WO2001064699A1

WO2001064699A1 - Novel 6-deoxy-6-carbonylthioglucopyranosyl acetimidates, novel intermediates for production thereof and processes for production of both

Info

Publication number: WO2001064699A1
Application number: PCT/JP2001/001607
Authority: WO
Inventors: Fumio Sugawara; Kengo Sakaguchi; Takayuki Yamazaki; Hiroshi Murata; Keisuke Ohta; Kazuyoshi Masaki
Original assignee: Toyo Suisan Kaisha, Ltd.
Priority date: 2000-03-03
Filing date: 2001-03-02
Publication date: 2001-09-07
Also published as: AU3604601A

Abstract

6-Deoxy-6-carbonylthioglucopyranosyl acetimidates of the general formula (I) [wherein R?11, R12 and R13¿ are each independently alkyl or silyl; R14 is hydrogen, alkyl, or aryl; R15 is alkyl; and R16 is hydrogen or alkyl]. These compounds are useful as intermediates for the synthesis of sulfoquinovosylacylglycerols useful as the active ingredient of anticancer and immunosuppressive drugs and so on.

Description

Specification

A new (6—Deoxy 1—6—Carbon thiol monocopyranosil) acetate imitate, a new way to make it Interim breaks and their manufacturing methods

Technical field

The present invention relates to a new intermediate for synthesizing Surhokino-Positive Glycerol, and a Surhokinobo using the same. Regarding the method of manufacturing shirring glycellol. More specifically, the present invention relates to 3 — O — (6 — Doxy 1 — 6 — Surhogulcopyranosil) 1, 1 — 2 — Di — O — Acyl Glycerol or 3 — O — (6 — Doxy 1 — 6 — Surgical Copiranosil) 1 1 — O — Glycerol A new intermediate for production and its use 3-O-(6-Deoxy 1 6-Surhogulcopyranosil) 1 1, 2 — di-O — acylglycerol or 3 — O — (6 — deoxy 6 — sur-hogulcopiranosil) 1 — O — Learn how to manufacture acylglycerol.

Furthermore, the present invention also relates to a method for producing the above-mentioned new intermediate, and to a new intermediate that can be used for this production method.

3 — O — (6 — deoxy 6 — Surhoguru Copirano, which can be manufactured by using the novel intermediates provided by the present invention. (Sil) 1, 2-di-O-acylglycerol or 3-O-(6-deoxy 1-6-sulhogylcopiranosil) 1-O-Acylglycerol includes anticancer drugs and immunosuppressants. It is useful as an active ingredient in medicines.

Background art It is known that some of the sulfur-containing glycolipids contained in natural products such as algae and higher plants have bioactivity.

For example, the literature by Ota et al. (Chemical & Pharmaceutica IB ulletin, 46 (4), (1998)) contains a specific algae obtained from the red alga Suginori. The surhokinotic glyceryl glycerol derivative induces higher-organism DNA synthase α and its inhibitory activities, as well as HIV-derived reverse transcriptase. It is noted that it indicates an inhibitory activity. In addition, literature on water products (Biochemical Pharmaco Iogy, 55, 537-541, (1998)) includes specific fertilizers obtained from fern plants. Of the mixture of the sulfoquinoposyl glyceryl glycerol derivatives of the present invention inhibits the co-ligand DNA synthase α-type and the rat DNA synthase β-type. It states that it shows activity but has no effect on reverse transcriptase activity from HIV.

-On the other hand, the publication of Sahara et al. (British Journal of Cancer, 75 (3), 32 4-33 32, (1997)) includes an assay from the penile intestinal tract. The sur-hokinoposil monosodium dalycellol fraction contained in the ton extract is anticancer at in, bipo and in.vitro. It is described that the operation is indicated.

However, the main method of obtaining these physiologically active Surhokino porcine acylglycerols is to extract them from natural products. It depends on the origin. Extraction methods from natural products are not always suitable or suitable for producing large quantities and stable bioactive substances.

Therefore, when these surhokinotic glyceryl glycerols are applied as a medicament, they must be used in large quantities, in a stable manner, and still be toxic. Intermediate body and other materials for synthesizing sur-hokinovosyl-glycerol safely without using high-quality materials, etc. It is desired to develop a method for producing surglycinosylglyceryl cellulose through such an intermediate body.

Disclosure of the invention

The present invention provides a useful intermediate for the production of sur-hokino-silicyl glycellol and a method for producing the intermediate. The purpose is to provide.

It is also an object of the present invention to provide a method for producing sur-hokino-vsyl-a-glyceryl cellulose using the above intermediate. .

The purpose of the above is to provide the following compounds and their production methods, as well as surhoquinopolysil using these compounds. It was achieved by the method of manufacturing glycerol.

(i) The following general formula (I):

(Wherein, R ¹¹ , R ¹² , and R ¹³ each independently represent an alkyl group or a silyl group, and R ¹⁴ represents a hydrogen atom Represents an alkyl group or an aryl group, R ¹⁵ represents an alkyl group, and R ¹⁶ represents a hydrogen atom, an alkyl group or an aryl group. (6 — Deoxy 6 — Power Relative Mono-Gluco Vilanosyl) One-set Immediate.

(ί ί) The following general formula (I:

(Wherein, R ^¹ 1, R 1 ² Contact good beauty R ^{1 3} is to independent to each other physician, the A Le key Le group or shea Li Le group. And Table, R ^{1 4} is hydrogen Represents an atom, an alkyl group or an aryl group.) 6 — Doxy 1-6 — Power .

(i i ί) The following general formula (I I I):

(Wherein, R ¹¹ , R ¹² , and R ¹³ independently of one another represent an alkyl group or a silyl group, and R ¹⁷ represents an alkyl group. Represents a sulfonyl group or arylsulphonyl group.) 6 —

0—Surphonyloxy glucolanose.

(i V) 3 — O — (6 — Dexoxy 6 — Surgical Copiranosil) 1 1, 2 — Di 1 O — Ash Glycerol or Is 3-O-(6-Doxy 6-Surrounding)

1 1 O — Intermediate represented by the general formula (I) of (i) above for producing acylglycerol.

(V) 3 — O — (6 — Dexoxy 6 — Slough-Gol Cosylanosil) 1 1, 2 — GeO — Acylic Glycerol or 3 — O — (6 — Doxy 6 — Sur Hogul Copiranosil) 1 1 1 o — Intermediate represented by the general formula (II) of the above (i) for producing acylglycerol.

(V i) 3-O-(6-Dexoxy 6-Surgical Copiranosil) 1 1, 2-Di 1 O-Ash Glycerol or Is 3 — O — (6 — Deoxy 1 — 6 — Surgical Copiranosil) 1 1 — O — For production of acylglycerol And an intermediate represented by the general formula (III) of the above (i ί ί).

(V ii) Acetimidization of the hydroxyl group bound to C 1 carbon of the compound represented by the general formula (II) described in the above (ii) A method for producing a compound represented by the general formula (I) described in (i) above, which is characterized in that:

(V i ί ί) One OR ¹基 group that binds to C 6 carbon of the compound represented by the general formula (III) described in the above (ί i 上) A method for producing a compound of the general formula (II) described in (ii) above, which is characterized in that the compound is converted into a hydrocarbon.

(i x) The following general formula (I V):

(Wherein, R ¹¹ , R ¹² , and R ¹³ , independently of each other, independently represent an alkyl group or a silyl group, and R ¹⁷ represents an alkyl group) Le scan Le e d Le group or to display the § rie ls e le e d le group, R 1 ⁸ is, C 1 charcoal protection based on table to.) in I Ri Table is Ru of compound an OR ¹ ⁸ group you join the element you and this you to hydroxyl groups as feature, placing serial upward Symbol (iii) A method for producing the compound represented by the general formula (III).

(X) From the compound represented by the general formula (I) of the above (i), characterized by having the following steps (1) to (3): 3-O-(6-Deoxy 1-6-Surgical Copiranosil) 1 1, 2-Di-O-Acylic Glycerol or 3-0 — (6—Doxy 1-6—Sul-Hogur Copiranosil) 1—11 O—How to make acylglycerol:

(1) The acyl imid group that binds to C 1 carbon of the compound represented by the general formula (I) described in (i) above The general formula (V) is:

(Wherein, R ^{¹ 1,} R ¹ ² Contact good beauty R ^{1 3} are independently of each other physician, the A Le key Le group or to display the sheet re le group, R ^{1 4} is hydrogen atom , the a Le key Le group or to display the § Li Lumpur group, R ^{1 0 1} is to display the § Shi Le residue of higher fatty acid, R ^{1 0 3,} the a Le key Le group or A fatty acid residue of a higher fatty acid.) And a step of obtaining a compound represented by the formula:

(2) above SL General formula you join the C 6-carbon of the of compounds of (V) one SC (= O) a R ^{1 4} group scan le phon acid salt of the following General Formula (VI):

(In the formula, R ^{1 1,} R ¹ 2 your good beauty R ^{1 3} parallel beauty in R ^{1 0 1} your good beauty R ^{1 0 3} is, Ru Oh the Ri you to have provisions above. M is, A A process for obtaining a compound represented by the following formula: (a metal atom or a alkaline metal atom).

(3) and deprotection of the upper Symbol General formula R a of compound of ^{^{(VI) 1 1 ~ R 1}} 3, a further, R ^{1 0 3} is the case of A Le key Le group R ^{1 0 3} Deprotection is carried out together with the following general formula (VII):

(In the formula, M your good beauty R ^{1 0 1} is Ru Oh the Ri you to have provisions above. R ¹ ^{0 2} is a high-class § Shi Le residue or hydrogen atom of the fatty acid 3 — O — (6 — Dexoxy 6 — Sur-Hogur Copiranosil) 11, 2 — Di-O — acyl Glycerol or 31 O — (6 — Deoxy 1 — 6-Surgical Copiranosil) 1 1 — o — Glycerol Obtaining process.

Best form to carry out the invention

In this specification, the “carbon number” of a protecting group refers to the number of carbon atoms when the protecting group is regarded as non-substituted. Thus, for example, if the group represented by R ¹¹ is a substituted alkyl group In this case, the number of carbon atoms refers to the carbon atom in the skeleton of the alkyl group that does not include the carbon atom of the substituent to be replaced with the alkyl group. Say the number of The same applies when the protecting group is other than the alkyl group.

The intermediates represented by general formula (I) of the present invention will be described in detail.

— In the general formula (I), the sugar skeleton includes one D—quinoboth (6—deoxy one α—D—glucose) and one D—quino. Both courses (6—Doxy 11D—Glucose) are included. In addition, the sugar skeleton can be arranged in either a boat shape or a chair shape. However, the chair type is preferred from the point of view of stability.

And have you In general formula ^{(I), R 1 1,} R 1 2 Contact good beauty R ^{1 3} is to independent to each other physician, the A Le key Le group or to display the sheet re le group.

The A Le key Le group R ^{¹ 1,} R ¹ ² Ru is re-table by your good beauty R ^{1 3,} the non-replacement or by Tsu Oh by the replacement of the A Le key group, good or was rather the It includes a lower alkyl group, more preferably an alkyl group having 2 to 2 carbon atoms (methyl, ethyl). The alkyl group is replaced. When it is an alkyl group, the substitution group may be a lower alkoxy group, preferably an alkoxy group having 1 to 2 carbon atoms. Xyl, ethoxy), non-substituted or substituted aryl groups, preferably 6-carbon aryl groups (for example, phenyl , P—method file) and the like.

Is an R ¹ R ^{1 2} Contact good beauty A Le key Le group by Ri Ru are table R ^{1 3,} in concrete terms, base down di Le group, p - main DOO key sheet base down di Le Group It contains a toxmethyl group and the like.

- general formula have you to (I), the sheet re le radical R ^{¹ 1,} R ¹ ² O Ri that will be table to your good beauty R ^{1 3,} unsubstituted or shea Li Le group substituted containing Also, substituted silyl groups are preferred.

R ^{1 1,} to the substituent of the case of R ^{1 2} your good beauty R ^{1 3} is substituted with re-group, low-grade A Le key group, good or to rather is having 1 to 4 carbon atoms A Le key Le group

(Eg, methyl, ethyl, isopropyl, t-butyl), and aryl groups, preferably C6 carbon Group (eg, phenyl group). R ^{¹ 1,} R ¹ ² your good beauty R ^{1 3} is, good or to rather than the 3 replacement of the city Ri Oh in the Li group, good Ri rather than the good or the t Ichipu Chi le di menu Chi Le Shi Li And triethylsilyl groups, trisopyl bilsilyl groups, etc.

R ^{¹ 1,} R ¹ ² your good beauty R ^{1 3} Table is Ru based on Ri by, the General formula

It is preferred that the compounds represented by (I) have the same group from the viewpoint of the easiness of the synthesis of the compound. In addition, the compound represented by the general formula (I) is used as an intermediate of a sulfoquinovolosylglycerol derivative. If you and taken into account, R ^{¹ 1,} R ¹ ² your good beauty R ^{1 3} group is table Ru Ri by, the stable of even the Ru Oh in Baie down di Le group as a protection group . sexual standpoint Kaka et al good or to have or, R ^{¹ 1,} R ¹ ² your good beauty R ^{1 3} force p - main door key sheet base down di Lumpur based or t - flop Chi le di menu Chi Le A silyl group or a triethylsilyl group is a sulfoxyquinoline having an unsaturated fatty acid residue bonded as an acyl group. of order to that form if Le § Shi Le grayed Li cell and Russia Lumpur induction body, later to have you on the reaction of about engineering, the children are found R ¹ 1, R 1 ² your good beauty R 1 3 groups From the point of view of the reaction to deprotection I like it. — In the general formula (I), R ¹⁴ represents a hydrogen atom, an alkyl group or an aryl group.

Alkyl groups represented by R ¹⁴ include unsubstituted or substituted alkyl groups, preferably lower alkyl groups, and the like. More preferably, it contains an alkyl group (methyl, ethyl) having 1 to 2 carbon atoms.

The aryl group represented by R ¹⁴ is a non-substituted or substituted aryl group, preferably an aryl group having 6 carbon atoms. Group (for example, phenyl).

As the group represented by R ^{14, a} methyl group is preferable from the viewpoint of the stability of the reaction.

— In the general formula (I), R ¹⁵ represents an alkyl group.

The alkyl group represented by R ¹⁵ is a non-substituted or substituted alkyl group, preferably a lower alkyl group having 1 to 3 carbon atoms. It includes a alkyl group, more preferably an alkyl group having 1 carbon atom (eg, methyl). When the alkyl group is a substituted alkyl group, the substituted group may be a halogen atom (for example, fluorine, chlorine, bromine), or the like. It contains a phenyl group and the like.

R ¹⁵ is preferably a substituted alkyl group, preferably from the viewpoint of reactivity, particularly preferably a trichloromethyl group. It is.

In the general formula (I), R ¹⁶ represents a hydrogen atom, an alkyl group, or a aryl group.

The alkyl group represented by R ¹⁶ is a non-substituted or substituted alkyl group, preferably a lower alkyl group having 1 to 3 carbon atoms. Ki It contains an alkyl group, more preferably an alkyl group having 1 carbon atom (a methyl group).

The aryl group represented by R ¹⁶ may be an unsubstituted or substituted aryl group, preferably an aryl group having 6 carbon atoms. (For example, a phenyl group).

R ¹⁶ is preferably a hydrogen atom from the viewpoint of reactivity.

As a combination of R 15 and R 16, it is preferable that R 15 is a trichloromethyl group and R ¹⁶ is a hydrogen atom. Yes.

The intermediate represented by the general formula (II) of the present invention binds to C 1 carbon in the compound represented by the general formula (I) described above. Except that the group is a hydroxyl group, it is the same as the compound represented by the general formula (I).

The intermediate represented by the general formula (III) of the present invention is a compound represented by the general formula (II) in which the group capable of binding to C 6 carbon is present. OR 17 (where R 17 is an alkyl sulfonyl group or an aryl

— Represents the lusul honyl group. Other than that, the compound is the same as the compound represented by the general formula (II).

— In the general formula (III), the alkyl group of the alkylsulfonyl group of R ¹ ′ includes a non-substituted or substituted alkyl group. , Preferably an unsubstituted alkyl group, more preferably a lower alkyl group, and more preferably an alkyl group having 1 to 2 carbon atoms. Group (eg, a methyl group, an ethyl group). The aryl group of the arylsulfonyl group of R ¹⁷ includes an unsubstituted or substituted aryl group, preferably an aryl group having 6 carbon atoms. A reel group (eg, a phenyl group) is included. In the case of a substituted aryl group, Examples of the substituent include a p-methyl group, a p-methoxy group and the like.

In the present invention, the intermediate represented by the general formula (IV) is a C 1 carbon in the compound represented by the general formula (III) described above. Except that the group that binds to is OR 18 (where R 18 represents a protecting group), and is represented by the general formula (III). It is the same as the compound. The intermediate represented by the general formula (IV) can be produced using glucose as a raw material. For example, the application of the present application Use the method described in the Japanese Patent Publication by the Toyo Fisheries Co., Ltd. (P200-0 — 143516A). And can be done.

The protecting group represented by R ¹⁸ is a group capable of protecting a hydroxyl group bonded to C 1 carbon of the general formula (IV), and is a deprotection reaction. There is no particular limitation as long as it can be deprotected by subjecting it to the above method. To give an example of a protecting group, there is a 2-propyl group.

The intermediate represented by the general formula (I) of the present invention is represented by the general formula (IV) after going through five processes using glucose as a starting material. Then, an intermediate represented by the general formula (III) is obtained, and then, an intermediate represented by the general formula (II) is produced. can do .

The following scheme 1 shows the process from the production of glucoose to the production of an intermediate represented by the general formula (IV).

Compound 1 Compound 2

Compound 4 Compound 5

(Compound of general formula (IV))

R ", R ¹² and R ¹³ = alkyl or silyl group

R ¹⁷ = alkylsulfonyl group or arylsulfonyl group

R ¹⁸ = protecting group, R ¹⁹ = alkyl group or substituted silyl group Hereinafter, steps A to E will be described in detail.

In step A, the hydroxyl group bonded to the C 1 carbon of the glucose is protected, and one OR 18 (here, R 18 is not particularly limited as long as it is a protecting group; For example, 2—pronyl, methyl, benzene Represents a jyl group or the like. ).

The protection of hydroxyl groups can be achieved, for example, by protecting the glucose and aryl alcohols with 2-propyl groups. In the presence of a strong acid such as sulfonic acid, usually at a temperature of 100 ° C from room temperature, preferably at a temperature of 80 ° C to 90 ° C, usually a half-hour. You can do this by reacting for two days from the day. However, the reaction time differs depending on the setting of the reaction conditions.

In its your factory as in B, and water group you bound to C 6 protects, with C 6 to-carbon Ru is join an OR ¹ 9 (here, R 1 9 is A Le Represents a killed group or a substituted silyl group.)

The alkyl group represented by R ¹⁹ is a bulky substituted lower alkyl group, preferably an alkyl group having 1 to 4 carbon atoms. It includes a killer group (for example, t-butyl group, trityl group). Alkyl groups represented by R ¹⁹ are preferred from the standpoint of ease of reaction with trityl groups.

The substituted silyl group represented by R ¹⁹ includes a lower alkyl group, preferably an alkyl group having 1 to 4 carbon atoms (eg, an alkyl group having 1 to 4 carbon atoms). For example, methyl, ethyl, isopropyl, t-butyl), and aryl groups, preferably aryl groups having 6 carbon atoms (eg, For example, a phenyl group) is included. The substituted silyl group represented by R ¹⁹ is preferably a trisubstituted silyl group, more preferably a t-butyldiphenyl. It contains a rusilyl group and the like.

In step B, the protection of the hydroxyl group may be carried out by using an organic solvent such as dry pyridine to obtain the compound 3 in which R 19 is an alkyl group. In the solution of the dissolved compound 2, R ¹⁹ ′ — X (where R ¹⁹ ′ is An alkyl group defined as R ¹⁹ and X represents a halogen atom such as a chlorine atom. ) And reacting at room temperature in the presence of a catalyst such as p-dimethylaminopyrrolidine (DMAP). However, the reaction time differs depending on the setting of the reaction conditions. As the compound R ¹⁹ '-X, trityl chloride is favorably used from the viewpoint of production cost and ease of reaction.

_When compound _{3 in} which _R 19 is a substituted silyl group is obtained, a solution of compound 2 contains R 19 "-X (where R 19" is X represents a halogen atom such as a chlorine atom, and X is a substituted silyl group defined as R 19, and a catalyst such as imidazole is added. In the presence, at room temperature, this can usually be achieved by reacting for half a day to two days. However, the reaction time differs depending on the setting of the reaction conditions.

R ¹⁹ "—X can be t-diphenyldiphenylsilyl chloride.

In the process C, the hydroxyl groups bound to C 2, C 3 and C 4 carbon are protected, and one OR〗 ¹ and one OR ^{12, respectively} . R ¹³ (Here, R 11 to R 13 are not particularly limited as long as the protection of the hydroxyl group can be performed. Specific examples thereof include general were also provisions in _{_R} 1 1 ~ _R 1 3 of formula (I) of the free or is Ru.) to you. The protection of these hydroxyl groups is carried out, for example, when the protecting group is a benzyl group, by using an organic solvent such as dry N, N-dimethylformamide (DMF). The hydroxyl group of the dissolved compound 3 which binds to C 2, C 3 and C 4 carbon is activated by sodium hydride or the like, and React at room temperature a compound that can protect hydroxyl groups such as You can do this with

Compounds that can protect the hydroxyl group include p-methoxybenzylrubide, t-butyldimide, in addition to benzyl bromide. Tilsilyl chloride, triethylsilyl chloride, etc. can also be used.

When a compound capable of protecting these hydroxyl groups is used, the reaction may be performed according to the reaction conditions suitable for each protecting group. It is done.

In step D, the C 6 carbon protecting group is deprotected. In step D, the deprotection is performed by dissolving the solution of compound 4 dissolved in an organic solvent such as methanol with a catalyst such as p_toluenesulfonic acid. It can be done by reacting at room temperature in the presence, usually from 12 hours to 1 day. However, the reaction time differs depending on the setting of the reaction conditions.

In the process E, the compound 6 (the same as R ^{17 in the} general formula (III)) is bonded to the C 6 carbon of the compound 5 by combining the compound 6 ( The compound of the general formula (IV) of the present invention is obtained.

The reaction to this one OR 17 group is due to the compound dissolved in the organic solvent.

Add a compound having an alkylsulfonyl group or a compound having an arylsulfonyl group to the solution of 5 and react. Can be introduced into C 6 carbon.

As the compound having an alkyl sulfonyl group, a compound represented by the formula: R 1 -X (wherein, R ¹⁷ ′ represents an alkyl sulfonyl group; And X represents a halogen atom.), And a concrete example thereof is methansulphoni. Le Cloride Includes tungsten chloride chloride.

- How, in the § rie ls e le e d Le based on to that of compound Yes, the formula: R ¹ '"- X (wherein, R ^{1 7"} is § rie ls e le e d , And X represents a nitrogen atom.). For example, p—toluene can be used. Includes Ensulfonyl chloride, p-methoxybenzenesulfonyl chloride, Benzensulfonyl chloride, etc. .

Of these compounds having an alkylsulfonyl group or an arylsulfonyl group, those having a tosyl group are those that have a reaction. Preferred from the point of view of ease.

In the reaction of the process E, as the organic solvent, dry pyridine, dried dichloromethane, or the like can be used.

The above reaction can be carried out, if necessary, in the presence of a catalyst such as DMAP at room temperature, usually for 2 hours to 1 day. However, the reaction time differs depending on the setting of the reaction conditions.

The compound 6 of the general formula (IV) is used as the starting material, with the compound 6 (the compound of the general formula (IV)) shown in the above-mentioned scheme 1 as the starting material. Compounds of the general formula (I) can be produced via the compounds of the general formula (II). These steps are shown in Scheme 2 below. Scheme 2

The steps F to H of the above-mentioned scheme 2 will be described in detail below. In step ", the C 1 carbon protecting group of the compound of the general formula (IV) is deprotected to obtain a compound of the general formula (III).

The deprotection of the C 1 carbon in step F involves the conversion of the compound of general formula (IV) to methanol, ethanol, tetrahydrofuran, or the like. It can be dissolved at room temperature in the presence of a catalyst such as palladium (II) chloride, iridium complex or ruthenium complex. However, the reaction time differs depending on the setting of the reaction conditions: D. '

In step G, the sulfonyloxy group (one OR 17) of the compound of the general formula (III I) is converted to a carbonylthio group (one SC (= O)

R ¹⁴ ) to give a compound of the general formula (II).

The conversion of a sulfonyloxy group to a carbonylthio group can be carried out by replacing the oxy group with a thio group in the compound of the general formula (III) in an organic solvent. (Hereinafter referred to as ォ choride material) U. ) Can be achieved by reacting

The fluorinated substances include alkali metal salts and alkaline earth metal salts of thiocarbonic acid. Thiocarbonic acids include thioformic acid and lower thiocarbonic acids, preferably having 1 to 10 carbon atoms.

Aliphatic carboxylic acids substituted with an aliphatic hydrocarbon (e.g., thioacetic acid, thiopropionic acid), and aromatic hydrocarbons having 6 to 10 carbon atoms It includes aromatic carboxylic acids substituted with hydrocarbons (for example, thiobenzoic acid).

Alkali metals that form these carboxylic acids and salts include potassium and sodium, and alkaline earth metals include magnesium. Includes gunsium, calcium, etc.

Of the above thiolated substances, salts of thioacetic acid are preferably used in view of the stability of the reaction and the fact that sulfur atoms are easily oxidized in the subsequent steps. it can .

The amount of the fluorinated substance to be added varies depending on the compound to be used, but it can usually be set to an equivalent to twice the amount of the compound of the general formula (III).

The organic solvent used for the reaction may be a dry alcohol, preferably a lower alcohol (for example, methanol, ethanol, propyl alcohol). ), Dried DMF, etc. are included.

The amount of the organic solvent to be used can be usually set to about 2 to 10 times the amount of the compound of the general formula (III) to be dissolved, which can be dissolved.

The above reaction can usually be performed by stirring for 1 to 24 hours, usually at room temperature or at the boiling point of the solvent used. . However, the reaction time differs depending on the setting of the reaction conditions.

In the process H, the imidate is introduced into C 1 carbon of the compound of the general formula (II) to obtain the compound of the general formula (I) of the present invention. .

The immiscible compound of the general formula (I) in which R ¹⁶ is H is a compound which has a suitable contact with the compound of the general formula (II) dissolved in an organic solvent. In the presence of a medium, the compound reacts with a nitrile compound represented by R ¹⁵ CN (where R 15 is defined by the general formula (I)). It can be obtained by responding.

The amount of addition of the nitrile compound represented by R ¹⁵ CN varies depending on the compound used and the compound used, but usually, the compound represented by the general formula (II) is used. It can be set to 1 or 2 times the amount of

The organic solvents used for the reaction include dried dichloromethane, dried chloroform, and dried tetrahydrofuran.

The amount of the organic solvent to be used is usually set to about 2 to 10 times the amount of the compound of the general formula (II) to be dissolved which can be dissolved. You can do it.

The catalyst obtained is 1,8-diazabicyclo [5,4,0] -7-denedecane, potassium carbonate, cesium carbonate, etc. Is included.

The above reaction can be usually carried out at 0 ° C. to room temperature by stirring the mixture for “! To 24. However, the reaction conditions can be changed. The reaction time differs depending on the setting of.

On the other hand, the present invention in which R ¹⁶ is an alkyl group or an aryl group

- compounds of general formula (I), under existence of appropriate catalysts, in ^{R 1 6 NHC (= O)} R 1 5 ( here, R 1 5 your good beauty _R 1 6 is, General formula

As specified in (I). ) And a general formula The compound (II) can be obtained by reacting a compound obtained by brominating C 1 carbon of the compound (II).

The compound of general formula (I) of the present invention obtained as described above can be used as an intermediate to obtain the following compound. scheme

After the steps I to K shown in Fig. 3, 3-Ο-(6-Deoxy-6-Suruga-Glycopyranosyl) 1, 1-2-G 0—Assy grease cell or 3—Ag — (6—Deoxy 1—Sulhogulcopyranosil) 1 A—Agile gly cell Rolls can be manufactured.

Scheme 3

The processes I to K will be described in detail below.

In the process I, the compound of the general formula (I) of the present invention is dissolved in an organic solvent, and the following general formula (VIII):

Wherein, R 1 ⁰ 1 is the § shea Le residues of high Kyuabura肪acid Table, R 1 ⁰ 3 is § Shi Le residues or A Le key Le group (favorable high grade fatty acid First, Represents a substituted lower alkyl group (for example, a benzyl group or a p-methoxybenzyl group). } To react with the acylglycerol represented by the general formula (V) to obtain the compound of general formula (V).

Above SL and have contact In general formula (VIII), the § Shi Le residues R ^{1 0 1} Contact good beauty R ^{1 0} by the ³ that are re table height Kyuabura肪acid, saturated or unsaturated It contains an acyl residue of the higher fatty acids of the present invention. Fatty acids providing an acyl residue include linear or branched, saturated or unsaturated higher fatty acids. Specific examples of the acyl residue include R—C (= O) (where R is an alkyl group or an alkyl group having 13 or more carbon atoms). ) Can be listed. The number of carbon atoms of R in the above-mentioned acyl residue is preferably 13 or more and 25 or less in consideration of manufacturing costs and the like, but is not limited to these. It is not something that can be done.

R ^{1 0 1} your good beauty R ^{1 0 3} of the above Symbol, general formula (VIII), 3 - O -

(6-Deoxy 1-6-Sur-Hogur Copiranosil) _ 1, 2-J-O-Agyl Glycerol It is preferable that both of them are acyl residues of higher fatty acids from the viewpoint of easiness of the reaction. In the acylglycerol of the general formula (VIII) used in the reaction of the process I, the carbon at the second position is an asymmetric carbon, and the S and R isomers are used. There is a stereoisomer of In process I, the general formula

In the case where diglyceryl cellulose is used as the compound of (VIII), the absolute arrangement of the diglyceryl cellulose is as follows: It is maintained as it is after binding to carbon C 1 carbon.

—, 3 — O — (6 — Doxy 6 — Surrounding Vilanosil) 1 1 1 When manufacturing O-Agyl Glycerol is, R ^{1 0 1} is Ri Ah in § Shi Le residues of high-grade fatty acid, R ^{1 0 3} is lower substituted Preferably, it is an alkyl group (eg, a benzyl group or a p-methoxybenzyl group).

The amount of acylglycerol used for the reaction can be from 1 to 1.2 parts relative to the compound of general formula (I). .

Examples of the organic solvent used for the reaction include dried dichloromethane and dried black mouth film. Although there is no particular limitation on the amount of the organic solvent used, it is usually 2 to 10% based on the amount of the compound of the general formula (VIII) to be dissolved which can be dissolved. It can be used about twice as much.

The reaction can usually be carried out at a temperature of 20 ° C. to room temperature for 1 hour to 1 day. However, the reaction time differs depending on the setting of the reaction conditions.

In addition, for example, when trifluoromethyl sulphonate trimethylsilyl is used as a catalyst, the bond of C1 carbon is arranged. When the compound of the general formula (V) is predominantly obtained and the trifluorobolan ether complex is used, the bond of C 1 carbon becomes ^. Compounds of general formula (V) of configuration are obtained predominantly.

In the process J, the carbonyl group bound to the carbon at the 6-position of the compound of the general formula (V) is converted into a sulfonate salt by the general formula (V). VI) is obtained.

Sulfonation is carried out by dissolving the above compound (V) in an organic solvent buffered with glacial acetic acid and potassium acetate, and OXONE (2 KHSO 5). This can be achieved by adding an oxidizing agent such as KHSO 4 K ₂ SO ₄ ) and reacting at room temperature for 12 to 24 hours. However, the reaction time differs depending on the setting of the reaction conditions. In step K, the compound of general formula (VI) C 2 carbon to c

4 General formula by deprotecting the protecting group that binds to carbon

The compound represented by the formula (VII) can be synthesized. Deprotection of this is, the kind you good beauty R ^{1 0 1} of the coercive Mamorumoto who were use, rows R ^{1 0} way of de-protection that conform to the type of by Ri table is Ru group at the ³ I can . For example, General and have your expression (VI), the table is Ru coercive Mamorumoto in R ¹ 1 ~ R 1 ³ is Ri Oh in Baie down di le group, R ^{1 0 1} your good beauty R ^{1 0 When 3} is an acyl residue of a higher-saturated fatty acid, the solution of the compound of the general formula (VI) dissolved in an organic solvent such as ethanol is used as a solvent. Deprotection of protective groups by reacting at room temperature in a hydrogen gas atmosphere in the presence of a catalyst such as radioactive charcoal (Pd-C) can do . In this case, the general formula (VI

The compound of I) can be produced. Hand, General and have your formula ^{(VI), R 1 1 ~} R 1 3 Ru are tables in coercive Mamorumoto Baie emissions di Le group Oh Li, R ^{1 0 1} High grade saturated fatty acids of § Shi Ri Ah Le residues, (if example embodiment, base down di Le group) R ^{1 0 3} is replacement lower a Le key Le group Ah Ru if in, R 1 ^{0 3} was above mentioned high _R 1 03 also de-protected to R 1 1 ~ de-protection Article Ken and conditions under the same of R 1 3 of Oh Ru If in § Shi Le residues of grade saturated fatty acids, mono § Shi Le grayed Compounds of the general formula (VII) in which resrides are combined can be produced. Also, R ^{1 1} to separate from the de-coercive Mamorujo matter of ~ R ^{1 3,} by the and this tting in conditions that were suitable for de-protection of R ^{1 0 3} Li, R ^{1 0 3} Can be deprotected to produce a compound of the general formula (VII), to which monoazyl glyceride is bonded. Et al is, General and have your formula (VI), R 1 0 1 Contact good beauty high Kyuabura肪the hand also Do rather a small of _R 1 0 3 by Ri tables are Ru group is unsaturated It is an acid residue. In such cases, the deprotection law should be set according to the protective group used, and should be such that the double bond of the unsaturated fatty acid can be maintained. Thus, a compound of general formula (VII) having mono or diglyceride linked to an acyl residue of a higher unsaturated fatty acid is produced. For example, in the case of a silyl protecting group, deprotection with an acid catalyst (for example, trifluoroacetic acid) can be performed. And can be done.

Example

Examples of the present invention are shown below, but the present invention is not limited to the following examples.

The scheme 4 shown below is the same as the one used in this example.

— Scars 3 — O — (6 — Doxy 1_ 6 _ Suroguru Korano Shir) _ 1, 2 — DiO — acyl glycellol And 3

-O-(6 — Deoxy 6 — Surrounding Copiranosil) 1 1 — 0 — An outline of the route that synthesizes acylglycerol. .

Scheme 4

Base

3-0-(6 deoxy-6-Surho a-D-Glucopyranosil)-1, 2-G-0-Stealoil-(S) Grease Synthesis of cellulose sodium salt

1) Process a; 1-0-(2-probel)-D Gluco-synthesis of (1)

Add 100 g of D-glucose (1) to 250 ml of aryl alcohol, dissolve it sufficiently, and add the solution to the solution under ice cooling. 0.8 ml of fluoromethansulphonic acid was gradually added. Thereafter, the reaction was carried out for 30 hours while stirring at 80 ° C. in an oil bath. At the stage where the reaction proceeded sufficiently, the reaction was neutralized with 1 mL of triethylamine and then decompressed and concentrated. A production rate of about 60 to 70% was confirmed in thin-layer chromatography.

2) Process b; 1-0-(2 prongs)-6-0-Triphenylmethyl-D-Synthesis of glucose (3)

1-0 _ (2—probe) — D-glucose (2) 100 g (455 mm

0 I) was dissolved in 350 mL of dry pyridine, and the solution was mixed with 170 g of trityl chloride (61 mmol) and 1.0 g of DMAP. 8.20 mmol) The mixture was added and reacted at room temperature for 36 hours with stirring. After that, the reaction was stopped by applying 800 mL of cold distilled water, and the reaction was stopped, extracted with ethyl acetate (500 mL x 3 times), and the organic layer was combined. After that, neutralize with dilute hydrochloric acid to pH 4, wash with saturated brine (500 ml LX twice), dry with anhydrous sodium sulfate, filter, It was concentrated under reduced pressure and purified with silica gel flash chromatography (dichloromethane: methanol = 20: 1). A production rate of about 800/0 was confirmed in the thin-layer chromatography.

3) Process. 2, 3, 4 Tris — 0 Benzyl — 1 — 0 — (2 prole) — 6 — 0 Triphenyl methyl — D — Glucose (4) Synthesis of

Take 2.0 g (6.6.5 mmol) of 80% hydrogenated sodium hydrogen dispersed in mineral oil into the reactor and dry it. After washing well with 50 mL, the hexane was removed and dissolved in dry DMF.

1-0-(2 prongs)-6-0-Triphenyl methyl-D Gluco (3) 10.0 g (21.6 mm 0 I) Was added gradually under ice-cooling. After 15 minutes, the temperature was returned to room temperature, and the mixture was reacted with stirring for 1 hour.

Next, the mixture was cooled again to ice and the benzil mid-mouth was added to 12.0 g (70.2 mm 0.

I) was gradually added, and after 15 minutes, the temperature was returned to room temperature, and the mixture was reacted for 3 hours under a stirring force. After that, add 20 mL of methanol and 30 mL of cold distilled water to stop the reaction, and extract with ethyl acetate (50 mL x 3 times). Combine the organic layers, wash with saturated saline (100 mL x 2 times), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. , It was refined with lash chromatograph (hexan: ethyl acetate = 10: 1) (yield 9.6 g (13.1 mmoo, Yield 60.6%).

4) Process d; 2, 3, 4 — Tri — 0 — Benzyl — 1 — 0 (2-probe)-D-glucose (5) synthesis

2, 3, 4 — Tri — 0 — Benzyl — 1 — 0 — (2 — Pronyl)-6 — 0-Triphenyl methylene — D — Gluco Dissolve 9.6 g (13.1 mm 0 I) of methane (4) in 100 mL of methanol and add P-toluenesulfonate monohydrate 3. 8 g (20.0 mm 0 I) was added, and the mixture was reacted for 16 hours with stirring. After that, the reaction was stopped by adding 100 mL of cold distilled water, and the reaction was stopped and extracted with ethyl acetate (200 mL x 3 times), and the organic layer was combined. After washing with saturated saline solution (300 mL x 2), dry with sodium sulfate anhydrous, filter, concentrate under reduced pressure, and concentrate on silica gel. The purified amount of the chromatograph (hexan: ethyl acetate = 11: 2-→ 4: 1 → 2: 1) yielded 5.15 g (10%). 5 mm 0 I), yield 80.2%).

5) Process e; 2, 3, 4-Tri-0-Benzyl-1-0-(2-Prole)-6-0-(4-Tril sur Honi ) — Synthesis of D-glucose (6)

/ OTs (6)

10.0 g (20.4 m-nioI) of lucose (5) was dissolved in 200 mL of dry pyridine, and DMAP 134 mg (1.10 mmol), p- Toluenesulfonyl chloride (9.2 g, 48.3 mm0 I) was added, and the mixture was reacted at room temperature for 16 hours with stirring. After that, the reaction was stopped by adding 300 mL of cold distilled water, the reaction was extracted with ethyl acetate (200 mL x 3 times), and the organic layers were combined. Neutralize with dilute hydrochloric acid to pH 4, wash with saturated saline (300 mL x 2), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. And purified with silica gel flash chromatography (hexane: ethyl acetate = 4: 1) (yield 12.0 g). (18.6 mmoI), yield 91.2%).

6) Process f; 2, 3, 4-Tri-0-Benzyl-6-0-(4-Trilusullonyl)-D-Glucco Vilanose (7 )

4.80 g (7.45 mmo I) of the compound (6) was dissolved in 200 mL of methanol, and the mixture was dissolved in palladium chloride (IU 3.11 g (17. 50 mmo I), and stirred at room temperature for 18 hours.The reaction solution was filtered, then decompressed and concentrated, and the silica gel flash chroma was added. The crystals were purified by chromatography (hexane: ethyl acetate = 4: 1) to give colorless and transparent crystals (yield 3.60 g, 5.95 mmol, yield Rate 79.9%).

¹ HNMR (300 MHz _N CDCI ₃ + TMS, δ); 7.75

(2H, d, J = 8.3, 11 on Ts6 side), 7.32 to 7.25 (15

H, m, A r), 7. 2 0 ~ 7. 1 5 (2 H, m, T s S 0 ₂ side H),

. 4 9 6 ~ 4. 4 1 . (7 H, m, H- 1 ', β & A r - GH 2), 4 2 7 to 3.2 8 (7 H, tii, H-2 '&H-3'& H-4 '& H-

5 '& H-6' a, b & O H), 2.3 9 & 2.3 3 (3 H, T s C

H_3).

7) Process g; 2, 3, 4 Tri-0 Benzyl-6 Dexoxy-6-Acetylthio-D Gluco Vilanose (8)

3.60 g (5.95 mmo I) of the compound (7) was dissolved in 100 mL of dry N, N-dimethylformamide, and the mixture was dissolved in thioacetic acid. 1.12 g (9.81 mm0 I) of potassium was added, and the mixture was stirred at 80 ° C for 3 hours. After cooling the reaction liquid, add 50 mL of cold water, extract with ethyl acetate (100 mL x 3 times), combine the organic layers, and use saturated saline water. After washing (100 mL x 2 times), dry over sodium sulfate-free, filter, concentrate under reduced pressure, and concentrate on silica gel flash chromatography. Purification by Rafi (hexane: ethyl acetate = 3: 1 → 3: 2) yielded pale brown crystals (yield 2.60 g 5.11 mm 0 K yield 85.9%). [JD ^ + ZA.S "(c 7.2, black mouth holm). Melting point: 91 ° C.

1 HNMR (3 0 0 MH z , GDCI 3 + TMS, δ);... 7 4 1 ~ 7 2 5 (1 5 H, m, A r), 5 1 2 (7 H, m, H - 1 'a, β & A r — G ϋ_2), 4.15-3.30 (6 H, m, H-2'& H-3 '&H-4'& H-5 '& Η-6 'a & 0H), 3.14 to 3.00 (1H, m, H-6'b), 2.32-2.29 (3H, s, SC0CH_3)

8) Process h; (2,3,4 tris-0 benzyl-6-deoxy-6-acetylthio-D glucopyranosyl)-1- 0— trick To date (9)

2.50 g (4.92 mmol) of the compound (8) was dissolved in 70 mL of dry dichloromethane, and trichloroacetonitrile was dissolved in 3.000 m. Add L (29.9 mm 0 I) and 1,8- diazabicyclo [5.4.0] -7-decane 6 20 mg! Then, the mixture was stirred for 100 hours at room temperature for 5.5 hours. Apply 50 mL of cold water to the reaction solution, extract with dichloromethane (100 mL x 3 times), combine the organic layers, and add saturated saline water. After washing (100 ml LX twice), drying with anhydrous sodium sulfate, filtration, concentration under reduced pressure, and silica gel chromatography. -(Hexane: ethyl acetate = 4: 1) to give a colorless transparent oily substance (yield 2.26 g 3.46 mmol, yield 70.3) %). [] Ri = +61.5 ° (G 0.41, cross mouth home).

¹ H NMR (300 MHz, CDGI ₃ + TS δ); 8.12 (Ν-isomer), 8.60 (Ν-isomer), 7.43 to 7.26 (15 H, m, Ar) , 6.41 (d, J = 3.48, H-1 'α form), 5.78 (d, J = 7.46, H-1' form), 5.03 to 4.60 (6H , M, Ar-C H_ 2), 4.07-3.1 0 (6H, m, H-2 '&H-3'& H-4 '

& H-5 '& H-6' a, b), 2.36 to 2.31 (3H, s, S G0C H_3) o

9) Process i; 3—0— (2, 3, 4 tris—0 benzyl-6-dexoxy—6 acetyl-thio—a—D Le) 1, 2-di — '

Compound (9) 408.2 mg dissolved in 2 OmL of dry dichloromethane in a reaction vessel containing 500 mg of molecular sieves 4A (0.625 mmo I) and (S) -1, 2 di-O-stereoyl-glycerol 435 mg (0.696 mm O I) were added, and nitrogen gas was added. The mixture was stirred at room temperature for 30 minutes in an atmosphere. Trifluoromethanthyl trimethylsilyl sulfonate (10 iL) was dissolved in the solution in 0.5 mL of dry dichloromethan. The solution was added, and the mixture was stirred at room temperature for 6 hours under a nitrogen gas atmosphere. After that, the reaction was stopped by adding 15 L of pyridine, the reaction solution was filtered, and the filtrate was depressurized and concentrated. Then, silica gel flash chromatography was performed. It was purified with Graphite (hexane: ethyl acetate = 10: 1-4: 1) to obtain a colorless roo-like substance (yield 441.7 mg 0 396 mmo I yield 63.4%). [H] D = + 32.5 ° (c 0.85, black mouth holm).

1 H NMR (300 MHz, GDGI ₃ + TMS, δ); 7.33-7.28 (15 H, m, Ar), 5.24 (1 H, m, H-2), 4.96 (1 H, d, J = 10.8 A r-C H_2) 4.89 (1 H, d, J = 10.7 _s Ar-GH_2), 4.79 (1 H, d, J = 1 0. 8, A r - G H_ 2) 4. 74 (1 H, d, J = 1 2. 0, A r - C H_2)> 4. 70~ 4. 59 (3 H, m, A r-C H_2 & H-1 '), 4.40 (1H, dd, J = 11.9 & 3.7, H-1a), 4.21 (1H, dd, J = 1 1 . 9 & 6.3, H-1 b), 3.94 (1H, t, J = 9.2, H-3 '), 3.79-3.73 (2H, m, H-3a &H-5') , 3.31 (1H, t, J = 9.3, H-4 '), 3.53-3.46 (2H, m, H-3b &H-2'), 2 3.3- (3H, s, SC0CH_3) .2.34-2.27 (4H, m, 0C0CH_2), 1.63-1.58 (4 . H, m, 0 G 0 GH 2 G ji_2), 1 2 5 (5 6 H, br, - G y_2 -..), 0 8 8 (6 H, t, J = 6 7, C H_ 3) ₀

1 0) Process j; 3-0-(2, 3, 4 tris-0 benzyl-6 deoxy-6-Surho a-D Glucopyranosil) 1 , 2-di-0 stearoyl-(S) glycerol sodium salt (11)

Stearoylation compound (1 0) 7 5. 8 mg (0. 0 6 7 9 mmol) acetic acid 3. 0 m L To _{dissolve, OXONE (2 KHS 0 5,} KHS 0 4, K 2 S 0 4 ) 150 mg and 33 mg of acetic acid potassium permeate were added, and the mixture was stirred at 55 ° C for 6 hours. Then, add 5 mL of cold water and 3 mL of 1 N sodium hydroxide solution to stop the reaction, and extract with ethyl acetate (20 mL). x 5 times), and the combined organic layers are washed with saturated sodium bicarbonate solution and saturated saline (50 ml LX twice each), and dried without water. After drying with sodium sulfate, the mixture is filtered, concentrated under reduced pressure, and purified by silica gel flash chromatography (dichloromethane: methanol). (50: 1 → 10: 1)) to obtain a colorless roa-like substance (yield: 42.Omg 0.03667 mmol, yield: 54.1%). . [] _D = + 33.2 ° (c 0.90, Chloroform). ^{... 1 HNMR (3 0} 0 MH z, GDCI 3 + TS, δ); 7 2 8 ~ 7 1 2 (1 5 H, m, A r), 5 2 3 (1 H, m, G ly - H-2), 4.95 to 4.55 (7H, mAr-GH_2 & H-1), 4.41 to 3.08 (10H, m, H-2 ') & H-3 '&H-4'& H-5 '&H-6' a, b &H-", b & H-3 a, b) _{s 2.2 3-2.19} (4

. H, m, 0 C 0 C H_2)> 1 5 3 (4 H, br, 0 C 0 CH 2 C H_2) ^ 1 - 2 1 (5 6 H, br, - G tl_2 -.), 0 8 8 (6 H, t, J = 6.7, G y_

3).

1 1) Process k; 3-0-(6 deoxy-6-Surho-D-Glucopyranosil)-1, 2-Di-0-Stealoil — (S) Glycerol sodium salt (12)

33.6 mg (0.0294 mmol) of the compound (11) was dissolved in 10 mU of ethanol, and 10% paradium-activated carbon was dissolved in 10 mg. Was added, the inside of the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 16 hours. After replacing the inside of the flask with nitrogen, the solution was subjected to suction filtration using Celite, and after concentration under reduced pressure, the silica gel flash chromatography was performed. (Dichloromethan: methanol = 10: 1 → dichloromethane: methanol: water = 65: 25: 4) A colorless substance was obtained (yield: 13.1 mg, 0.015 mm0, yield: 51.0%).

[H] D = + 38.8 ° (c 0.42, cross-section home: methanol: water = 65: 25: 4). ^{1 HNMR (6 0 0 MH z} , DMS 0 - d 6 + D 2 0, δ);.. 5 1 2 (1 H, m, H - 2), 4 5 5 (1 H, d, J = 3 4, H-1 '), 4.3 3 (1H, dd, J = 11.9 & 2.4, H-1a), 4.12 (1H, dd, J = 1 1 9 & 7.3, H-1b), 3.87 (1H, dd, J = 3.87, H-3a), 3.38 (1H, mH-3b3) . 7 6

H, ddd, J = 9.3 & 6.4 & 4.4 H-5, 3.35 H, ddd, J = 9.3 & 9.3 & 4.4 H-3, 3.17 H, ddd, J = 9.3 & 6.4 & 3.4 H-2 '2.9 1 H, ddd, J = 9.3 & 9.3 & 3.4 H-4' 2.8 7

H, dd, J = 14.2 & 4.4, H-6'a), 2.53 (1H, dd, J = 14.2 & 6.4, H-6'b), . 2 3 0 -... .. 2 2 0 (4 H, m, 0 C 0 C H_2) 1 5 5 ~ 1 4 3 (4 H, m, 0 C 0 CH 2 C H_ 2) 1 2 0 (56H, br, -CH2-), 0.84 (6H, t, J = 6.3, CH_3) <Synthesis example 2>

Compound (9) obtained in step h of the above synthetic example 1 (9) Carla 3-0- (6 deoxy-6 sulfo-D-glucopyranosyl) — 1, 2 — Di — 0 — Sparroyl — (S) Glycerol sodium salt was synthesized.

1 2) Process i 3 — 0— (2, 3, 4 tris—0—benzyl—6 deoxy 6-acetyl thio-; 8—D-glucose Nosil) — 1, 2-G 0 — Stealoil — (S) Glycerol (10,)

Compound dissolved in 1 OmL of dry dichloromethane was placed in a reaction vessel containing 1.00 g of molecular sieve 4A (9). 1 3 4 mg (2 18 mo I) and (S)-1,2-di-0-Stearyl-dalycerol 1 36 mg (2 18 m 0 I) Was added, and the mixture was stirred at room temperature for 30 minutes in an argon gas atmosphere. Dried-in mouth liquid methane was dissolved in 0.5 mL of this solution, and it was dissolved in a volume of 27 mL (21.8 imol) of boron trifluoride ethylene. The tellurium complex was added, and the mixture was stirred at room temperature for 6 hours in an argon gas atmosphere. After that, the reaction was stopped by applying 1 mL of a 10% trichloroamine solution of dichloromethane [] to stop the reaction. The reaction solution was filtered, and the filtrate was filtered. After depressurizing and concentrating, use silica gel flash chromatography (hexane: ethyl acetate = 10: 1 → 9: 1 → 8: 1). The product was purified to give a colorless roa-like substance (yield: 1332 mg 118 m0I, yield 54.10 / ₀ ). [QJ] _d = + 18.8 ° (c 1.04, cross-section home).

1 HNMR (300 MH z, GDCI 3 + TMS, δ);... 7 34 - 7 2 7 (1 5 H, m, A r), 5 2 6 (1 H, m, H - 2), 4 9 2 (1H, d, J = 11.0, Ar-CH_2)> 4.91 (1H, d, J = 11.0, Ar-CH_2) 4.86 (1 H, d, J = 1 0 9, A r -. C H_ 2) 4. 7 7 (1 H, d, J = 1 0 9, A r -. C H_2) ^ 4. 6 8 (1 H, d, J = 1 1 0, A r -.. CH 9), 4 6 2 (1 H, d, J = 1 0 7, A r -.. GH 2), 4 44 (1 H, dd , J = 11.8 & 3.8, H-1a), 4.35 (1H, d, J = 7.8, H-1 '), 4.22 (1H, dd, J = 11.8 & 6.6, H-1b), 3.99 (1H, dd, J = 10.9 & 4.3, H-3a), 3.71 (1H , Dd, J = 10.9 & 4.8, H-3b), 3.62 (1H, t, J = 8.8, H-3 '), 3.51 (1H, d, J = 1 3. 7, H-6'a), 3.46-3.35 (3H, m, H-2 '&H-4'& H-5 '), 2.96 (1H, dd, J = 1 3.5 & 6.7, H-6'b), 2.34-2.24 (7H, m, SC0CH_3 & 0G0GH_2), 1.60 to 58 (4H _{, m, 0 G 0 GH 2} G i_2), 1 25 (56 H, br, -. CJJ_2-), 0. 88 (6 H, t, J = 6. 7, C H_ 3) 0

1 3) Process j '; 3-0-(2,3,4 Tris-0 Benzils-6-Deoxy-6 Surho--D Glucopyranosil)- 1,2 di — 0-stealoil — (S) glycerol sodium salt (1 1 ')

Of compound (1 0 ') to 222 mg (1 99 ju mo门was dissolved in acetic acid 20 m L, 0 X 0 NE (2 KHS 0 5, KHS 0 4> K 2 S 0 4) 520 mg Contact good beauty After adding 1.00 g of potassium acetate, the mixture was stirred at room temperature for 20 hours, and then 100 mL of cold water and 3N sodium hydroxide solution were added. Add 100 mL to stop the reaction, extract with ethyl acetate (100 mL x 3 times), combine the organic layers, and saturate sodium hydrogen carbonate. After washing with a solution and saturated saline (50 mL x 2 each), drying with sodium hydroxide anhydrous, filtration, concentration under reduced pressure, and concentration. Purified by Kageru Flash Chromatography (Dichloromethane: Methanol = 50: 1-10: 1), colorless raw The substance was obtained (yield: 174 mg 152 / m0I, yield: 76.4%) [a] _D = + 11.8 ° (c 0.92, black mouth home).

¹ H NMR (300 MHz, GDG ¹³ + TMS, δ); 7.29 to 7.25 (15H, m, Ar), 5.34 (1H, m, Gly-H-2), 4.95 to 4.25 (9H, m, Ar-GtL2 & H-1 '& H-1 a, b), 4.0 1 to 3.1 1 (8 H, m, H-2'& H-3 '&H-4'& H-

5 '& H _ 6' a b & H-b), 2.2 4-2.2 0 (4

. H, m, 0 C 0 C L2), 1 5 3 (4 H, br, 0 G 0 CH 2 G y_2), 1 2 3 (5 6 H, br, -. GH c -.) 0 9 0 (6H, t, J = 6.7, CH_

3).

1 4) Process; 3-0-(6-deoxy 6-Surho) 8-D Glucopyranosil) 1, 2-Di-0-Stealloy Le (S)-Grease mouth

Dissolve 162 mg (142 imol) of the compound (11,) in 20 mL of ethanol, and add 100 mg of 10% paradium-activated carbon to the solution. Then, the inside of the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 16 hours. After replacing the inside of the flask with nitrogen, the mixture was subjected to suction filtration using celite, and after concentration under reduced pressure, the silica gel flash chromatography was performed. (Dichloromethane: Metallanol = 10: 1 → Dichloromethane: Metabolol: Water = 65: 25: 4) A color-row-like substance was obtained (yield 5

4.2 mg 6 2.1 mol, yield 43.7%). [α] ο ⁼ + 3.13 °

(c 1.04, black mouth home: methanol: water = 65:25:

Four ) .

¹ HNMR (300 MHz, CDGIQ + GD 0 D + D ₂₀ , δ); 5.33 to 5.28 (1H, m, H-2), 4.38 (1H, dd, J = 12.1 & 2.8, H-1a), 4.33 (1H, d, J = 7.7, H-1 '), 4.23 (1H, dd, J = 12.0 & 7.4, H-1b), 4 0.3 (1H, dd, J = 11.1 & 5.5, H-3a), 3.78 to 3.71 (2H, m, H-5, & H_3b ), 3.45 (1H, t, J = 9.1, H-3 '). 3.34 (1H, dd, J = 14.6 & 3.1, H-6'a ), 3.27 (2H, t, J = 9.1H-2 '&H-4'), 3.09 (1H, dd, J = 14.6 & 7.3, H -... 6 'b) , 2 3 7 ~ 2 2 9 (4 H, m, 0 G 0 G y_2), 1 6 0 (4 H, br, 0 C 0 CH 2 C H_ 2), 1. 2 7 (56H, br, -G tL2-), 0.89 (6H, t, J = 6.6, CH_3) o

From compound (9) obtained in step h of Synthesis Example 1 above, 3-0- (6-dexoxy-6-sulfo-D-glucopyranosi ) — 1 — 0-Stearyl-Glycerol sodium salt.

1 5) Process! 2; 0 benzyl—3—0— (2, 3, 4 tri—0—benzyl—6 deoxy—6—acetyl thiol—a—D—dal (Copying)-1-0-sparoil-grease mouth (10 ")

R ¹ ^ Stearoid Remolecule Sieves 4 A. In a reaction vessel containing SOO mg, compound dissolved in 2 OmL of dry dichloromethane (9 ) 34.6.1 mg (0.530 mmo I) and (S) — 2-0 benzyl — 1-0-steer To the mixture, 237.8 mg (0.530 mmo I) of royal glycerol was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen gas atmosphere. Dissolve 10〃L of trifluoromethanthyl trisulfonate trihydrate in 0.5 ml of dry dichloromethan in the solution. The solution was added, and the mixture was stirred at room temperature for 6 hours under a nitrogen gas atmosphere. Thereafter, the reaction was stopped by adding 15 L of pyridin, the reaction solution was filtered, the filtrate was depressurized and concentrated, and then the silica gel flash chromatograph was removed. Purified with Graphite (hexane: ethyl acetate: = 10: 1 → 4: 1) to obtain a colorless raw material.

(Yield 301.6 mg 0.32 mmol, yield 60.6%). [] D = +30.0 ° (c 1.02, cross mouth home).

¹ HNMR (400 MHz, CDCI 3+ TMS, δ); 7.35 to 7.25

(20H, m, Ar), 4.99-4.60 (9H, m, Ar-C H_2 & H1 '), 4.39 to 4.10 (3H, m, H1a, b & H2), 3.98-3.93 (1H, m, H3 '), 3.84 to 3.73 (2H, m, H3a & H 5 '), 3.5 3-3.44 (2H, m, H3b & H2'), 3.41 to 3.36 (1H, m, H6'a), 3.34 to 3.29 (1H, m, H4 '), 3.08-3.02 (1H, m, H6'b), 2.33-2.30

(5 H, m, C 0 G H_2 & SG 0 G tL3), 1 -. 6 1 (2 H, m, G 0 CH 2 C H_2), 1 2 5 (2 8 H, br, C H_2), 0.90-0.86 (3H, m, Cϋ_3).

2 6 benzyl-3-0-(2, 3 and 4 tris-0-benzyl-6-deoxy-6-Surho-- D — Dalcopyranosyl)-1-0 — Sterol-Glycerol sodium salt (1 1 ")

Of compound (1 0 ") 2 6 1 mg of (0. 2 7 8 mmol) was dissolve in acetic acid l 9 m L, 0 X 0 NE (2 KHS 0 5, KHS 0 4, K 2 S 0 4 683 mg and 2.85 g of sodium acetate acetic acid were added, and the mixture was stirred at 55 ° C for 6 hours, and then cooled with 20 mL of cold water and 3 mL of cold water. The reaction was stopped by applying 100 mL of the N-hydroxylated sodium solution, and the reaction was stopped. The organic layer was extracted with ethyl acetate (30 mL x 5 times). Combine, wash with saturated sodium hydrogen carbonate solution and saturated saline (50 ml LX twice each), and then use anhydrous sodium sulfate. After drying, it is filtered, concentrated under reduced pressure, and purified by silica gel flash chromatography (dichloromethane: methanol = 50: 1 → 1). 0: 1) to give a colorless roa-like substance (yield: 108.5 mg 0.12 mm 0 K, yield: 40.3%). ] D = + 21.5 ° (G1.05, black mouth home).

1 HNMR (40 0 MH z, CDGI 3 + TMS, δ);.... 7 3 1 ~ 7 2 0 (2 0 H, m, A r), 4 8 9 ~ 3 2 1 (2 0 H, m, Ar-C H_2 & H 1 a, b & H 2 & H 3 a, b & H 1 'H 2'& H 3 '& H 4'& H 5 '& H 6' a, b), 2. 1 8 ~ 2. 1 5 (2 H, m, G 0 C H_2), 1. 7 (2 H, br, C 0 GH 2 C H_ 2), 1. 2 5 (2 8 H, br, C H_2), 0. 8 9 ~ 0. 8 6 (3 H, m, C H_ 3).

1F) Process "; 3-0-(6 deluxe-6-Suruga-D-Glycopyranosil)-1-0-Stealoil grease Cellulum sodium salt (1 2 ") ¹

76.3 mg (0.0789 mmol) of the compound (11 ") was dissolved in 15 mL of ethanol, and 250 mg of 10% paradium-activated charcoal was added. Then, the inside of the flask was replaced with hydrogen, and the mixture was stirred at room temperature for 16 hours, and the inside of the flask was replaced with nitrogen, and then suction filtration was performed using celite. After decompression and concentration, the silica gel flash chromatograph (closure hood: methanol = 10: 1 → chloro) Purification was carried out by using a mixture of form: methanol: water = 65: 25: 4) to obtain a colorless roa-like substance (yield 29.7 mg 0.0490 mmol, yield 62.4). %).

[a] D ^{= +} 28.8 ° (c 0.89, black hole home: methanol: water = 70: 30: 4)

¹ HNR (400 MHz, GDGI ₃ + GD ₃₀ D + TMS δ); 4.85 4.83 ( ¹ HmH1 ') 4.26 4.02 (6HmH1a, b & H 2 & H 3 ab & H 5 '), 3.73 3.67 (1 Hm H 3') 3.52-3.49 (1 Hm H 2 ') 3.42 to 3.38 ( 1 H m H 6 'a) 3.2 1 3 .17 (1 H m H 4') 3.05 2.99 (1 H m H 6 'b) 2.41 2.39 (2 H m C 0 C H_2) 1.63 (2 H m, C 0 CH ₂ C H_ ₂ ) 1-2 7 (28 H br C H_ ₂ ) 0.91 0.87 (3 H m C H_ ₃ )

Combination example 4>

From compound (9) obtained in step h of synthesis example 1 above, 3-0- (6 deoxy—6 surho D glucopyranosil) 1 — 0- Sparoil-glycerol sodium salt was synthesized.

1 8) Process i *: 2-0 benzyl-3-0-(2,3,4 tri-0-benzyl-6 deoxy-6 acetyl chloride- — D— Darcoylanosil)-1 — 0— Steal-oil grease roll (10 *)

In a reaction vessel containing 4 g of molecular sieves 4A 1.0 g, the compound dissolved in 3 OmL of dry dichloromethane was added. ) 5 28 mg (0.809 mmo I) and (S) — 2 — 0-benzyl — 1 — 0 Steroidal grease Glycerol 36 63 mg (0.809 mm 0 I) was added, and the mixture was stirred at room temperature for 30 minutes in a nitrogen gas atmosphere. 143 L (1.154 mmol) of boron trifluoride ethyl dissolved in 1.5 mL of dried mouth mouth methane dissolved in the solution The ether complex was added, and the mixture was stirred at room temperature for 6 hours under a nitrogen gas atmosphere. Then, add 5 mL of 10% triethylamine solution to the solvent, stop the reaction, filter the reaction solution, and reduce the filtrate. After concentration under pressure, purify with silica gel flash chromatograph (hexan: ethyl acetate = 10: 1-9: 1-8: 1). and manufactured to give a free color b c-like substance (yield 4 4 5. 4 mg 0. 4 7 4 mmol, yield 5 9. 0 ./ _0). [a] n = + 17.9 ° (G1.26, black mouth holm).

¹ H NMR (400 MHz, CDCI 3 + TMS _s δ); 7.35 to 7.25 (20 H, m, Ar), 4.94 to 4.61 (8 H, m, Ar-C H_2), 4.40 to 4.27 (2H, m, H2 & H1 '), 4.21-4.14 (1H, m, H1a) ), 3.98 to 3.94 (1H, m, H3a), 3.96 to 3.82 (1H, m, H1b), 3.71 to 3.67 (1H, m, H3b), 3.65 to 3.60 (1H, m, H3 '), 3.56 to 3.51 (1H, m, H6'a), 3.44 to 3.35 (3H, tn, H2 '&H4'& H5 '), 2.98 to 2 93 (1H, m, H6'b), 2.34 to 2.29 (5H, m, C0CH_2 & SG0Gti_3), 1.60 (2H, m, C0CH2) GH_2), 1.25 (28H, br, GH_2), 0.90-0.86 (3H, m, GH_3) ₀

1 9) Process j *; 2-0 benzyl-3-0-(2, 3, 4-tri-0-benzyl-6 deoxy-6 surho; 3- D-Glucopyranosyl) — 1 — 0-Stearyl-Glycerol sodium salt (1 1 *)

Dissolve 415 mg (0.472 tnmol) of the compound (10 *) in 20 mL of acetic acid, and add 0X0 NE (2 KHS 0 ₅ s KHS 0 ₄ .K ₂ S 0 ₄ ) 1088 mg Then, 3.00 g of acetic acid-rich lithium was added, and the mixture was stirred at room temperature for 20 hours. Then, add 100 mL of cold water and 100 mL of 3N sodium hydroxide solution to stop the reaction, and extract with ethyl acetate (100 mL x 3). The organic layers are combined, washed with saturated sodium bicarbonate solution and saturated saline (50 ml LX twice each), and then dried without sulfuric acid. After drying with acid sodium, filtration, concentration under reduced pressure, and silica gel flash chromatograph (cloth porch: methanol) = 50: 1 → 10: 1) to give a colorless roux (yield 209 mg, 0.216 mmol, 48.9% yield). [H] D = + 2.41 ° (C1.12, Rolo Home).

¹ HNR (400 MHz, CDCI 3 + TSδ); 7.29 to 7.21 (20H, m, Ar), 4.80 to 3.24 (20H, m, Ar-CH_2 & H 1 a, b & H 2 & H 3 a, b & H 1 'H 2'& H 3 '& H 4'& H 5 '& H 6' a, b), 2.1 2 to 2.05 (2 H, m, G 0 G H_2), 1. 46 (2 H, br, G 0 CH 2 G H_2), 1. 25 (28 H, br, C H_2), 0. 89~ 0. 86 ( _{3 H, m, C H_ 3} ).

2 0) Process k *; 3-0— (6 deoxy-6th Surho i3—D-Gluco Vilanosil) — 1—0—Stearyl grease Roll sodium salt (1 2 *)

The compound (11 *) (172 mg, 0.178 tnmol) was dissolved in ethanol (20 mL), and 10% paradium-activated carbon (450 mg) was added. The inside of the sco was replaced with hydrogen, and the mixture was stirred at room temperature for 16 hours. After replacing the inside of the flask with nitrogen, suction filtration was performed using celite, and after concentration under reduced pressure, silica gel flash chromatography was performed. It is refined with one (micrometer: methanol = 10: 1 → dichloromethan: methanol: water = 65: 25: 4) and is colorless. A roux-like substance was obtained (yield: 27 mg, 0.0445 mmol, yield: 25.0%). [] D = +2.50 ° (G 0.96, black hole home: metal: water = 70:30: 4) o

^{1 HNMR (400 MH z, CDGI} a + CD ^ OD + TMS, δ); 4. 37 ~ 4. 34 (1 H, m, H 1 '), 4. 1 9 ~ 3. 68 (6 H, m , H 1 ≡ ο

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Claims

The scope of the claims

The following general formula (I)

(Wherein, R ¹¹ , R ¹² , and R ¹³ independently represent an alkyl group or a silyl group, and R ¹⁴ represents a hydrogen atom , the a Le key Le group or to display the § Li Lumpur group, R ^{1 5} is to display the a Le key Le group, R ¹ ⁶ is hydrogen atom, a Le key Le group or § Li (6-Doxy 1-6-Dol-1------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- .

2. The following general formula (II):

(Wherein, R ^{¹ 1,} R ¹ ² Contact good beauty R ^{1 3} are independently of each other physician, the A Le key Le group or to display the sheet re le group, R ^{1 4} is hydrogen atom , Which represents an alkyl group or an aryl group.) 6 — Deoxy 6 — Carbylthio-glucovranose .

3. The following general formula (III):

(Wherein, R ^{1 1,} R ¹ ² Contact good beauty R 1 ³ is to independent to each other physician, A Le key Le groups or to display the sheet re le group, R ^{1 7} is A Le key Represents a sulfonyl group or an arylsulfonyl group.) 6 — O — Sulfonyloxy group .

4. 3-O-(6-Deoxy 1-6-Suroglucopyranosyl) 1 1, 2-Di-O-acylglycerol or 3- O —

(6 — Deoxy 6 — Sur-Hogur Copiranosil) _ 1 — Claims for manufacturing O-Agyl Glycerol Intermediate represented by the general formula (I) in the term.

5.3-O-(6-Dexoxy 1-6-Surgical Copiranosil) 1 1, 2-Di-O-acyl glycerol or 3 — O —

(6-Deoxy 1-6-Sur-Hogur Copiranosil) 1 1-Scope of Claims for Manufacturing O-Acyl Glycerol An intermediate represented by the general formula (II) in the second term.

6 — 3 — O — (6 — Deoxy 1 — 6-Through-Gol Copyranosil) 1 1, 2 — Di 1 O — Acylic Glycerol or 3 — O —

(6—Deoxy 1—Sur-Ho-Glu Copyranosil) _ 1 — Scope of Claim for Manufacture of O-Acyl Glycerol Intermediate represented by the general formula (III) of the term.

7. Scope of the claim The hydroxyl group that binds to C 1 carbon in the compound represented by general formula (II) described in paragraph 2 of the claim is acetoimid. A method for producing a compound represented by the general formula (I) described in claim 1, characterized in that the compound is represented by the general formula (I).

8. The scope of the claim is defined as a compound represented by general formula (III) described in Paragraph 3 of the claim, and one OR17 group that binds to C6 carbon is included in the carbohydrate. A process for producing a compound of the general formula (II) described in claim 2, characterized in that it is converted into a dithiol.

9. The following general formula (IV):

(Wherein, R ^{1 1,} R ¹ 2 Contact good beauty _R 1 3 is to independent to each other physician, A Le key Le groups or to display the sheet re le group, R ^{1 7} is A Le key Le scan Le e d Le group or to display the § Li one ls e le e d le group, R ^{1 8} is, C 1 charcoal protection based on table to.) in I Ri Table is Ru of compound an OR 1 ⁸ group you join the element shall be the feature and this you to hydroxyl groups, compounds of the billed the range general formula that will be described in paragraph 3 (III) Manufacturing method.

10. The compound represented by the general formula (I) in claim 1, which is characterized by having the following steps (1) to (3). From 3 — 0 — (6 — Doxy 1 — 6-Through-Gol Copyranosil) 1 1, 2 — Di-O — Acylic Glycerol or 3 — O —

(6-Deoxy 1-6-Surgical Coylanosil) 1-O-Method for producing acylglycerol:

(1) Scope of the claim The amide imid group that binds to the C 1 carbon of the compound represented by the general formula (I) described in paragraph 1 of the claim Lug After recellulation, the following general formula (V)

(Wherein, R ^{¹ 1,} R ¹ ² Contact good beauty R ^{1 3} is to independent to each other physician, the A Le key Le group or to display the sheet re le group, R ^{1 4} is hydrogen Hara R 101 represents an acyl residue of a higher fatty acid; R 103 represents an alkyl group or an aryl group; and R 103 represents an alkyl group or an aryl group of a higher fatty acid. Represents an acyl residue of a higher fatty acid.)) And obtaining a compound represented by the formula:

(2) above SL General formula you join the C 6-carbon of the of compounds of (V) one SC (= O) a R ^{1 4} group scan le phon acid salt of the following General Formula (V

(VI)

(In the formula, R ^{¹ 1,} R ¹ 2 your good beauty R 1 3 R 1 0 1 your good beauty R 1 03 to the parallel beauty is, Ru Oh the Ri you to have provisions above. M is, A Le And a process for obtaining a compound represented by the following formula:

(3) and deprotection of the R 1 1 ~ R 1 3 above Symbol of compounds of General Formula (VI), in a further, R ^{1 0 3} is the case of A Le key Le group R 1 03 de Protection is also provided by the following general formula (VII):

(Table wherein, M Contact good beauty R ^{1 0 1} is Ru Oh the Ri Contact with the provisions above. R ¹ ² is a high-grade § Shi Le residues or hydrogen atom of the fatty acid ) 3 — O — (6 — Deoxy 1 6 — Surhogulcopyranosyl) 1 1, 2 — Di O — Ash Recellol or 3-O- (6-Dexoxy 1-6-Sulfoglucopyranosil)-1-O-Obtain acylglycerol Process.