative is formed at the − position. An acid derivative is formed at the 6-position of the U unit, and -
In the derivatives used to liberate the OH group and carry out the functionalization step, the semi-permanent group occupying the position to be nalphated is constituted by a 10-acetyl group. What is the position that will interfere with the 1OH group that you want to release? A semi-permanent group constituted by a benzyl group occupies the 2-position hNa or NH-Coo -C of the A unit.
Substituted by a group such as Hm -C@Hs, U
It is claimed that the 6-position of the unit is held by an alkyl group, especially methyl, and occupied by a 9-carboyacyl group! 1. The method according to any one of paragraphs 1 to 914, wherein the αn functionalization step is a primary step, selective introduction of a sulfate group; this introduction is followed by removal of the 10-acetyl protoxy group by a saponification reaction. This saponification reaction is carried out using a strong base such as soda, preferably at a temperature below room temperature, especially O
The alkylation is carried out at a temperature close to CK, followed by the action of an alkylating agent to introduce the alkyl group retained on the carboxyl group (which is removed by hydrolysis), and the alkylation is followed by the formation of sulfate. In order to introduce a sulfate group at the position liberated by hydrolysis and at the position in the free form after the action of an alkylating agent, the sulfation is carried out using a sulfating agent, such as a trimethylamine/80S-complex. The reaction is carried out in a solvent medium, particularly #1III, such as dimethylformamide, preferably at a temperature υ above the rich temperature, usually around ti50c, for a reaction time of about 12 hours. (Left below) Liberation of the -OH group blocked by one benzyl group; This liberation is carried out by removal of the benzyl group by catalytic hydrogenation, and the condition of this catalytic hydrogenation is that the nalphate group O
It is compatible with the maintenance and conversion of silicon groups into amino groups, preferably carried out in water and an organic solvent medium, especially an alcoholic medium, in the presence of a catalyst of the Pd/C type under hydrogen pressure. -N-acetyl group O formation; this is carried out by the action of an acetylating agent such as acetic anhydride on the product of the water bulking reaction, which reaction is advantageously carried out in an aqueous medium at a pH close to the basic pH %Kil. formation of N-sulfate groups; this is carried out using a sulfating agent of the type mentioned above at a pH higher than 9, advantageously of the order of 9-10, - for example for use in exchange 4Iily111 Process according to claim 16, characterized in that it consists of the salification of the syl group in the carbo with the desired cation, in particular sodium, potassium, lithium, magnesium, calcium. al In the method according to any one of claims 111 to 17, [an oligosaccharide constituting an intermediate. 111 Enchainment a-b, a-e or vice versa (a is D-glucosa ξn, b is D-Dalcuron gorge,
C stands for L-Izuron III).
U)n or (U-A)n (where n is an integer from 1 to 6), consisting of a chain, #J
A secondary component unit is (&) completely conserved and has a reactive group on the anomeric carbon of the terminal terminal unit or has only one free -011 group on the non-reducing terminal unit. This is -OH
The group occupies the 3-14- or 6-position in the case of the A unit and
(b) consists entirely of 9 units, such as those obtained at the end of the glycosylation step, or (C) consisting of a product in which one or several 10H groups are free, optionally containing one or several consecutive a% b or C units and/or di or several units; Oligosaccharide according to claim 18, characterized in that it may contain neutral sugars and/or several deoxy Ilts in its structure. J cl −+ 4h, al → 4b%ml −+
4c and bl' + 4-containing bond, Q phosphorus or -
- The oligosaccharide according to claim WAIE 19, which has a structure of a q-lansulfate fragment. υ Formula■ [In the formula, R1 is the same or different from each other, and is necessarily connected to R according to 1', and represents a protective group, particularly a semi-permanent group sp or a permanent group p, T is a temporary group t, a permanent group p or a hydrogen atom, N represents a nitrogen-containing group, i.e., amine or amine derivative fin precursor, R represents an aliphatic or aromatic group, 41 represents an alkyl group having 1 to 4 carbon atoms, and OR represents Contains at least 41 units having a structure of the blA4a type with a reactive group (e.g. halide, where R is an alkyl group), a group blocking the MFi acid function], preferably , formula (II), (II) or GV) [wherein,
The various symbols have the same meanings as above and are used in formulas GI) to (I
The symbols V) have the following meanings independently or in combination, M represents a hydrogen atom or methyl at the alkyl group 411, and s
Is p an acyl group 4? represents acetyl, p represents benzyl as substituted alkyl group 41, Rei & or β acyl group *
represents acetyl group, methyl represents alkyl group%, or benzyl represents substituted alkyl group 41, -OR represents halo2, especially bromide or imidoyl group, N represents an azide group, T represents a group, that is, acetyl group represents acyl group 41 , a halogenated acyl group, especially a monochloro- and especially a trichloroacetyl group,
or when the group p, i.e. the substituted alkyl group %, represents a benzyl group, and furthermore, in some cases, when the group formation of said unit is reversed, /
Claim I that contains at least one unit of [Q-ramethoxy or hydrogen atom] is t% mold! i second
01 [Oligosaccharide described in K. c! 4 Formula (V) N O- Preferably formula (Vl) or (■) N Op [In the formula, various symbols preferably represent formulas (n) to (Iv)
Formula (VI) has nine special meanings II and is defined for
or 8 in (■) further preferably represents a propenyl, allyl, imidoyl group or -H, in which case N represents -HN-acetyl group in %] () A unit having a structure of the type 4b Claim 20J, characterized in that it contains at least one
Oligosaccharide listed on JIKIe. (C) contains at least 41 units having a 61'% 4a type structure of formula 01) [in which the substituent CI) is defined with respect to K and has nine meanings], preferably B (IX); and (X) ``P N [wherein the various groups and p may be the same and represent an acyl group, especially acetyl, or different and may be an acyl group, especially an acetyl group, or benzoyl, an aryl group, or a substituted alkyl group. NHCO
O- (substituted alkyl group), preferably → former-COO-C
Hs-C, Hs group, which can be used for nitrogen-containing groups to form different aino derivatives at the 2-position of the A unit, T is acetyl, a halogenated acyl group% denotes a monochloro- or trichloroacetyl or p-methoxybenzoyl group, the symbols p%M and R are preferably of the formula (II) to (
The saccharide according to claim 20, characterized in that it contains at least one unit having the structure [defined for IV) and has a favorable meaning]. (2) al-! of formula (XI) [wherein the substituents have the meanings defined for K in formula (I)]! 44s-type structure, preferably of the formula (II) or (Xm) [wherein the substituents are defined for K in formulas (II) to (IV) and have a preferred meaning. 21. The origin saccharide according to claim 20, characterized in that the origisaccharide contains at least one unit having the structure. (2) If the protective group is partially removed during the synthesis process,
# instead of 1 hit J) Formation containing K-OH group -
The origin saccharide according to claim 20, characterized in that it corresponds to. @kBcDE1i'GM,σI)EFGH,AB,
BC, CD#, ABC, BCD, etc., BCD, BC
DE Hiro, ABCDE etc., ^BCDKF etc., ABCD)C
The structure of FG or BCDEFGH, preferably the trisaccharide structure, especially the formula % () [wherein the substituents have the meanings defined above and NI and N are preferably the same] are mutually KA&, and the azide or -M-acyl group * shows -NHN butyl], or the DIF structure corresponding to the formula (X
ll) [wherein the various symbols i are defined above and have nine meanings, and two substituents N1 of the two mercosine units of structure F and H
As in natural products, the compounds may be the same, but advantageously different, such as azide, -NH-Cω-7, and the basic K-
NH-COO-7-k f Rumatti -NH-COO
-C island -C@indicates a mountain] Oha ■ - structure, tetrasaccharai "structure, especially formula Oα■) has a favorable meaning] K corresponding EFGHIII structure, or pentasaccharide structure, especially formula Oα■) Ωα■) [In the formula, various symbols have the above-mentioned preferred meanings, and N
l, Nl and Ns are the same or different from each other and are selected from the nine meanings defined above.
An intermediate product corresponding to the original saccharide containing the H111 structure. (Foundation) 411 In response to the formation according to any one of Claims 20 and 25, O-O, III, several or all o-oH groups are liberated during the acid-containing process, and/or containing five or several functional groups, the O functional group is preferably composed of an ester, more preferably an inorganic anion containing 7 esters. or in the form of phosphate esters), these functional groups are derived from one or several primary alcohol and/or secondary alcohol and/or primary adenyl functional groups, with the proviso that Disaccharide [2-N-sulfate (or 2-N-
Acetyl)-6-0-nalphate-D-dal': It
- Origi saccharides except methyl-D-dalcuron. (c) The 6-position and/or the 3-position are substituted by esters, preferably from inorganic or organic cations, in particular metal cations, and also alkali metals, such as sodium, or silicon-containing organic bases. The cation to be introduced, for example in the form of the O salt with triethylamine, is preferably substituted in the 2-position by a primary amine function, advantageously a sulphate or an acyl group, such as an acetyl group. further preferably in the free state or in the form of a salt with an organic or inorganic cation as defined above, or as defined above. Contains a bs position or 0 unit with a carboxyl group that is protected, and more preferably tL<嬬. Contains a C unit having a nalphate group in the 2-position and/
It also contains a sulfate group on the ab unit, characterized in that the hydroxyl group of the pyra II of the units a, + or e is either free or retained by a permanent group of the alkyl type, especially a methyl group. Patent claim O
O oligosaccharides described in Scope No. 87. (2) Formula (1) Noda (XI [I) and 0 ■) No Yuu (XX
IV) (wherein 1 is substituted with an anion), corresponding to the product of 11. Oricinaccharide according to claim 26 or 27, characterized in that < contains an M doacyl group, in particular -NHCOCH, or an NHs01 group on one unit. (The following is a blank space) (30) The oligosaccharide according to claim 429, which contains a hexasaccharide enchainment corresponding to the formula (XXV). (31) corresponds to any one of the formulas (XXV) to (XXXI)O, contains a free -OH group of ]K in place of the -Op group, and optionally contains a part of the 108O1- group 10H The oligosaccharide according to claim 0 @ boxed item 30, which is substituted with a group. (32) The oligosaccharides described in Claims II, Items 27 to 31, which can be used as biological reagents:
A pharmaceutical composition containing an effective amount of Hirokasumi Conductor 50 (11 g of rattan), preferably an oligosaccharide of 90% (XXXII), together with an inert carrier.