WO2006126633A1

WO2006126633A1 - Deacylation

Info

Publication number: WO2006126633A1
Application number: PCT/JP2006/310448
Authority: WO
Inventors: Hiroshi Suzuki
Original assignee: National University Corporation Obihiro University Of Agriculture And Veterinary Medicine
Priority date: 2005-05-26
Filing date: 2006-05-25
Publication date: 2006-11-30

Abstract

A process for the production of an organic compound having one or more free hydroxyl and/or thiol groups by subjecting an organic compound whose hydroxyl and/or thiol groups are at least partially acylated (hereinafter referred to as “an acylated organic compound”) to deacylation, wherein the deacylation is conducted by bringing the acylated organic compound into contact with a basic ion-exchange resin. The invention provides a process of deacylation which is applicable even to pH-sensitive compounds, compounds little extractible with an organic solvent because of their high water solubility, and compounds little separable from inorganic salts and which permits easy and simple deacylation without neutralization.

Description

Specification

Deacylation reaction

Technical field

[oooi] The present invention relates to a method for producing an organic compound by removing the acyl group from an organic compound in which a hydroxyl group and Z or a thiol group are acylated using a simple deacylation reaction.

Background art

[0002] The acyl group is widely used as a protecting group for alcohols and thiols. Deacylation is performed using a base and often must be neutralized with acid after use (TW Greene and PGM Wuts, PROTECTING GROUPS IN OR GANIC SYNTHESIS Second Edition, JOHN WILEY and SONS INC., (1990), non-patent literature 1). Neutralization requires a lot of labor and produces a large amount of inorganic salt. For compounds that are sensitive to pH, compounds that are highly water-soluble and difficult to extract with organic solvents, and compounds that are difficult to separate from inorganic salts, desolvation using the above bases is not a solution. There are many problems to be done.

[0003] For example, when a acetyl group is used as a hydroxyl-protecting group in the synthesis of a sugar-related compound, the deprotection, that is, deacetylation, has conventionally been performed using a strong base such as MeONa or KOH. The ability to flow ammonia gas through the reaction system.

[0004] [Chemical 1]

[0005] However, in the former method, when the alkali is neutralized with an inorganic acid or a cationic ion exchange resin, in the former case, the pH must be very careful, and further, the generated salt and Product separation may be difficult. The latter also has a problem in separating the generated acetamide from the product. In all cases, the reaction time was short, but there was a problem that post-processing was time consuming.

[0006] Therefore, the object of the present invention is to provide a neutralization treatment that can be applied to compounds that are sensitive to pH, compounds that are highly water-soluble and difficult to extract with an organic solvent, and compounds that are difficult to separate from inorganic salts. It is an object of the present invention to provide a method that can be easily deasserted without the need for the above.

Disclosure of the invention

[0007] By using basic ion exchange resin, the present inventor can perform product separation by simply neutralizing and filtering the resin simultaneously with deacylation. As a result, the present invention was completed.

[0008] The present invention is as follows.

[1] Organic compounds in which at least some hydroxyl groups and Z or thiol groups are acylated This is a method for producing an organic compound in which the acyl group is eliminated and the acylated hydroxyl group and Z or thiol group are unsubstituted hydroxyl group and Z or thiol group. And

The method, wherein the elimination of the acyl group is performed by bringing the organic acyl compound into contact with a basic ion exchange resin.

[2] The acylated organic compound is a sugar-related compound in which at least part of hydroxyl group and Z or thiol group is sacylated, or at least part of hydroxyl group and z or thiol group is substituted. Or unsubstituted linear or branched alkyl, substituted or unsubstituted alkene, substituted or unsubstituted alkyne, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaromatic, or substituted or unsubstituted heterofatty The method according to [1], which is a tribe.

[3] The method according to claim 1, wherein the acylated organic compound is a sugar-related compound in which at least a part of hydroxyl groups and Z or thiol groups are acylated.

[4] The acyl group strength is at least one selected from the group force comprising acetyl group, benzoyl group, bivaloyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, thioacetyl group, and thiobenzoyl group force [1] to The method according to any one of [3].

[5] The acyl group power is a group power consisting of a acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, and a thioacetyl group, and is at least one selected from [1] to [3] Method.

[6] The method according to any one of [1] to [5], wherein the basic ion exchange resin is a strongly basic type or a weakly basic type.

[7] The method according to any one of [1] to [5], wherein the basic ion exchange resin is a strongly basic type or a weakly basic type.

[8] The method according to any one of [1] to [7], wherein the contact between the acylated organic compound and the basic ion exchange resin is performed in the presence of a solvent.

[9] The method according to [8], wherein the solvent is alcohol or water or a mixture thereof.

[10] The method according to [9], which is the alcohol phenol.

In the method of the present invention, for example, ion exchange of 1.5 times the weight of the substrate in methanol is performed. The target product can be obtained almost quantitatively simply by stirring the coconut resin at room temperature for 30 minutes, filtering off the resin insoluble in methanol, and concentrating the mother liquor. For example, it is particularly effective when synthesizing a compound having a pyridine nitrogen, for example, when there is no need to worry about pH in the post-treatment. BEST MODE FOR CARRYING OUT THE INVENTION

[ooio] The present invention relates to an organic compound in which at least a part of hydroxyl groups and Z or a thiol group are acylated (the acyl compound and the organic compound) are eliminated, and the acylated hydroxyl group is This is a method for producing an organic compound which is an unsubstituted hydroxyl group and z or a thiol group. The present invention is characterized in that the elimination of the acyl group is carried out by bringing the acylated organic compound into contact with a basic ion exchange resin.

[0011] The elimination of the acyl group used in the method of the present invention, the acylated organic compound as a raw material, and the organic compound as a product are shown in the following reaction formula.

[0012] [Chemical 2]

[0013] The acylated organic compound (1) which is a raw material compound in the method of the present invention is an organic compound in which at least a part of hydroxyl groups and Z or thiol groups are acylated. In the formula (1), R is, for example, a sugar, a C to C linear alkyl, a C to C branched alkyl, a C

1 15 1 15 1

~ C haloalkyl, C ~ C alkene, C ~ C alkyne, phenol, heteroaromatic

15 1 15 1 15

Mention may be made of the family and heteroaliphatics. However, any organic compound having an acyl group can be used in the production method of the present invention. The alkyl, haloalkyl, alkene, alkyne, phenyl, heteroaromatic and heteroaliphatic may be unsubstituted or have a substituent. Examples of the substituent include an alkoxy group, a thioalkoxy group, a nitro group, a nitroso group, a cyano group, an isocyano group, a halogen group, and a silyl group. However, it is not limited to these. In the present specification, the heteroaliphatic includes cyclic heteroaliphatics and linear and branched heteroaliphatics.

[0014] An acyl organic compound in which R is a sugar is a sugar-related compound. Examples of sugar include Monosaccharides such as lucose, galactose, mannose, idose, talose, altrose, their reducing sugars, amino sugars such as sialic acid, sugar chains by the above combinations, C of these sugars

1

~ C linear alkyl, c ~ c branched alkyl, c ~ c haloalkyl, c ~ c

15 1 15 1 15 1 15 Alkenes, C-c alkynes, ferrules, aryls, heteroaromatics, heteroaliphatics, amino

1 15

Examples include acids, peptides, and polypeptide derivatives.

[0015] In the formula (1), X and X are independently an oxygen or sulfur atom.

1 2

[0016] In the formula (1), Y represents C to C linear alkyl, C to C branched alkyl, C to C

1 15 1 15 1 15 haloalkyl, C to C alkene, C to C alkyne, ferrule, and complex

1 15 1 15

Aromatics can be mentioned. The alkyl, haloalkyl, alkene, alkyne, phenol, heteroaromatic and heteroaliphatic may be unsubstituted or may have a substituent. Examples of alkyl etc. are the same as R.

More specifically, examples of the asil group include a acetyl group, bezoyl group, bivaloyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, thioacetyl group, and thiobenzoyl group.

In formula (2), R and X are the same as in formula (1).

2

[0019] A basic ion exchange resin has an anion exchange group such as an ammonium salt supported on a polymer compound such as polystyrene, and the counter ion is converted to a hydroxide ion in an alkaline aqueous solution. It is a rosin that shows basicity. It can be said that OH-type anion exchange resin is a solid granular alkali that does not dissolve in water. A typical ion exchange resin is a styrene ion exchange resin, but the ion exchange resin used in the present invention is not limited to a styrene ion exchange resin.

[0020] Ion exchange resin is generally classified into a cation exchange resin and an anion exchange resin depending on whether it has an acidic group or a basic group. It is divided into strong basic type and weak basic type. Strong basic ion-exchange resins are further classified into type I (which has a slightly higher basicity than type II) and type II, and type I is sometimes referred to as the strongest basic anion exchange resin. In the present invention, any basic ion exchange resin can be used, and the basic ion exchange resin here includes both strong basic type and weak basic type. However, the deacylation reaction proceeds smoothly under mild reaction conditions at room temperature. From the viewpoint, it is preferably a strongly basic type ion-exchange resin that easily releases hydroxide ions. The exchange group of the strongly basic anion exchange resin (type I) is, for example, RN (CH3) + (fixed ion) + OH (counter ion).

[0021] Even if the counter ion of the ion-exchange resin is an anion other than a hydroxide ion, it can be applied to the method of the present invention by counter-ion exchange with a metal hydroxide.

[0022] The basic ion exchange resin used in the method of the present invention may be any fine resin, such as spherical fine particles, films, fibers, etc., if the resin and their reaction residues are insoluble in the reaction solvent. It can be. From the standpoint of easy handling, spherical fine particles are preferred.

[0023] Examples of basic ion exchange resin include Amberlite IRA-67, Amberlite IRA-4 10, Amberlite IRA-900, Amberlite IRA-743, Amberlyst A-21, Amberlyst A-26 (OH), DOWEX 1X2—100, DOWEX 1X2—200, DOWEX 1X2—400, DOWEX 1X4—50, DO WEX 1X4-100, DOWEX 1X8-100, DOWEX 1X8-200, DOWEX 1X8-400, DOWEX 21K Cl, DOWEX 2X8—100, DOWEX 2X8—200, DOWEX 22—Cl, DOWEX MARAT HON A, DOWEX MARATHON A2, DOWEX 550A OH, DOWEX 66, DOWEX M ARATHON WBA, DOWEX WGR-2, Dulite A-7, and the like.

[0024] The deacylation reaction of the present invention is suitably performed in the presence of a solvent. As the solvent, for example, polar solvents such as water and alcohol (for example, methanol, ethanol, etc.) are desirable. However, in the case where rosin and their reaction residues are insoluble, it is also possible to use, Ν-dimethylformamide or dimethyl sulfoxide as a solvent. In addition, when the product is hardly soluble in a polar solvent and the resin and their reaction residue are insoluble in the reaction solvent, toluene, benzene, hexane, jetyl ether, tetrahydrofuran, dioxane, etc. are used as solvents. It can also be used as

[0025] The amount of ion exchange resin used is appropriately determined in consideration of the type of ion exchange resin, the type of organic compound, the type of acyl group, the degree of acyl group (the number of acyl groups per molecule of the organic compound), etc. can do. The amount of ion exchange resin used is suitably 2 to 6 times the mass of the substrate (an acylated organic compound), for example. However, it is not limited to this range.

[0026] When the acylated organic compound is a saccharide-related compound, for example, the saccharide is deacylated. In, there are 3-5 acyl groups per molecule. In this case, it is desirable to use 2 to 3 times the mass of the ion exchange resin as the substrate (the compound related to the acylyl sucrose). For disaccharides or more, a mass obtained by adding the number of sugars to the weight of sallow to be used for monosaccharides can be used.

[0027] The temperature and time of the deacylation reaction can be appropriately selected according to the type of the acylation organic compound and the ion exchange resin. Deacylation can usually be performed at room temperature, for example, in the range of 10-30 ° C. The time for the deacylation reaction is, for example, in the range of 10 minutes to 6 hours, and preferably in the range of 30 minutes to 3 hours.

Example

Hereinafter, the present invention will be described in more detail with reference to examples.

[0029] Example 1

4- (β-O-D-Darcosyloxy) -quinoline

[0030] [Chemical 3]

[0031] A methanol suspension (50 ml) of 4- (β-0-tetraacetyl-D-darcosyloxy) -quinoline (2.89 g, 19.92 mmol) and Amberlite A-26 (OH) (5.78 g) at room temperature And stirred for 1 hour. Methanol insolubles were filtered, washed with a large amount of methanol, combined with the filtrate, and methanol was distilled off under reduced pressure. The residue was dried to give the title compound (1.85 g, 99%).

[0032] Example 2

Saccharose

[0033] [Chemical 4]

[0034] Example 1 was followed except that octacacetyl sucrose (1.00 g, 1.47 mmol), Amberlite A-26 (OH) (6.00 g) and the reaction time was 2 hours. Saccharose (0.45 g, 89%) was obtained.

[0035] Example 3

2-acetamido-2-deoxy-D-glucose

[0036] [Chemical 5]

[0037] 2-Acetamido-1, 3, 4, 6-tetraacetyl-2-deoxy-jS-D-glucose (500 mg, 1.

28 mmol) and Amberlite A-26 (OH) (1.50 g). The residue was washed with ethyl acetate to give 2-acetamido-2-deoxy-D-glucose (206 mg, 71%).

[0038] Example 4

4- (β-O-D-Darcosyloxy) -quinoline

[0039] [Chemical 6]

4- (jS-O-tetraacetyl-D-darcosyloxy) -quinoline (500 mg, 1.05 mmol), methanol suspension (25 ml) of Dowex 550A (OH) (1.50 g) and the reaction time was 4 hours Except that, Example 1 was followed. The title compound (302 mg, 93%) was obtained.

[0040] Comparative Example 1

Sodium methoxide (1.70 g, 31.5 mmo) to a methanol solution (50 ml) of 4- (β-0-tetraacetyl-D-darcosyloxy) -quinoline (1.0 0 g, 2.10 mmol), the same as the raw material of Example 1. 1) was kept at room temperature and stirred for 1 hour at room temperature. To the reaction mixture was added 1M sulfuric acid in methanol (15 ml), and the solvent was distilled off under reduced pressure. The obtained residue was extracted with ethanol, and the solvent was distilled off from the extract under reduced pressure to obtain 4- (| 8-D-darcosiloxy) -quinoline (0.52 g, 81%).

[0041] In Comparative Example 1 above, sulfuric acid is used for force neutralization in which sodium methoxide was used for deacetylation, requiring extraction, and it takes time to isolate the product. Furthermore, if the pH is greatly inclined to the acidity during the neutralization reaction, salt formation with quinoline and sugar elimination due to solvolysis may occur, resulting in a problem in reproducibility.

Industrial applicability

[0042] The present invention can be used in the field of organic synthesis.

Claims

The scope of the claims

[1] At least a portion of the hydroxyl group and an organic compound in which Z or thiol group is acylated (hereinafter referred to as an acyl compound) is eliminated, and the acylated hydroxyl group and Z or thiol group A method for producing an organic compound which is an unsubstituted hydroxyl group and a Z or thiol group,

[2] The acylated organic compound is a sugar-related compound in which at least a part of hydroxyl group and Z or thiol group is sacylated, or at least a part of hydroxyl group and z or thiol group is substituted. Or unsubstituted linear or branched alkyl, substituted or unsubstituted alkene, substituted or unsubstituted alkyne, substituted or unsubstituted phenyl, substituted or unsubstituted heteroaromatic, or substituted or unsubstituted heterofatty 2. The method of claim 1, wherein the method is a tribe.

[4] The atyl group is at least one selected from the group force consisting of a acetyl group, a benzoyl group, a bivaloyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a thioacetyl group, and a thiobenzoyl group. The force according to any one of the items 1 to 3.

[5] The method according to any one of claims 1 to 3, wherein the asil group is at least one selected from the group power consisting of a acetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, and a thioacetyl group. the method of.

6. The method according to claim 1, wherein the basic ion exchange resin is a strongly basic type or a weakly basic type.

[7] The method according to any one of [1] to [5], wherein the basic ion exchange resin is of a strongly basic type.

8. The method according to any one of claims 1 to 7, wherein the contact between the organic compound and the basic ion exchange resin is carried out in the presence of a solvent. The method according to claim 8, wherein the solvent is alcohol or water or a mixture thereof.

10. A process according to claim 9 which is said alcohol methanol.