TW201629077A

TW201629077A - Ascorbic acid derivative and glycoside production method using same

Info

Publication number: TW201629077A
Application number: TW104134562A
Authority: TW
Inventors: Keiko Shimamoto; Tatsuo Matsuoka
Original assignee: Suntory Holdings Ltd
Priority date: 2014-10-21
Filing date: 2015-10-21
Publication date: 2016-08-16
Also published as: CN106795129A; JP6691483B2; WO2016063896A1; JPWO2016063896A1

Abstract

Provided is an ascorbic acid derivative that can be used to obtain a glycoside of which ascorbic acid is the aglycone. The abovementioned derivative is the compound represented by formula (A) (i.e., 2,3,6-tri-O-acyl-ascorbic acid). (In the formula, R1 indicates an acyl group.)

Description

抗壞血酸衍生物及使用該衍生物的配醣體之製造方法 Ascorbic acid derivative and method for producing glycoside using the same

本發明係關於新穎抗壞血酸衍生物、使用該衍生物將抗壞血酸作為糖苷配基的配醣體[2-O-(β-D-吡喃葡萄糖基)抗壞血酸等]之製造方法、及新穎配醣體。 The present invention relates to a novel ascorbic acid derivative, a method for producing a glycoside [2-O-(β-D-glucopyranosyl)ascorbic acid or the like using ascorbate as an aglycone, and a novel glycoside .

下述式所示2-O-(β-D-吡喃葡萄糖基)抗壞血酸係作為維生素原C之有用化合物，依據該優良性質，可適用於化妝品、醫藥部外品、醫藥品、食品等種種領域中而被檢討(專利文獻1)。 The 2-O-(β-D-glucopyranosyl)ascorbic acid represented by the following formula is a useful compound of provitamin C, and can be applied to various cosmetics, pharmaceutical products, pharmaceuticals, foods, and the like according to the excellent properties. It is reviewed in the field (Patent Document 1).

專利文獻1中揭示2-O-(β-D-吡喃葡萄糖基)抗壞血酸係由將中間體之2-O-(2,3,4,6-四-O-醯基-β-D-吡喃葡萄糖基)抗壞血酸經鹼水解後而得(即下述步驟)。 Patent Document 1 discloses that 2-O-(β-D-glucopyranosyl)ascorbic acid is derived from 2-O-(2,3,4,6-tetra-O-indenyl-β-D- as an intermediate. Pyran Glucosyl) Ascorbic acid is obtained by alkaline hydrolysis (ie, the following step).

(式中，各R各獨立為碳數1~5的烷基)。 (wherein each R is independently an alkyl group having 1 to 5 carbon atoms).

而該文獻中記載上述中間體可經由下述步驟所製造。 However, it is described in the literature that the above intermediate can be produced by the following procedure.

(1)將5,6-異亞丙基抗壞血酸的第3位羥基藉由溴化苯甲基使其苯甲基醚化，可得到3-O-苯甲基-5,6-O-異亞丙基抗壞血酸之步驟 (式中，Bn為苯甲基)。 (1) The 3rd hydroxyl group of 5,6-isopropylidene ascorbic acid is benzylated by bromination of a benzyl group to obtain 3-O-benzyl-5,6-O- Steps of propylene ascorbic acid (wherein Bn is a benzyl group).

(2)將3-O-苯甲基-5,6-O-異亞丙基抗壞血酸與2,3,4,6-四-O-醯基-β-D-吡喃葡萄糖基碳酸酯(烷基、被鹵化的烷基、可被取代的芳基碳酸酯)在非極性溶劑中，或者在無溶劑以100~200℃進行加熱的步驟 (式中，R’為烷基、經鹵化的烷基、或可被取代的芳基，Bn及R與前述相同)。 (2) 3-O-Benzyl-5,6-O-isopropylidene ascorbic acid and 2,3,4,6-tetra-O-mercapto-β-D-glucopyranosyl carbonate ( Alkyl, halogenated alkyl, aryl carbonate which may be substituted) in a non-polar solvent or in a solvent-free manner at 100 to 200 ° C (wherein R' is an alkyl group, a halogenated alkyl group, or an aryl group which may be substituted, and Bn and R are the same as defined above).

(3)將2-O-(2,3,4,6-四-O-醯基-β-D-吡喃葡萄糖基)-3-O-苯甲基-5,6-O-異亞丙基抗壞血酸的異亞丙基以酸觸媒進行水解除去後得到2-O-(2,3,4,6-四-O-醯基-β-D-吡喃葡萄糖基)-3-O-苯甲基抗壞血酸之步驟 (式中，Bn及R與前述相同)。 (3) 2-O-(2,3,4,6-tetra-O-indolyl-β-D-glucopyranosyl)-3-O-benzyl-5,6-O-iso The isopropylidene group of propyl ascorbic acid is hydrolyzed by an acid catalyst to obtain 2-O-(2,3,4,6-tetra-O-indolyl-β-D-glucopyranosyl)-3- O-Benzyl ascorbic acid step (wherein Bn and R are the same as described above).

(4)將2-O-(2,3,4,6-四-O-醯基-β-D-吡喃葡萄糖基)-3-O-苯甲基抗壞血酸的苯甲基進行氫化分解之步驟 (式中，Bn及R與前述相同)。 (4) Hydrogenation of benzyl of 2-O-(2,3,4,6-tetra-O-indolyl-β-D-glucopyranosyl)-3-O-benzyl ascorbic acid step (wherein Bn and R are the same as described above).

然而，在上述一連串2-O-(β-D-吡喃葡萄糖基)抗壞血酸之製造步驟中具有必須經改善之點。 However, there is a point that must be improved in the above-described series of production steps of 2-O-(β-D-glucopyranosyl)ascorbic acid.

例如在步驟(1)中，雖抗壞血酸的第3位羥基必須經苯甲基醚化，該反應的選擇性並非高，第2位及第3位雙方羥基經苯甲基醚化的化合物或於第2位碳由苯甲基所取代的二羰基體等會副產生。 For example, in the step (1), although the hydroxyl group at the 3rd position of ascorbic acid must be etherified with benzyl, the selectivity of the reaction is not high, and the compounds of both the 2nd and 3rd hydroxyl groups are benzylated or The dicarbonyl group in which the second carbon is substituted by a benzyl group may be produced by-product.

又，在步驟(2)中，因使用第5,6位經對酸不安定的丙酮基所保護之化合物(3-O-苯甲基-5,6-O-異亞丙基抗壞血酸)，無法使用廣泛使用於配醣化反應之酸觸媒，在反應必須經100~200℃之加熱。在如此高溫之加熱，尤其設定在如工業上規模等大規模之步驟時，由難以控制在均勻溫度之觀點來看，或能量或裝置之要求性能的觀點來看不能言為較佳狀況。 Further, in the step (2), the compound (3-O-benzyl-5,6-O-isopropylidene ascorbic acid) protected by the acid-unstable acetone group at the 5th, 6th position is used. It is not possible to use an acid catalyst widely used in the saccharification reaction, and the reaction must be heated at 100 to 200 °C. Heating at such a high temperature, especially when set to a large-scale step such as industrial scale, cannot be said to be preferable from the viewpoint of difficulty in controlling the uniform temperature or the required performance of energy or equipment.

且，在步驟(2)中，因僅有β配置之碳酸酯進行反應，必須保持開始原料之β配置下製造碳酸酯，不得不使用高價且對環境負荷高之試藥(溴化氫、碳酸銀)。 Further, in the step (2), since the reaction is carried out only by the carbonate having a β arrangement, it is necessary to maintain the carbonate in the β configuration of the starting material, and it is necessary to use a reagent which is expensive and has a high environmental load (hydrogen bromide, carbonic acid). silver).

[先行技術文獻] [Advanced technical literature] [專利文獻] [Patent Literature]

[專利文獻1]專利第4713832號公報(請求項、段落[0024]~[0029]、實施例) [Patent Document 1] Patent No. 4713832 (Request, paragraph [0024] to [0029], Example)

本發明之目的為提供一種新穎抗壞血酸衍生物及其製造方法。 It is an object of the present invention to provide a novel ascorbic acid derivative and a process for its production.

本發明之其他目的為提供一種將抗壞血酸作為糖苷配基的配醣體可有效率地製造的方法。 Another object of the present invention is to provide a method for efficiently producing a glycoside having ascorbic acid as an aglycone.

本發明之另一其他目的為提供一種將抗壞血酸作為糖苷配基的新穎配醣體。 Another additional object of the present invention is to provide a novel glycoside having ascorbic acid as an aglycone.

本發明者們，欲解決上述課題進行詳細檢討結果，將抗壞血酸的四醯化物使用鹼(第2級胺等)進行脫醯化時，意外地發現第3位的醯化物以高選擇性下被脫醯化，得到新穎抗壞血酸衍生物(僅抗壞血酸之第2、5及6位被醯化的化合物)(以特高產率下得到)、又將如此新穎抗壞血酸衍生物作為原料所得之特定苯甲基醚體(抗壞血酸的第5及6位經醯化，第3位經苯甲基醚化、第2位經脫醯化的化合物)對於酸為安定，在酸之存在下，若與糖供體(例如糖的亞胺酸酯體等)可有效率地進行反應(糖苷鍵)時，進一步藉由可成為藉由酸可使其亞胺酸酯活性化，作為糖供體，不僅使用β端基異構體(β體)，即使亦使用α端基異構體(α體)的亞胺酸酯，作為配醣體只有1,2-反式異構體(例如β糖苷或β半乳糖苷)可選擇性地獲得，進一步重複檢討的結果，完成本發明。 In order to solve the above problems, the inventors of the present invention conducted a detailed review and found that the tetraterpene of ascorbic acid was deuterated using a base (second-order amine or the like), and it was unexpectedly found that the third-order telluride was highly selective. Destaining, obtaining a novel ascorbic acid derivative (a compound which is deuterated at the 2nd, 5th and 6th positions of ascorbic acid only) (obtained in a very high yield), and thus is novelly resistant The specific benzyl ether body obtained by using the ascorbic acid derivative as a raw material (the 5th and 6th positions of ascorbic acid are deuterated, the 3rd position is benzyl etherified, and the 2nd depurinated compound) is Stabilization, in the presence of an acid, if it is efficiently reacted (glycosidic bond) with a sugar donor (for example, a imidate body of a sugar), it can be further made to be an imidic acid by an acid. The ester is activated, and as a sugar donor, not only the β anomer (β-form) but also the imidate of the α-anomer (α-form) is used, and only 1,2- as a glycoside. The trans isomer (e.g., β-glycoside or β-galactoside) can be selectively obtained, and the results of the review are further repeated to complete the present invention.

即，本發明之化合物(抗壞血酸衍生物)為下述式(A)。 That is, the compound of the present invention (ascorbic acid derivative) is represented by the following formula (A).

(式中，R¹表示醯基)所示。 (wherein R ¹ represents a fluorenyl group) is shown.

本發明為含有使用鹼，將下述式(A’)。 (式中，R¹與前述相同)。 The present invention contains the use of a base and the following formula (A'). (wherein R ¹ is the same as described above).

所示化合物經脫醯化處理(詳細為於式(A’)所示化合物的第2位所取代的基-OR¹經選擇性脫醯化)，製造前述式(A)所示化合物(抗壞血酸衍生物)之方法。 The compound shown in the above formula (A) is produced by a depurination treatment (specifically, the group -OR ¹ substituted at the second position of the compound represented by the formula (A') is selectively depurinated) (ascorbic acid) Method of derivative).

對於如此抗壞血酸之製造方法，鹼可為第2級胺(例如N-單取代哌嗪)。又，可使用對於前述方法，對於式(A’)所示化合物為當量或幾乎為當量(例如0.8~1.2莫耳當量)之鹼。 For the production method of such ascorbic acid, the base may be a second-order amine (for example, N-monosubstituted piperazine). Further, a base which is equivalent or almost equivalent (e.g., 0.8 to 1.2 mol equivalent) to the compound represented by the formula (A') can be used.

又，本發明亦含有製造下述式(1)。 Further, the present invention also encompasses the production of the following formula (1).

(式中，Su表示自糖除去糖苷性羥基之基)。 (In the formula, Su represents a group from which a glycosidic hydroxyl group is removed from a sugar).

所示化合物或其衍生物(配醣體)的方法，其為含有使下述式(B) (式中，R²表示芳基甲基，R¹與前述相同)。 A method of expressing a compound or a derivative thereof (glycoside) which comprises the following formula (B) (wherein R ² represents an arylmethyl group, and R ¹ is the same as defined above).

所示化合物與下述式(C) 【化11】ASu-X (C) (式中，ASu表示自經醯化的糖除去糖苷性羥基之基，X表示脫離基)。 The compound shown is of the following formula (C) [11] ASu-X (C) (wherein ASu represents a group from which a glycosidic hydroxyl group is removed from a deuterated sugar, and X represents a leaving group).

所示化合物進行反應，得到下述式(D) (式中，R¹、R²及ASu與前述相同)。 The compound shown is reacted to give the following formula (D) (wherein R ¹ , R ² and ASu are the same as defined above).

所示化合物之糖基化步驟與使式(D)所示化合物的基R¹及基R²進行脫離的脫離步驟之製造方法。 A method of producing a saccharification step of the compound shown, and a detachment step of removing the group R ¹ and the group R ^{2 of the} compound of the formula (D).

該方法(配醣體之製造方法)亦可含有進一步將前述式(A)所示化合物與芳基甲基化劑(例如苯甲基鹵化物等芳基甲基鹵化物)進行反應後，使用鹼進行脫醯化處理，製造式(B)所示化合物之步驟(芳基甲基化．脫醯化步驟)。 This method (method for producing a glycoside) may further comprise reacting a compound represented by the above formula (A) with an arylmethylating agent (for example, an arylmethyl halide such as a benzyl halide). The step of dehydrocycling the base to produce a compound of the formula (B) (aryl methylation. depurination step).

且，藉由與芳基甲基鹵化物之反應，可得到前述式(A)所示化合物之芳基甲基化物，即下述式(B’)所示化合物。 (式中，R¹及R²與前述相同)。 Further, an arylmethyl compound of the compound represented by the above formula (A), that is, a compound represented by the following formula (B') can be obtained by a reaction with an arylmethyl halide. (wherein R ¹ and R ^{2 are the} same as defined above).

對於芳基甲基化．脫醯化步驟，式(C)所示化合物可特別為α體與β體之混合物。本發明中，即使使用如此混合物，亦可將最終生成物之配醣體作為1,2-反式異構體獲得。 For aryl methylation. In the depurination step, the compound of the formula (C) may specifically be a mixture of an alpha body and a beta body. In the present invention, even if such a mixture is used, the glycoside of the final product can be obtained as the 1,2-trans isomer.

又，對於前述式(C)，X例如可為亞胺酸酯基(2,2,2-三氯乙醯亞胺基氧基等)。 Further, for the above formula (C), X may be, for example, an imidate group (2,2,2-trichloroacetamidooxy group or the like).

本發明之方法(配醣體之製造方法)為可進一步含有使用鹼，將下述式(C’)。 The method of the present invention (method for producing a glycoside) may further contain a base using the following formula (C').

【化14】ASu-OR¹ (C') (式中，R¹及ASu與前述相同)。 [Chem. 14] ASu-OR ¹ (C') (wherein R ¹ and ASu are the same as described above).

所示化合物進行脫醯化處理，得到下述式(C”)。 The compound shown is subjected to a deuteration treatment to give the following formula (C").

【化15】ASu-OH (C") (式中，ASu與前述相同)。 [15] ASu-OH (C") (wherein ASu is the same as described above).

所示化合物之步驟、及將前述式(C”)所示化合物與對應脫離基X之化合物進行反應得到前述式(C)所示化合物之步驟。 The step of the compound shown and the step of reacting the compound of the above formula (C)) with a compound corresponding to the leaving group X to obtain the compound of the above formula (C).

對於如此方法，式(C’)所示化合物可為α體與β體之混合物。又，鹼可為第2級胺(N-單取代哌嗪等)。 For such a method, the compound of the formula (C') may be a mixture of an alpha body and a beta body. Further, the base may be a second-order amine (N-monosubstituted piperazine or the like).

於本發明之方法(配醣體之製造方法)中，在酸之存在下，可使式(B)所示化合物與式(C)所示化合物進行反應。又，將式(B)所示化合物與式(C)所示化合物之反應可在非加熱下進行。 In the method of the present invention (method for producing a glycoside), a compound represented by the formula (B) and a compound represented by the formula (C) can be reacted in the presence of an acid. Further, the reaction of the compound of the formula (B) with the compound of the formula (C) can be carried out without heating.

且，對於本發明之方法(配醣體之製造方法)，可含有脫離步驟為將式(D)所示化合物進行氫化處理，得到下述式(E) (式中，R¹及ASu與前述相同)。 Further, the method of the present invention (method for producing a glycoside) may include a step of removing the compound represented by the formula (D) by hydrogenation to obtain the following formula (E). (wherein R ¹ and ASu are the same as described above).

所示化合物之步驟、及將式(E)所示化合物經脫醯化處理後得到式(1)所示化合物之步驟。 The step of the compound shown and the step of deprotecting the compound of the formula (E) to give a compound of the formula (1).

對於本發明之方法，糖例如可為單糖(例如葡萄糖、半乳糖等己糖)。 For the method of the present invention, the sugar may be, for example, a monosaccharide (e.g., hexose such as glucose or galactose).

於本發明中含有前述抗壞血酸衍生物以外，亦含有本發明之方法中所製造的所謂新穎化合物(配醣體、配醣體之前驅體或中間體等)。且，如此新穎化合物，非必要為藉由前述方法所製造者。 In addition to the aforementioned ascorbic acid derivative in the present invention, a so-called novel compound (glycoside, glycoside precursor or intermediate, etc.) produced in the method of the present invention is also contained. Moreover, such novel compounds are not necessarily those manufactured by the aforementioned methods.

如此新穎化合物，特別含有新穎配醣體。如此配醣體對於式(1)，其為Su非D-葡萄糖之糖的化合物，例如可為下述式(1B)。 Such novel compounds, in particular, contain novel glycosides. Glycosome The compound of the formula (1) which is Su non-D-glucose sugar can be, for example, the following formula (1B).

所示化合物或其衍生物。 A compound or derivative thereof.

又，於本發明中含有前述式(1)所示化合物或其衍生物。如此化合物或其衍生物一般可藉由前述方法獲得。 Further, in the present invention, the compound represented by the above formula (1) or a derivative thereof is contained. Such a compound or a derivative thereof can generally be obtained by the aforementioned method.

且，本發明含有具有前述式(1)所示化合物或其衍生物之組成物。如此組成物，例如可為飲食品、醫藥品、醫藥部外品、化妝品等。 Further, the present invention contains a composition having the compound represented by the above formula (1) or a derivative thereof. Such a composition can be, for example, foods and drinks, pharmaceuticals, pharmaceutical products, cosmetics, and the like.

且，又本發明中含有混合前述式(1)所示化合物或其衍生物與組成物之構成成分(其他成分)，製造前述組成物之方法。 Further, in the present invention, a method of producing the above-mentioned composition by mixing a compound represented by the above formula (1) or a derivative thereof and a constituent component (other component) of the composition.

本發明中，可將抗壞血酸的四醯化物之第3位進行選擇性脫醯化。因此，在本發明中可得到新穎抗壞血酸衍生物(即，抗壞血酸的第2、5及第6位經醯化之新穎抗壞血酸衍生物)。 In the present invention, the third position of the tetraterpene of ascorbic acid can be selectively depurated. Therefore, novel ascorbic acid derivatives (i.e., the second, fifth, and sixth positions of ascorbic acid) can be obtained in the present invention. Ying ascorbic acid derivatives).

如此衍生物在有效率地製造將抗壞血酸作為糖苷配基的新穎配醣體(於抗壞血酸的第2位有糖鍵結(糖苷鍵)之配醣體)為有用。 Such a derivative is useful for efficiently producing a novel glycoside having ascorbate as an aglycone (a glycoside having a sugar bond (glycosidic bond) at the second position of ascorbic acid).

又，在本發明可提供將抗壞血酸作為糖苷配基之新穎配醣體。如此配醣體為於抗壞血酸之第2位具有非過去β-D-葡萄糖的糖(例如半乳糖)作為糖苷鍵之新穎結構，與2-O-(β-D-吡喃葡萄糖基)抗壞血酸同樣地，作為維生素原C為有用的化合物。因此，適用於化妝品、醫藥部外品、醫藥品、食品等種種領域。 Further, in the present invention, a novel glycoside having ascorbic acid as an aglycone can be provided. Such a glycoside is a novel structure having a sugar (for example, galactose) which is not a past β-D-glucose at the second position of ascorbic acid as a glycosidic bond, and is the same as 2-O-(β-D-glucopyranosyl)ascorbic acid. It is a useful compound as provitamin C. Therefore, it is suitable for various fields such as cosmetics, pharmaceutical products, pharmaceuticals, and food.

[實施發明之形態] [Formation of the Invention] <抗壞血酸衍生物(2,5,6-三-O-醯基抗壞血酸)> <ascorbic acid derivative (2,5,6-tri-O-decyl ascorbic acid)>

本發明之化合物(抗壞血酸衍生物)為下述式(A)所示。即，本發明之抗壞血酸衍生物為，僅抗壞血酸的第2、5及6位被醯化(醯基酯化)的化合物(2,5,6-三-O-醯基抗壞血酸)。 The compound of the present invention (ascorbic acid derivative) is represented by the following formula (A). That is, the ascorbic acid derivative of the present invention is a compound (2,5,6-tri-O-indenyl ascorbic acid) which is deuterated (mercaptoesterified) only at the 2nd, 5th and 6th positions of ascorbic acid.

(式中，R¹表示醯基)。 (wherein R ¹ represents a fluorenyl group).

對於上述式(A)，作為醯基R¹為，自作為含氧酸之羧酸除去羥基的基，例如可舉出脂肪族醯基[例如烷醯基(例如甲醯基、乙醯基、丙醯基、丁醯基等C_1-10烷醯基，較佳為C_1-6烷醯基，更佳為C_1-4烷醯基)等飽和脂肪族醯基]、芳香族醯基[例如芳醯基(例如苯甲醯基等C_6-10芳醯基)]等可舉出。又，於醯基中亦含有自作為含氧酸的非羧酸(磺酸、磷酸等)除去羥基的基[例如烷烴磺醯基(例如甲烷磺醯基)等]。 In the above formula (A), the thiol group R ¹ is a group from which a hydroxyl group is removed from a carboxylic acid as an oxo acid, and examples thereof include an aliphatic fluorenyl group (for example, an alkyl fluorenyl group (for example, a fluorenyl group, an ethyl fluorenyl group, a C _1-10 alkyl fluorenyl group such as a propyl fluorenyl group or a butyl fluorenyl group, preferably a C _1-6 alkano fluorenyl group, more preferably a C _1-4 alkyl fluorenyl group; a saturated aliphatic fluorenyl group; An aryl group (for example, a C _6-10 aryl fluorenyl group such as a benzamidine group) can be exemplified. Further, a group in which a hydroxyl group is removed from a non-carboxylic acid (sulfonic acid, phosphoric acid or the like) as an oxo acid (for example, an alkanesulfonyl group (for example, methanesulfonyl group) or the like) is also contained in the mercapto group.

彼等中，以烷醯基等脂肪族醯基為佳，特佳為乙醯基。 Among them, an aliphatic fluorenyl group such as an alkyl fluorenyl group is preferred, and an ethoxy group is particularly preferred.

且，對於前述式(A)，3個R¹可為相同或相異的醯基，一般可為相同醯基。 Further, for the above formula (A), the three R ^{1 's} may be the same or different fluorenyl groups, and may generally be the same fluorenyl group.

於代表性抗壞血酸衍生物中含有即第2、5及6位的3個R¹皆為乙醯基的化合物(即，2,5,6-三-O-乙醯抗壞血酸)。 Among the representative ascorbic acid derivatives, three compounds in which R ¹ is at the 2nd, 5th, and 6th positions are acetyl groups (that is, 2,5,6-tri-O-acetylascorbic acid).

如此抗壞血酸衍生物，例如如作為配醣體中之糖苷配基或其前驅體(中間體)為有用。例如如此抗壞血酸衍生物為僅於第3位具有羥基，故可有效率地於第3位鍵結糖[單糖(葡萄糖、半乳糖等)等後述糖](配醣化)。特別為本發明之抗壞血酸衍生物如後述，作為式(1)所示特定之化合物(即，於抗壞血酸的第2位鍵結糖之配醣體)的原料(中間體、前驅體)為有用。 Such an ascorbic acid derivative is useful, for example, as an aglycone in a glycoside or a precursor (intermediate) thereof. For example, since the ascorbic acid derivative has a hydroxyl group only at the third position, it is possible to efficiently bind a sugar (monosaccharide (glucose, galactose, etc.) or the like described later) to the third position (glycation). In particular, the ascorbic acid derivative of the present invention is useful as a raw material (an intermediate or a precursor) of a specific compound represented by the formula (1) (that is, a glycoside of a second-bonded sugar of ascorbic acid).

[抗壞血酸衍生物之製造方法] [Method for producing ascorbic acid derivative]

抗壞血酸衍生物雖無特別限定，例如可將下述式(A’)所示化合物(即，2,3,5,6-四-O-醯基抗壞血酸)(詳細為下述式(A’)所示化合物的第3位所取代的基-OR¹)進行脫醯化(脫醯化處理)而製造。 The ascorbic acid derivative is not particularly limited, and for example, a compound represented by the following formula (A') (that is, 2,3,5,6-tetra-O-indenyl ascorbic acid) can be used (detailed by the following formula (A') The group -OR ¹ ) substituted at the third position of the compound shown is produced by depurination (depuration treatment).

(式中，R¹與前述相同)。 (wherein R ¹ is the same as described above).

對於上述式(A’)，R¹與前述式(A)相同。於作為代表性化合物(A’)中含有第2,3,5及6位的4個R¹皆為乙醯基的化合物(即，2,3,5,6-四-O-醯基抗壞血酸)。 For the above formula (A'), R ¹ is the same as the above formula (A). In the representative compound (A'), four compounds in which R ^{1 is} in the 2nd, 3rd, 5th, and 6th positions are acetyl groups (ie, 2,3,5,6-tetra-O-indenyl ascorbic acid) ).

(式(A’)所示化合物之製造方法) (Method for producing a compound represented by formula (A'))

式(A’)所示化合物為可藉由將抗壞血酸(L-抗壞血酸)與醯化劑進行反應而得。 The compound of the formula (A') can be obtained by reacting ascorbic acid (L-ascorbic acid) with a deuteration agent.

作為醯化劑，對應基R¹的醯化劑，例如可舉出酸酐(例如乙酸酐等)、酸鹵化物(例如乙酸氯化物等)、酸酯等。醯化劑可單獨或組合2種以上使用。 The halogenating agent corresponding to the group R ¹ may, for example, be an acid anhydride (for example, acetic anhydride or the like), an acid halide (for example, acetic acid chloride or the like), an acid ester or the like. The oxime agents may be used singly or in combination of two or more.

醯化劑之使用比例為抗壞血酸的4個羥基皆為可進行醯化(醯基酯化)之範圍即可，例如對於抗壞血酸1莫耳而言為4莫耳以上(例如4~10莫耳)。 The use ratio of the deuteration agent is such that the four hydroxyl groups of ascorbic acid are in the range of deuteration (mercaptoesterification), for example, 4 mol or more for ascorbic acid 1 mol (for example, 4 to 10 mol) .

且，反應可配合醯化劑種類等在無溶劑中進行，亦可在溶劑(後述溶劑等)中進行。 Moreover, the reaction can be combined with the type of oximation agent in a solvent-free manner. This can also be carried out in a solvent (solvent or the like described later).

抗壞血酸與醯化劑之反應可在酸觸媒(例如硫酸、鹽酸、硝酸等無機酸等)的存在下進行。又，反應可在加溫下[例如反應溫度50℃以上(例如60~180℃，較佳為80~150℃)，更佳在100~140℃]下進行。又，反應可在攪拌下進行，亦可在空氣中或惰性環境(氮、稀有氣體等)中進行。 The reaction of ascorbic acid with a oximation agent can be carried out in the presence of an acid catalyst such as a mineral acid such as sulfuric acid, hydrochloric acid or nitric acid. Further, the reaction can be carried out under heating (e.g., a reaction temperature of 50 ° C or higher (e.g., 60 to 180 ° C, preferably 80 to 150 ° C), more preferably 100 to 140 ° C]. Further, the reaction can be carried out under stirring or in an air or an inert environment (nitrogen, rare gas, etc.).

反應時間並無特別限定，例如1分鐘以上(例如2分鐘~48小時)，較佳為3分鐘以上(例如4分鐘~24小時)，更佳為5分鐘以上(例如10分鐘~12小時)程度亦可。且，使用薄層層析法(TLC)等慣用方法可確認反應之進行。 The reaction time is not particularly limited, and is, for example, 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), and more preferably 5 minutes or longer (for example, 10 minutes to 12 hours). Also. Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

且，反應混合物(含有式(A’)所示化合物之混合物)無須經分離(或回收)，可直接提供於後述脫醯化反應，亦可經分離(或回收)。 Further, the reaction mixture (mixture containing the compound of the formula (A')) is not required to be isolated (or recovered), and may be directly supplied to the deuteration reaction described later or may be isolated (or recovered).

自反應混合物的分離(或純化)可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。 The separation (or purification) of the reaction mixture can be carried out by a conventional method (e.g., filtration, extraction, concentration, washing, sorption, membrane separation, chromatography, etc.).

(脫醯化) (dissociation)

式(A’)所示化合物的脫醯化(脫醯化反應)通常可使用鹼進行(或與鹼進行反應)。 The depurination (depurification reaction) of the compound represented by the formula (A') can be usually carried out using a base (or reacting with a base).

作為鹼，可舉出有機鹼[胺類、烷氧化物(例如鹼金屬烷氧化物(例如鈉甲氧化物、鈉異丙氧化物等鈉烷氧化物)等金屬烷氧化物)等]、無機鹼[例如碳酸鹽(例如碳酸鈉、碳酸鉀等碳酸鹼金屬鹽或碳酸鹼土類金屬鹽)的弱酸鹽等]等。特別作為鹼，由純化觀點等來看，以使用胺類為較佳。本發明中，除例外，在抗壞血酸的第2位醯基之脫醯化不容易產生，可使第3位醯基在較高選擇性下脫醯化。 Examples of the base include an organic base [amines, alkoxides (for example, metal alkoxides such as alkali metal alkoxides (for example, sodium methoxide or sodium isopropoxide); a base [such as a carbonate (such as carbon) a weak acid salt of an alkali metal carbonate such as sodium carbonate or potassium carbonate or a metal salt of an alkali earth carbonate). Particularly, as the base, it is preferred to use an amine from the viewpoint of purification or the like. In the present invention, the depurination of the second sulfhydryl group of ascorbic acid is not easily generated, and the third sulfhydryl group can be deuterated at a higher selectivity.

作為胺類，可使用第1級胺、第2級胺等，特別以使用第2級胺為佳。 As the amine, a first-order amine, a second-order amine or the like can be used, and in particular, a second-order amine is preferably used.

作為第1級胺，例如可舉出鏈狀脂肪族胺(例如乙基胺、異丙基胺等烷基胺)、芳香脂肪族胺(例如苯甲基胺等)等。 Examples of the first-grade amine include a chain aliphatic amine (for example, an alkylamine such as ethylamine or isopropylamine), an aromatic aliphatic amine (for example, benzylamine), and the like.

又，作為第2級胺，例如可舉出鏈狀胺[例如鏈狀脂肪族胺(例如二異丙基胺等二烷基胺)]、環狀胺[或雜環式胺、例如吡咯烷、吡唑烷、咪唑烷、哌嗪、N-單取代哌嗪(例如1-甲基哌嗪、1-乙基哌嗪等1-烷基哌嗪，較佳為1-C_1-4烷基哌嗪)、嗎啉、硫代嗎啉等單環式胺]等。 Further, examples of the second-order amine include a chain amine (for example, a chain aliphatic amine (for example, a dialkylamine such as diisopropylamine)], a cyclic amine [or a heterocyclic amine such as pyrrolidine. , pyrazolidine, imidazolidine, piperazine, N-monosubstituted piperazine (eg 1-methylpiperazine, 1-ethylpiperazine, etc. 1-alkylpiperazine, preferably 1-C _1-4 alkane Monopiular amines such as piperazine), morpholine, thiomorpholine, and the like.

這些第2級胺之中，特別以具有N-單取代哌嗪(1-烷基哌嗪等)等第3級胺基之第2級胺為佳。使用如次第2級胺時，藉由酸洗淨可容易地回收(純化)生成物(式(A’)所示化合物)(純化)。 Among these second-order amines, a second-order amine having a third-order amine group such as N-monosubstituted piperazine (1-alkylpiperazine or the like) is particularly preferred. When a second-order amine is used, the product (the compound represented by the formula (A')) (purified) can be easily recovered (purified) by acid washing.

鹼(胺類等)可單獨或組合2種以上使用。 Alkali (amines, etc.) can be used individually or in combination of 2 or more types.

對於脫醯化，鹼的量可配合鹼種類等做選擇，例如對於式(A’)所示化合物為0.3莫耳當量以上(例如0.4~10莫耳當量)，0.5莫耳當量以上(例如0.6~5莫耳當量)，較佳為0.7莫耳當量以上(例如0.8~3莫耳當量)程度。 For deuteration, the amount of the base may be selected in accordance with the type of the base or the like, and for example, the compound represented by the formula (A') is 0.3 mol equivalent or more (for example, 0.4 to 10 mol equivalent), and 0.5 mol equivalent or more (for example, 0.6). ~5 molar equivalents), preferably more than 0.7 molar equivalents (eg, 0.8 to 3 mole equivalents) degree.

特別為式(A’)所示化合物中使用當量或幾乎為當量的鹼時，可容易產生在第3位之選擇性脫醯化反應。因此，對於式(A’)所示化合物，鹼以使用當量或幾乎當量(例如0.7~1.5莫耳當量，較佳為0.8~1.2莫耳當量，更佳為0.9~1.1莫耳當量，特佳為0.95~1.05莫耳當量)為佳。 Particularly, when an equivalent or almost equivalent base is used for the compound represented by the formula (A'), the selective depurination reaction at the third position can be easily caused. Therefore, for the compound of the formula (A'), the base is used in an equivalent or almost equivalent amount (for example, 0.7 to 1.5 mole equivalents, preferably 0.8 to 1.2 mole equivalents, more preferably 0.9 to 1.1 mole equivalents, particularly preferably It is preferably 0.95 to 1.05 mole equivalent).

且，鹼以使用2當量或幾乎2當量時，可使第2位及第3位進行選擇性脫醯化。即，藉由使用2當量或幾乎2當量時，可有效率地得到下述式(A”)所示化合物(即，5,6-二-O-醯基抗壞血酸)。 Further, when the base is used in an amount of 2 equivalents or almost 2 equivalents, the second and third positions can be selectively deuterated. That is, when 2 equivalents or almost 2 equivalents are used, the compound represented by the following formula (A") (i.e., 5,6-di-O-indenyl ascorbic acid) can be efficiently obtained.

(式中，R¹與前述相同)。 (wherein R ¹ is the same as described above).

脫醯化可在溶劑中進行。作為溶劑，僅為不阻礙脫醯化之溶劑即可，並無特別限定，例如可舉出烴類[例如脂肪族烴類(例如己烷、庚烷、環己烷等)、芳香族烴類(例如苯、甲苯、二甲苯等)等]、鹵化烴類(例如二氯甲烷、氯仿等)、醚類[例如鏈狀醚類(例如二乙基醚等)、環狀醚類(例如四氫呋喃、二噁烷等)等]、醯胺類[例如N-取代醯胺(N,N-二甲基甲醯胺等N-烷基取代烷烴醯胺)]、醇類(例如甲醇、乙醇、異丙醇等鏈烷醇)等。 Depurination can be carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit deodorization, and examples thereof include hydrocarbons (for example, aliphatic hydrocarbons (for example, hexane, heptane, cyclohexane, etc.), and aromatic hydrocarbons. (e.g., benzene, toluene, xylene, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), ethers (e.g., chain ethers (e.g., diethyl ether), cyclic ethers (e.g., tetrahydrofuran) , dioxane, etc.), guanamines [eg N-substituted decylamine (N-alkyl substituted alkane guanamine such as N,N-dimethylformamide)], alcohol Classes (such as alkanols such as methanol, ethanol, isopropanol, etc.).

特別在可進行選擇性脫醯化時，可使用在脫醯化反應為惰性之溶劑(例如烴類、醚類、鹵化烴類等)等為佳。 In particular, when selective dehalation can be carried out, a solvent (for example, a hydrocarbon, an ether or a halogenated hydrocarbon) which is inert to the deuteration reaction can be used.

這些溶劑可單獨或組合2種以上使用。 These solvents may be used alone or in combination of two or more.

使用溶劑時，溶劑的使用量並無特別限定，例如對於式(A’)所示化合物(及鹼)1重量份而言，例如0.5~100重量份，較佳為1~50重量份，更佳為2~30重量份程度。 When a solvent is used, the amount of the solvent to be used is not particularly limited. For example, for 1 part by weight of the compound (and base) represented by the formula (A'), for example, it is 0.5 to 100 parts by weight, preferably 1 to 50 parts by weight, more preferably Good for 2 to 30 parts by weight.

反應可在常溫(或室溫)下，冷卻下或加溫下進行。 The reaction can be carried out at room temperature (or room temperature) under cooling or under heating.

又，反應可在攪拌下進行，亦可在空氣中或惰性環境(氮、稀有氣體等)中進行。 Further, the reaction can be carried out under stirring or in an air or an inert environment (nitrogen, rare gas, etc.).

反應時間並無特別限定，例如為1分鐘以上(例如2分鐘~48小時)、較佳為3分鐘以上(例如4分鐘~24小時)，更佳為5分鐘以上(例如10分鐘~12小時)程度。且，使用薄層層析法(TLC)等慣用方法來確認反應進行。 The reaction time is not particularly limited, and is, for example, 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), and more preferably 5 minutes or longer (for example, 10 minutes to 12 hours). degree. Further, the reaction was confirmed by a conventional method such as thin layer chromatography (TLC).

如上述，得到抗壞血酸衍生物(式(A)所示化合物)。反應混合物(含有式(A)所示化合物之混合物)無需經分離(或回收)，可直接使用於後述反應中進行分離(或回收)。 As described above, an ascorbic acid derivative (a compound represented by the formula (A)) is obtained. The reaction mixture (mixture containing the compound of the formula (A)) is not isolated (or recovered) and can be directly used in the reaction described later for separation (or recovery).

自反應混合物之分離(或純化)中，可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。特別為藉由脫醯化之副產物(羧酸醯胺等)，如前述若使用特定鹼時，可藉由自萃取物的酸洗淨而容易地分離除去。 From the separation (or purification) of the reaction mixture, conventional methods (e.g., filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be utilized. Especially by byproducts of depurination (carboxylic acid amide, etc.), as before When a specific base is used, it can be easily separated and removed by washing with acid from the extract.

<式(1)所示化合物(或其衍生物)及其製造方法> <The compound represented by the formula (1) (or a derivative thereof) and a method for producing the same>

本發明中含有下述式(1)所示化合物或其衍生物(配醣體)。 In the present invention, a compound represented by the following formula (1) or a derivative thereof (glycoside) is contained.

對於上述式(1)，Su為自糖(或糖鎖)除去糖苷性羥基(半縮醛性羥基)之基(殘基)。換言之，基-OSu可為自糖除去構成糖苷性羥基(鍵結於端基異構體碳之羥基)之氫原子的基(殘基)。 In the above formula (1), Su is a group (residue) from which a glycosidic hydroxyl group (hemiacetal hydroxyl group) is removed from a sugar (or a sugar lock). In other words, the base-OSu may be a group (residue) which removes a hydrogen atom constituting a glycosidic hydroxyl group (a hydroxyl group bonded to an anomer carbon) from a sugar.

即，式(1)所示化合物亦可為將抗壞血酸作為糖苷配基之O-糖苷(抗壞血酸的第2位羥基與糖之糖苷性羥基之間進行縮合(糖苷鍵)的配醣體)。 That is, the compound represented by the formula (1) may be an O-glycoside (a glycoside in which a hydroxyl group at the 2nd position of ascorbic acid and a glycosidic hydroxyl group of a sugar are condensed (glycosidic bond)) with ascorbic acid.

對於式(1)，作為對應基Su的糖(即，Su-OHH)，雖無特別限定，可為單糖(單糖類)、寡聚糖、多糖(多糖類)等。且寡聚糖及多糖可為同多糖、雜多糖中任一種。 The sugar (i.e., Su-OHH) as the corresponding group Su in the formula (1) is not particularly limited, and may be a monosaccharide (monosaccharide), an oligosaccharide, a polysaccharide (polysaccharide) or the like. Further, the oligosaccharide and the polysaccharide may be any of a homopolysaccharide and a heteropolysaccharide.

對於單糖，碳數並無特別限定，例如可為戊糖、己糖。又，單糖例如可為呋喃糖或吡喃糖。 For the monosaccharide, the carbon number is not particularly limited, and for example, it may be pentane Sugar, hexose. Further, the monosaccharide may be, for example, a furanose or a pyranose.

具體糖中可舉出單糖[例如戊糖(例如核糖、***糖、木糖、脫氧核糖等)、己糖(例如果糖、塔格糖、阿洛糖、阿卓糖、葡萄糖、甘露糖、半乳糖、鼠李糖、葡萄糖胺、半乳糖胺、葡萄糖醛酸)等]、這些單糖類所鍵結的寡聚糖或多糖[例如二糖(例如麥芽糖、曲二糖、纖維二糖、異麥芽糖、龍膽二糖、乳糖等)等]等。 Specific sugars include monosaccharides [for example, pentose sugars (for example, ribose, arabinose, xylose, deoxyribose, etc.), hexoses (for example, sugar, tagatose, allose, altrose, glucose, mannose, Galactose, rhamnose, glucosamine, galactosamine, glucuronic acid, etc.], oligosaccharides or polysaccharides bound by these monosaccharides [eg disaccharides (eg maltose, kojtose, cellobiose, iso) Maltose, gentiobiose, lactose, etc.), etc.

這些之中，作為代表性糖中含有單糖(例如葡萄糖、半乳糖等己糖)。 Among these, a monosaccharide (for example, hexose such as glucose or galactose) is contained as a representative sugar.

且，糖可為D體、L體、這些混合物中任一種。 Further, the sugar may be a D body, an L body, or any of these mixtures.

又，式(1)所示化合物可為α體(α端基異構體、α-糖苷)、β體(β端基異構體、β-糖苷)、這些混合物中任一種，特別可為β體。本發明中，如後述，作為糖可使用α體或α體與β體之混合物，以得到1,2-反式異構體之式(1)所示化合物的情況為多。 Further, the compound represented by the formula (1) may be an α-form (α-anomer, α-glycoside), a β-form (β-anomer, β-glycoside), or any of these mixtures, and particularly Beta body. In the present invention, as the sugar, an α-form or a mixture of the α-form and the β-form can be used as the sugar to obtain a compound represented by the formula (1) of the 1,2-trans isomer.

例如糖為葡萄糖時，獲得β體，為甘露糖時，獲得α體。 For example, when the sugar is glucose, the β body is obtained, and when it is mannose, the α body is obtained.

作為代表性式(1)所示化合物中，例如含有下述式(1A)所示化合物(對於式(1)，糖為D-葡萄糖之β-糖苷)、下述式(1B)所示化合物(即，對於式(1)，糖為D-半乳糖之β-糖苷)等。 The compound represented by the following formula (1), for example, contains a compound represented by the following formula (1A) (for the formula (1), the sugar is a β-glycoside of D-glucose), and a compound represented by the following formula (1B) (i.e., for the formula (1), the sugar is a β-glycoside of D-galactose) or the like.

式(1)所示化合物中，式(1A)所示化合物(即，對於式(1)，糖為D-葡萄糖之β-糖苷)以外的化合物[例如式(1B)所示化合物]為新穎化合物。因此，本發明中亦含有如此新穎化合物(新穎配醣體)。 Among the compounds represented by the formula (1), a compound other than the compound of the formula (1A) (that is, a compound of the formula (1), wherein the sugar is a D-glucose β-glycoside) [for example, a compound represented by the formula (1B)] is novel. Compound. Therefore, such novel compounds (novative glycosides) are also contained in the present invention.

作為式(1)所示化合物的衍生物，例如式(1)所示化合物的羥基(構成抗壞血酸骨架及糖(Su)骨架之羥基)可舉出形成鹽的化合物(即，式(1)所示化合物的鹽)或於脫離基進行取代的化合物等。作為鹽，例如可舉出金屬鹽(例如鈉鹽、鉀鹽、鈣鹽等鹼或鹼土類金屬鹽)、胺鹽、銨鹽等與鹼之鹽。 The derivative of the compound represented by the formula (1), for example, the hydroxyl group of the compound represented by the formula (1) (the hydroxyl group constituting the ascorbic acid skeleton and the sugar (Su) skeleton) may be a salt-forming compound (that is, the formula (1) A salt of the compound or a compound substituted with a leaving group or the like. The salt may, for example, be a salt of a metal salt (for example, an alkali or alkaline earth metal salt such as a sodium salt, a potassium salt or a calcium salt), an amine salt or an ammonium salt, and a base.

又，作為脫離基，可舉出醯基氧基(例如乙醯氧基、丙醯基氧基、丁醯基氧基、辛醯基氧基、棕櫚醯氧基、硬脂醯基氧基等脂肪族醯基氧基等)等。具有如此醯基氧基的化合物可為式(1)所示化合物的醯化物(醯基酯)。 Further, as the leaving group, a mercaptooxy group (for example, acetamidine) is mentioned. An oxy group, a propyl fluorenyloxy group, a butyl fluorenyloxy group, a decyloxy group, a palmitoyloxy group, an aliphatic decyloxy group such as a stearyl methoxy group, etc.). The compound having such a mercaptooxy group may be a telluride (mercapto ester) of the compound represented by the formula (1).

而本發明之配醣體(式(1)所示化合物或其衍生物)通常可經由將下述式(B)所示化合物與下述式(C)所示化合物進行反應後得到下述式(D)所示化合物之糖基化步驟、與使式(D)所示化合物的基R¹及基R²進行脫離的脫離步驟而製造。 Further, the glycoside of the present invention (the compound represented by the formula (1) or a derivative thereof) can be usually obtained by reacting a compound represented by the following formula (B) with a compound represented by the following formula (C): The glycosylation step of the compound shown in (D) is carried out by a detachment step of separating the group R ¹ and the group R ^{2 of the} compound represented by the formula (D).

(式中，R²表示芳基甲基，R¹與前述相同)。 (wherein R ² represents an arylmethyl group, and R ¹ is the same as defined above).

【化25】ASu-X (C) (式中，ASu表示自經醯化的糖除去糖苷性羥基的基，X表示脫離基)。 [Chem. 25] ASu-X (C) (In the formula, ASu represents a group from which a glycosidic hydroxyl group is removed from a deuterated sugar, and X represents a leaving group).

(式中，R¹、R²及ASu與前述相同)。 (wherein R ¹ , R ² and ASu are the same as defined above).

以下對於製造方法詳細敘述。 The manufacturing method will be described in detail below.

<式(B)所示化合物> <Compound represented by formula (B)>

對於式(B)，R²為芳基甲基。作為芳基甲基(R²)，例如可舉出苯甲基、取代苯甲基[例如烷基苯甲基(例如4-甲基苯甲基等C_1-4烷基苯甲基)等]等。較佳芳基甲基為苯甲基。 For formula (B), R ² is an arylmethyl group. Examples of the arylmethyl group (R ² ) include a benzyl group and a substituted benzyl group (for example, an alkylbenzyl group (for example, a C _1-4 alkylbenzyl group such as 4-methylbenzyl group). ]Wait. Preferred arylmethyl is benzyl.

又，對於式(B)，R¹與前述相同(即，醯基)，較佳態樣亦與前述相同。 Further, with respect to the formula (B), R ¹ is the same as the above (i.e., sulfhydryl group), and the preferred aspect is also the same as described above.

作為代表性的式(B)所示化合物中含有第5及第6位的R¹為乙醯基，R²為苯甲基之化合物(即，3-O-苯甲基-5,6-二-O-乙醯-抗壞血酸)。 As a representative compound of the formula (B), R ¹ in which the 5th and 6th positions are an ethyl fluorenyl group, and R ² is a benzyl group (ie, 3-O-benzyl-5,6-) Di-O-acetamidine-ascorbic acid).

[式(B)所示化合物的製造方法] [Method for Producing Compound of Formula (B)]

式(B)所示化合物，例如可將前述式(A)作為原料(中間體、前驅體)製造。即，式(B)所示化合物為可將式(A)所示化合物與芳基甲基化劑進行反應(芳基甲基化反應)後，經由脫醯化處理(詳細為取代抗壞血酸或式(A)所示化合物的第2位的基-OR¹經脫醯化)步驟(芳基甲基化．脫醯化步驟)而得。 The compound represented by the formula (B) can be produced, for example, from the above formula (A) as a raw material (intermediate, precursor). That is, the compound represented by the formula (B) is obtained by reacting a compound represented by the formula (A) with an arylmethylating agent (arylmethylation reaction), followed by dehalogenation treatment (detailed substitution of ascorbic acid or a formula) The base-OR ¹ at the 2nd position of the compound (A) is subjected to a depurination step (arylmethylation. depurination step).

且，欲得到式(B)所示化合物，可考慮使用僅第5,6位經醯化的抗壞血酸(5,6-二醯基抗壞血酸)。 Further, in order to obtain a compound represented by the formula (B), it is conceivable to use ascorbic acid (5,6-dimercapto ascorbic acid) which is only deuterated at the 5th and 6th positions.

然而，5,6-二醯基抗壞血酸雖為將抗壞血酸與醯化劑 (例如乙酸酐等)進行反應所得之化合物，但將第5及6位以選擇性進行醯化為困難，通常得到含有在第5位或第6位被醯化的抗壞血酸、僅在第3位被醯化的抗壞血酸等副產物之混合物。而自該混合物僅將5,6-二醯基抗壞血酸以選擇性分離為困難。又，即使分離5,6-二醯基抗壞血酸，僅在第3位進行選擇性芳基甲基醚化(苯甲基醚化等)為困難。 However, 5,6-dimercapto ascorbic acid is an ascorbic acid and a sulphurizing agent. (for example, acetic anhydride or the like), the compound obtained by the reaction, but it is difficult to selectively deuterate the 5th and 6th positions, and usually contains ascorbic acid which is deuterated at the 5th or 6th position, and is only in the 3rd position. A mixture of deuterated by-products such as ascorbic acid. It is difficult to selectively separate 5,6-dimercapto ascorbic acid from the mixture. Further, even if 5,6-dimercapto ascorbic acid is isolated, it is difficult to carry out selective arylmethyl etherification (benzyl etherification or the like) only at the third position.

因此，本發明中作為式(B)所示化合物的原料，未使用5,6-二醯基抗壞血酸，使用式(A)所示化合物(2,5,6-三醯基抗壞血酸)。 Therefore, in the present invention, as the raw material of the compound represented by the formula (B), 5,6-dimercapto ascorbic acid is not used, and the compound of the formula (A) (2,5,6-tridecyl ascorbic acid) is used.

作為芳基甲基化劑，例如可舉出芳基甲基鹵化物(或鹵代甲基芳烴，例如氯化苯甲基、溴化苯甲基等苯甲基鹵化物)等對應芳基甲基之試藥。 Examples of the arylmethylating agent include a corresponding aryl group such as an arylmethyl halide (or a halogenated methyl arene such as a benzyl chloride such as benzyl chloride or benzyl bromide). Based on the test.

對於芳基甲基化反應，芳基甲基化劑的使用比例對於式(A)所示化合物1莫耳，例如0.8莫耳以上(例如0.9~10莫耳)，較佳為1莫耳以上(例如1.1~5莫耳)，更佳為1.2莫耳以上(例如1.3~3莫耳)。 For the aryl methylation reaction, the arylmethylating agent is used in a ratio of 1 mole to the compound represented by the formula (A), for example, 0.8 mol or more (for example, 0.9 to 10 mol), preferably 1 mol or more. (for example, 1.1 to 5 m), more preferably 1.2 m or more (for example, 1.3 to 3 m).

芳基甲基化反應可在鹼的存在下進行。作為鹼，例如可舉出碳酸鹽(例如碳酸鈉、碳酸鉀、碳酸銫等碳酸鹼金屬鹽)酸化銀、吡啶類(吡啶、甲基吡啶)等。鹼可單獨或組合2種以上使用。 The aryl methylation reaction can be carried out in the presence of a base. Examples of the base include silver carbonate, pyridine (pyridine, methylpyridine), and the like, which are carbonates (for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, and cesium carbonate). The base may be used singly or in combination of two or more.

鹼的使用比例例如可為對於式(A)所示化合物(或芳基甲基化劑)，例如1莫耳當量以上(例如1~5莫耳當量)。 The proportion of the base to be used may be, for example, a compound represented by the formula (A) (or an arylmethylating agent), for example, 1 molar equivalent or more (for example, 1 to 5 molar equivalents).

又，芳基甲基化反應可在亞硫酸氫鈉(連二亞硫酸鈉)、硫代硫酸鈉等還原劑存在下進行。還原劑的使用比例，例如對於式(A)所示化合物，例如可為1莫耳當量以上(例如1~5莫耳當量)。 Further, the arylmethylation reaction can be carried out in the presence of a reducing agent such as sodium hydrogen sulfite (sodium dithionite) or sodium thiosulfate. The ratio of use of the reducing agent, for example, to the compound represented by the formula (A), may be, for example, 1 mol equivalent or more (for example, 1 to 5 mol equivalent).

且，芳基甲基化反應亦可在溶劑中進行。作為溶劑，可舉出前述例示的溶劑(例如N,N-二甲基甲醯胺等醯胺類)等。 Further, the arylmethylation reaction can also be carried out in a solvent. Examples of the solvent include the above-exemplified solvents (for example, decylamines such as N,N-dimethylformamide).

使用溶劑時，溶劑的使用量並無特別限定，例如對於式(A)所示化合物1重量份，例如1~100重量份，較佳為2~50重量份程度。 When the solvent is used, the amount of the solvent to be used is not particularly limited. For example, 1 part by weight of the compound represented by the formula (A) is, for example, 1 to 100 parts by weight, preferably 2 to 50 parts by weight.

反應可在常溫(或室溫)下、冷卻下或加溫下進行。反應溫度例如為30~150℃，較佳為40~120℃，更佳為50~100℃程度。反應可在攪拌下進行，亦可在空氣中或惰性環境(氮、稀有氣體等)中進行。 The reaction can be carried out at room temperature (or room temperature), under cooling or under heating. The reaction temperature is, for example, 30 to 150 ° C, preferably 40 to 120 ° C, more preferably 50 to 100 ° C. The reaction can be carried out under agitation or in air or in an inert environment (nitrogen, noble gas, etc.).

反應時間例如1分鐘以上(例如1.5分鐘~24小時)，較佳為2分鐘以上(例如3分鐘~12小時)，更佳為5分鐘以上(例如10分鐘~3小時)程度。且，可使用薄層層析法(TLC)等慣用方法，確認反應的進行。 The reaction time is, for example, 1 minute or longer (for example, 1.5 minutes to 24 hours), preferably 2 minutes or longer (for example, 3 minutes to 12 hours), and more preferably 5 minutes or longer (for example, 10 minutes to 3 hours). Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

如上述，得到式(A)所示化合物的芳基甲基化物，即下述式(B’)所示化合物。 As described above, an arylmethyl compound of the compound of the formula (A), which is a compound represented by the following formula (B'), is obtained.

(式中，R¹及R²與前述相同)。 (wherein R ¹ and R ^{2 are the} same as defined above).

且，作為代表性的式(B’)所示化合物中含有第2、5及6位的R¹為乙醯基，R²為苯甲基之化合物(即，3-O-苯甲基-2,5,6-三-O-乙醯-抗壞血酸)。 Further, as a representative compound of the formula (B'), a compound in which R ¹ at the ^2nd , 5th and 6th positions is an ethyl fluorenyl group and R ² is a benzyl group (ie, 3-O-benzyl group- 2,5,6-tri-O-acetamidine-ascorbic acid).

反應混合物(含有式(B’)所示化合物之混合物)無須經分離(或回收)可直接提供於後述反應(脫醯化)，亦可經分離(或回收)。自反應混合物的分離(或純化)可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、層析法等)。 The reaction mixture (mixture containing the compound of the formula (B')) can be directly supplied to the latter reaction (disintegration) without isolation (or recovery), or can be isolated (or recovered). The separation (or purification) of the reaction mixture can be carried out by a conventional method (e.g., filtration, extraction, concentration, washing, sorption, chromatography, etc.).

(脫醯化) (dissociation)

藉由經芳基甲基化後繼續進行脫醯化，可得到式(B)所示化合物。 The compound represented by the formula (B) can be obtained by further depolymerization after arylmethylation.

脫醯化(脫醯化反應)通常可使用鹼進行(或與鹼進行反應)。 The depurination (depurification reaction) can usually be carried out using a base (or reacting with a base).

作為鹼，使用胺類為佳。作為胺類，可舉出前述例示的胺類(例如第2級胺)等。作為胺類，若使用具有N-單取代哌嗪(1-烷基哌嗪等)等第3級胺基之第2級胺時，與前述同樣地，藉由酸洗淨可容易回收(純化)生成物(式(B)所示化合物)。 As the base, an amine is preferably used. Examples of the amines include the above-exemplified amines (for example, second-order amines). When a second-order amine having a third-order amine group such as N-monosubstituted piperazine (1-alkylpiperazine or the like) is used as the amine, it can be easily recovered by acid washing in the same manner as described above (purification) A product (a compound represented by the formula (B)).

對於脫醯化，鹼的量可配合鹼種類等做選擇，例如對於式(A)所示化合物或式(B’)所示化合物為0.5莫耳當量以上(例如0.7~10莫耳當量)、0.8莫耳當量以上(例如0.9~5莫耳當量)，較佳為1莫耳當量以上(例如1~3莫耳當量)程度。 For deuteration, the amount of the base may be selected in accordance with the type of the base or the like, and for example, the compound represented by the formula (A) or the compound represented by the formula (B') is 0.5 mol equivalent or more (for example, 0.7 to 10 mol equivalent), 0.8 molar equivalents or more (e.g., 0.9 to 5 mole equivalents), preferably about 1 mole equivalent or more (e.g., 1 to 3 mole equivalents).

脫醯化可在溶劑中進行。作為溶劑，若不阻礙脫醯化之溶劑即可並無特別限定，可使用前述例示之溶劑等。 Depurination can be carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit the deodorization, and the solvent and the like exemplified above can be used.

且，將芳基甲基化反應混合物直接提供於脫醯化時，可將使用於芳基甲基化反應之溶劑作為在脫醯化之溶劑。 Further, when the arylmethylation reaction mixture is directly supplied to the deuteration, the solvent used in the arylmethylation reaction can be used as a solvent for deuteration.

反應時間雖無特定限定，例如1分鐘以上(例如2分鐘~48小時)，較佳為3分鐘以上(例如4分鐘~24小時)，更佳為5分鐘以上(例如10分鐘~12小時)程度。且，可使用薄層層析法(TLC)等慣用方法確認反應的進行。 The reaction time is not particularly limited, and is, for example, 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), and more preferably 5 minutes or longer (for example, 10 minutes to 12 hours). . Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

如上述，得到式(B)所示化合物。反應混合物(含有式(B)所示化合物之混合物)無須經分離(或回收)，可直接提供於後述反應(糖苷反應)，亦可經分離(或回收)。 The compound represented by the formula (B) is obtained as described above. The reaction mixture (mixture containing the compound of the formula (B)) is not required to be isolated (or recovered), and may be directly supplied to the reaction (glycoside reaction) described later, or may be isolated (or recovered).

在自反應混合物的分離(或純化)中，可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。特別藉由脫醯化之副產物(羧酸醯胺等)如前述，若使用特定鹼時，可藉由自萃取物之酸洗淨而容易地分離除去。 In the separation (or purification) of the reaction mixture, conventional methods (for example, filtration, extraction, concentration, washing, sorption, membrane separation, Chromatography, etc.). In particular, by-deuteration by-product (carboxylic acid decylamine or the like), as described above, when a specific base is used, it can be easily separated and removed by washing with an acid from the extract.

<式(C)所示化合物> <Compound represented by formula (C)>

對於式(C)為自ASu為經醯化(醯基酯化)的糖除去糖苷性羥基(於半縮醛性羥基、端基異構體碳所鍵結的羥基)之基(殘基)。換言之，ASu為，對於在前述式(1)中之基Su，糖苷性羥基以外之所有羥基經醯化的基(或羥基以醯基氧基進行取代之基)。 The formula (C) is a group (residue) in which a glycosidic hydroxyl group (a hydroxyl group bonded to a hemiacetal hydroxyl group or an anomer carbon) is removed from a sugar which is deuterated (mercaptoesterified) from ASu. . In other words, ASu is a group in which all of the hydroxyl groups other than the glycosidic hydroxyl group are deuterated (or a group in which the hydroxyl group is substituted with a mercaptooxy group) in the group Su in the above formula (1).

因此，除經醯化以外，ASu與Su共通，較佳態樣亦與Su之情況相同。 Therefore, in addition to the deuteration, ASu and Su are common, and the preferred aspect is the same as that of Su.

對於經醯化的糖(或醯基氧基)，作為醯基，可例示與前述R¹(乙醯基等)之相同醯基。醯基可為相同或相異的醯基。 With respect to the deuterated sugar (or mercaptooxy group), the same mercapto group as the above R ¹ (ethinyl group or the like) can be exemplified as the mercapto group. The thiol groups can be the same or different sulfhydryl groups.

且，式(C)所示化合物(或基ASu)可為α體(α端基異構體、α-糖苷)、β體(β端基異構體、β-糖苷)、這些混合物中任一種。本發明中，特別由製程效率的觀點來看，使用α體與β體之混合物為佳。 Further, the compound of the formula (C) (or the group ASu) may be an α-form (α-anomer, α-glycoside), a β-form (β-anomer, β-glycoside), or any of these mixtures. One. In the present invention, a mixture of an α body and a β body is preferably used from the viewpoint of process efficiency.

作為具體之基ASu，例如含有下述式(ASu-1)所示基、下述式(ASu-2)所示基(即，對應Su為D-葡萄糖或D-半乳糖之基、四-O-醯基-D-吡喃葡萄糖基、四-O-醯基-D-半乳糖吡喃基)等。 Specific examples of ASu include, for example, a group represented by the following formula (ASu-1) and a group represented by the following formula (ASu-2) (that is, a group corresponding to Su being D-glucose or D-galactose, and four- O-fluorenyl-D-glucopyranosyl, tetra-O-fluorenyl-D-galactopyranoyl) and the like.

(式中，波線表示α體、β體或其混合物，R¹與前述相同)。 (wherein, the wave line represents an α body, a β body or a mixture thereof, and R ¹ is the same as described above).

對於式(C)，基X為脫離基。即，式(C)所示化合物可為於ASu之端基異構體碳鍵結基X之化合物(或ASu的糖苷性羥基由脫離基所取代之化合物)。 For formula (C), base X is a leaving group. That is, the compound represented by the formula (C) may be a compound of the anionic carbon bond group X of ASu (or a compound in which the glycosidic hydroxyl group of ASu is substituted by a leaving group).

作為脫離基X，若可與式(B)所示化合物的羥基(第2位的羥基)進行反應，可形成糖苷鍵之基(活化ASu的端基異構體碳或端基異構體位之基)即可，並無特別限定，例如可舉出亞胺酸酯基{例如2,2,2-三氯乙醯亞胺基氧基(基-O-C(=NH)-CCl₃)、(N-苯基)三氟乙醯亞胺基氧基(基-O-C(=NPh)-CF₃)等}、碳酸酯基(或碳酸酯基、例如2,2,2-三氯乙氧基羰基氧基等)、醯基氧基(例如乙醯氧基等前述基-OR¹所示基)、鹵素原子(氟原子、氯原子、溴原子等)等。 As the leaving group X, if it can react with the hydroxyl group of the compound of the formula (B) (the hydroxyl group at the 2nd position), a glycosidic bond group can be formed (the activated isomer of the terminal isomer carbon or the isomer position of ASu) The base is not particularly limited, and examples thereof include an imidate group (for example, 2,2,2-trichloroacetammineoxy group (yl-OC(=NH)-CCl ₃ ), ( N-phenyl)trifluoroacetamidinooxy (yl-OC(=NPh)-CF ₃ ), etc., carbonate group (or carbonate group, for example 2,2,2-trichloroethoxy) A carbonyloxy group or the like, a mercaptooxy group (for example, a group represented by the above-mentioned group -OR ¹ such as an ethoxy group), a halogen atom (such as a fluorine atom, a chlorine atom or a bromine atom).

彼等中，亞胺酸酯基中，式(C)所示化合物(或ASu)即使為α體、β體中任一種，因與式(B)所示化合物可糖苷鍵結(且可得到1,2-反式異構體)，故作為式(C)所示化合物，使用α體或α體與β體之混合物的情況時為較佳。特別無須使α體與β體分離，故使用α體與β體之混合物為佳。 In the imidate group, the compound represented by the formula (C) (or ASu) may be glycosidically bonded to the compound represented by the formula (B) even if it is any one of the α form and the β form (and can be obtained) When the 1,2-trans isomer is used, it is preferred to use a compound of the formula (C) in the case of using an α-form or a mixture of an α-form and a β-form. In particular, it is not necessary to separate the α body from the β body, so it is preferred to use a mixture of the α body and the β body.

作為代表性的式(C)所示化合物之亞胺酸酯體，例如含有下述式(C1)所示化合物、下述式(C2)所示化合物(即，ASu經醯化的D-葡萄糖或D-半乳糖、X為2-三氯乙醯亞胺基氧基之化合物)等。 The imidate body of the compound represented by the formula (C) includes, for example, a compound represented by the following formula (C1) and a compound represented by the following formula (C2) (that is, D-glucose deuterated by ASu). Or D-galactose, X is a compound of 2-trichloroacetamidooxy group, and the like.

[式(C)所示化合物的製造方法] [Method for Producing Compound of Formula (C)]

式(C)所示化合物可使用販賣品的可獲得者，亦可使用合成(製造)者。 As the compound represented by the formula (C), a commercially available product can be used, and a synthetic (manufacturer) can also be used.

作為式(C)所示化合物的製造方法，並無特別限定，例如可經由將下述式(C’)所示化合物經脫醯化處理(脫醯化)，得到下述式(C”)所示化合物之步驟(脫醯化步驟)、使式(C”)所示化合物與對應脫離基X之化合物進行反應的步驟(脫離基導入步驟)而獲得。 The method for producing the compound represented by the formula (C) is not particularly limited. For example, the compound represented by the following formula (C') can be subjected to a depurination treatment (disintegration) to obtain the following formula (C"). The step of the compound shown (depurification step), the step of reacting the compound of the formula (C") with the compound corresponding to the leaving group X (the leaving group introduction step) is obtained.

且，若式(C’)所示化合物與式(C)所示化合物為相同[即，脫離基X為式(C)中之醯基氧基(-OR¹)]時，無須經由如此步驟。 Further, if the compound represented by the formula (C') is the same as the compound represented by the formula (C) [that is, the leaving group X is a mercaptooxy group (-OR ¹ ) in the formula (C)], there is no need to go through such a step. .

【化30】ASu-OR¹ (C') (式中，R¹及ASu與前述相同)。 [Chem. 30] ASu-OR ¹ (C') (wherein R ¹ and ASu are the same as described above).

【化31】ASu-OH (C") (式中，ASu與前述相同)。 [31] ASu-OH (C") (wherein ASu is the same as described above).

(式(C’)所示化合物) (compound represented by formula (C'))

對於式(C’)，R¹為與前述相同(即，醯基)。如前述，ASu為自經醯化的糖除去糖苷性羥基之基，基-OR¹為醯基氧基(即，醯化或經醯基酯的羥基)。即，式(C’)所示化合物為含有糖苷性羥基之所有的羥基經醯化(醯基酯化)的化合物。 For formula (C'), R ¹ is the same as previously described (ie, fluorenyl). As mentioned above, ASu is a group from which a glycosidic hydroxyl group is removed from a deuterated sugar, and the group -OR ¹ is a mercaptooxy group (i.e., a hydroxyl group of a deuterated or decyl ester). That is, the compound represented by the formula (C') is a compound in which all of the hydroxyl groups having a glycosidic hydroxyl group are deuterated (mercaptoesterified).

且，式(C’)所示化合物如前述所示，可為_α體(α端基異構體、α-糖苷)、β體(β端基異構體、β-糖苷)、對應這些之混合物中任一者的基。本發明中無論α體、β體皆可得到配醣體。 Further, as shown above, the compound represented by the formula (C') may be an _α- form (α-anomer, α-glycoside), a β-form (β-anomer, β-glycoside), or the like. The base of either of the mixtures. In the present invention, a glycoside can be obtained regardless of both the α body and the β form.

作為代表性的式(C’)所示化合物含有下述式(C，1)所示化合物、下述式(C’2)所示化合物[即，ASu經醯化的D-葡萄糖或D-半乳糖、R¹為醯基的化合物(戊-O-醯基-D-葡萄糖、戊-O-醯基-D-半乳糖)]等。 The compound represented by the formula (C') includes a compound represented by the following formula (C, 1) and a compound represented by the following formula (C'2) [ie, ASu-deuterated D-glucose or D- A compound of galactose and R ¹ is a thiol group (pentyl-O-mercapto-D-glucose, pentyl-O-indolyl-D-galactose) and the like.

(式(C’)所示化合物的製造方法) (Method for producing a compound represented by the formula (C'))

式(C’)所示化合物可藉由反應糖與醯化劑而得。 The compound of the formula (C') can be obtained by reacting a sugar with a hydrating agent.

作為糖，可舉出前述例示的糖(例如葡萄糖、半乳糖等單糖)等。且，糖為α體、β體、這些之混合物中任一者皆可。 Examples of the sugar include the sugars exemplified above (for example, monosaccharides such as glucose and galactose). Further, the sugar may be any of an α form, a β form, and a mixture of these.

作為醯化劑，對應基R¹之醯化劑例如可舉出酸酐(例如乙酸酐等)、酸鹵化物(例如乙酸氯化物等)等。醯化劑可為單獨或組合2種以上。 The halogenating agent corresponding to the group R ¹ may, for example, be an acid anhydride (for example, acetic anhydride or the like), an acid halide (for example, acetic acid chloride or the like). The oxime agent may be used alone or in combination of two or more.

醯化劑的使用比例若為糖的所有羥基皆可經醯化(醯基酯化)之範圍者即可，例如對於糖之羥基1莫耳而言可為1莫耳以上(例如1~5莫耳，較佳為1.2~3莫耳)。 The use ratio of the oximation agent may be any range in which all of the hydroxyl groups of the sugar can be deuterated (mercaptoesterification), for example, 1 mol or more for the hydroxyl group 1 of the sugar (for example, 1 to 5) Moor, preferably 1.2 to 3 moles).

且，反應為配合醯化劑之種類等，可在無溶劑中進行，亦可在溶劑(前述溶劑等)中進行。 Further, the reaction may be carried out in a solvent-free manner in combination with a type of the oximation agent, or may be carried out in a solvent (such as the solvent described above).

糖與醯化劑之反應可在鹼[例如弱酸之鹽(乙酸鈉等)、氫氧化物(氫氧化鈉等)]、酸(例如硫酸、鹽酸、硝酸等無機酸等)等存在下進行。 The reaction between the sugar and the oximation agent can be carried out in the presence of a base such as a weak acid salt (sodium acetate or the like), a hydroxide (sodium hydroxide or the like), an acid (for example, a mineral acid such as sulfuric acid, hydrochloric acid or nitric acid).

又，反應亦可在加溫下或迴流下進行。又，反應亦可在攪拌下進行，亦可在空氣中或惰性環境(氮、稀有氣體等)中進行。 Further, the reaction can also be carried out under heating or under reflux. Further, the reaction may be carried out under stirring or in an air or an inert environment (nitrogen, rare gas, etc.).

反應時間並無特別限定，例如為1分鐘以上(例如2分鐘~48小時)，較佳為3分鐘以上(例如4分鐘~24小時)，更佳為5分鐘以上(例如10分鐘~12小時)程度。且可使用薄層層析法(TLC)等慣用方法，確認反應的進行。 The reaction time is not particularly limited, and is, for example, 1 minute or longer (for example, 2 minutes to 48 hours), preferably 3 minutes or longer (for example, 4 minutes to 24 hours), and more preferably 5 minutes or longer (for example, 10 minutes to 12 hours). degree. Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

且，反應混合物(含有式(C’)所示化合物之混合物)無須分離(或回收)後，直接供給於後述脫醯化反應，亦可進行分離(或回收)。 Further, the reaction mixture (mixture containing the compound of the formula (C')) is not required to be separated (or recovered), and is directly supplied to the deuteration reaction described later, and may be isolated (or recovered).

自反應混合物的分離(或純化)，可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。 From the separation (or purification) of the reaction mixture, conventional methods (e.g., filtration, extraction, concentration, washing, sorption, membrane separation, chromatography, etc.) can be utilized.

如上述，得到式(C’)所示化合物。作為糖，使用α體與β體之混合物時(進一步僅使用α體或β體時)，於式(C’)所示化合物亦可得到α體與β體之混合物。 The compound represented by the formula (C') is obtained as described above. When a mixture of an α body and a β body is used as the sugar (when only the α body or the β body is used), the compound represented by the formula (C') can also give a mixture of the α body and the β body.

且，如此混合物可藉由再結晶等方法，分離α體與β體，在本發明中，無須進行如此分離，可直接將混合物供給於後述脫醯化。 Further, in such a mixture, the α body and the β body can be separated by a method such as recrystallization, and in the present invention, the mixture can be directly supplied to the subsequent depurination without being so separated.

(脫醯化步驟) (dissociation step)

式(C’)所示化合物的脫醯化(脫醯化反應)通常可使用鹼進行(或與鹼進行反應)。 The depurination (depurification reaction) of the compound of the formula (C') can usually be carried out using a base (or reacting with a base).

作為鹼，使用胺類、醯肼(乙酸醯肼等羧酸醯肼)等為佳。作為胺類，可舉出前述例示之胺類(例如第2級胺)等。作為胺類，若使用N-單取代哌嗪(1-烷基哌嗪等)等具有第3級胺基的第2級胺時，與前述同樣地，藉由酸洗淨容易回收(純化)生成物(式(C”)所示化合物)。 As the base, an amine, ruthenium (ruthenium carboxylate such as ruthenium acetate) or the like is preferably used. Examples of the amines include the above-exemplified amines (for example, a second-order amine). When a second-order amine having a third-order amine group such as N-monosubstituted piperazine (1-alkylpiperazine or the like) is used as the amine, it is easily recovered (purified) by acid washing in the same manner as described above. Product (compound represented by formula (C")).

對於脫醯化，鹼之量可配合鹼之種類等進行選擇，例如對於式(C’)所示化合物為0.5莫耳當量以上(例如0.7~10莫耳當量)、0.8莫耳當量以上(例如0.9~5莫耳當量)，較佳為1莫耳當量以上(例如1~3莫耳當量)程度。 For deuteration, the amount of the base can be selected in accordance with the type of the base or the like, and for example, the compound represented by the formula (C') is 0.5 mol equivalent or more (for example, 0.7 to 10 mol equivalent) and 0.8 mol equivalent or more (for example, 0.9 to 5 mole equivalents, preferably about 1 mole equivalent or more (for example, 1 to 3 mole equivalents).

脫醯化可在溶劑中進行。作為溶劑，僅不阻礙脫醯化的溶劑即可，並無特別限定，可使用前述例示之溶劑等。 Depurination can be carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit the deodorization, and the solvent and the like exemplified above can be used.

反應可在常溫(或室溫)下、冷卻下或加溫下進行。 The reaction can be carried out at room temperature (or room temperature), under cooling or under heating.

反應時間雖無特別限定，例如1分鐘以上(例如2分鐘~72小時)，較佳為5分鐘以上(例如10分鐘~48小時)，更佳為30分鐘以上(例如1~36小時)程度。且可使用薄層層析法(TLC)等慣用方法，確認反應的進行。 The reaction time is not particularly limited, and is, for example, 1 minute or longer (for example, 2 minutes to 72 hours), preferably 5 minutes or longer (for example, 10 minutes to 48 hours), and more preferably 30 minutes or longer (for example, 1 to 36 hours). Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

如上述，得到式(C”)所示化合物。反應混合物(含有式(C”)所示化合物之混合物)無須經分離(或回收)，可直接供給於後述反應，亦可經分離(或回收)。 The compound represented by the formula (C") is obtained as described above. The reaction mixture (mixture of the compound represented by the formula (C") does not need to be separated (or recovered), and may be directly supplied to the reaction described later, or may be isolated (or recovered). ).

在自反應混合物之分離(或純化)中，可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。特別藉由脫醯化之副產物(羧酸醯胺等)如前述若使用特定鹼，可自萃取物藉由酸洗淨而容易地分離除去。 In the separation (or purification) from the reaction mixture, conventional methods (e.g., filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.) can be utilized. In particular, a by-product of depurination (melamine amide or the like) can be easily separated and removed from the extract by acid washing if a specific base is used as described above.

且，作為代表性的式(C”)所示化合物含有下述式(C”1)所示化合物、下述式(C”2)所示化合物(即，ASu為經醯化的D-葡萄糖或D-半乳糖之化合物)等。 Further, the compound represented by the formula (C") includes a compound represented by the following formula (C"1) and a compound represented by the following formula (C"2) (that is, ASu is a deuterated D-glucose). Or a compound of D-galactose).

(脫離基導入步驟) (disengagement base import step)

在脫離基導入步驟中，將式(C”)所示化合物與對應脫離基X之化合物進行反應。 In the leaving group introduction step, the compound of the formula (C") is reacted with a compound corresponding to the leaving group X.

作為對應脫離基X之化合物，僅可將前述脫離基與式(C”)所示化合物進行反應導入脫離基X之化合物即可，例如可舉出亞胺酸酯基導入劑(例如三氯乙腈等)、碳酸酯基導入劑(例如氯甲酸2,2,2-三氯乙基(TrocCl)等)、鹵素導入劑(例如氯化氫、溴化氫等鹵化氫)等。 As the compound corresponding to the leaving group X, only the compound having the above-mentioned leaving group and the compound of the formula (C)) can be introduced into the compound of the leaving group X, and examples thereof include an imido ester group introducing agent (for example, trichloroacetonitrile). And the like, a carbonate-based introducing agent (for example, 2,2,2-trichloroethyl chloroformate (TrocCl) or the like), a halogen introducing agent (for example, hydrogen halide such as hydrogen chloride or hydrogen bromide), or the like.

對應脫離基X的化合物之使用比例，例如對於式(C”)所示化合物1莫耳而言為1莫耳以上(例如1~5莫耳，較佳為1.2~3莫耳)。 The ratio of use of the compound corresponding to the leaving group X is, for example, 1 mole or more (for example, 1 to 5 moles, preferably 1.2 to 3 moles) of the compound 1 mole represented by the formula (C").

反應為配合對應脫離基X之化合物的種類等，可在鹼之存在進行。作為鹼(或鹼觸媒)為前述例示之鹼，例如可舉出胺(第2級胺等)、吡啶類、碳酸鹽等。 The reaction can be carried out in the presence of a base in accordance with the type of the compound corresponding to the leaving group X and the like. The base (for the base catalyst) is exemplified as the base, and examples thereof include an amine (such as a second-order amine), a pyridine or a carbonate.

鹼的使用比例例如對於式(C”)所示化合物1莫耳而言為0.01莫耳當量以上(例如0.05~3莫耳當量，較佳為0.1~2莫耳當量，更佳為0.2~1.5莫耳當量)。 The ratio of use of the base is, for example, 0.01 mole equivalent or more (for example, 0.05 to 3 mole equivalents, preferably 0.1 to 2 mole equivalents, more preferably 0.2 to 1.5) for the compound 1 mole represented by the formula (C"). Moer equivalent).

反應可在溶劑中進行。作為溶劑，若為不阻礙反應之溶劑即可，並無特別限定，可使用前述例示之溶劑(例如鹵化烴類)等。 The reaction can be carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and the above-exemplified solvents (for example, halogenated hydrocarbons) can be used.

如上述，得到式(C)所示化合物。反應混合物(含有式(C)所示化合物之混合物)無須經分離(或回收)，可直接供給於後述反應(糖苷反應)，亦可經分離(或回收)。 The compound represented by the formula (C) is obtained as described above. The reaction mixture (mixture containing the compound of the formula (C)) is not required to be isolated (or recovered), and may be directly supplied to the reaction (glycoside reaction) described later, or may be isolated (or recovered).

自反應混合物之分離(或純化)可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。 Separation (or purification) from the reaction mixture can utilize conventional methods (eg Filtration, extraction, concentration, washing, sorption, membrane separation, chromatography, etc.).

<糖基化步驟> <Glycosylation step>

在糖基化步驟中，將式(B)所示化合物與式(C)所示化合物進行反應可得到式(D)所示化合物。且使用於反應的式(C)所示化合物與前述相同，可為α體、β體、這些之混合物中任一種。 In the glycosylation step, a compound of the formula (B) is reacted with a compound of the formula (C) to give a compound of the formula (D). Further, the compound represented by the formula (C) used in the reaction may be any of the α form, the β form, and a mixture thereof, as described above.

對於糖基化步驟，式(B)所示化合物與式(C)所示化合物之使用比例，例如為式(B)所示化合物/式(C)所示化合物(莫耳比)=1/0.5~1/2，較佳為1/0.7~1/1.5，更佳為1/0.8~1/1.2程度。 For the glycosylation step, the ratio of the compound represented by the formula (B) to the compound represented by the formula (C) is, for example, a compound represented by the formula (B) / a compound represented by the formula (C) (mole ratio) = 1 / 0.5 to 1/2, preferably 1/0.7 to 1/1.5, more preferably 1/0.8 to 1/1.2.

糖基化步驟特別可在、酸(酸觸媒)之存在下進行。式(B)所示化合物因對於酸為安定，故在本發明中可進行在酸存在下之糖基化反應。因此，在高反應效率下可進行糖基化。 The glycosylation step can be carried out in particular in the presence of an acid (acid catalyst). Since the compound represented by the formula (B) is stable against an acid, the glycosylation reaction in the presence of an acid can be carried out in the present invention. Therefore, glycosylation can be carried out under high reaction efficiency.

作為酸，可舉出質子酸{例如無機酸[例如鹵化氫(氯化氫、溴化氫、碘化氫等)、硫酸、硝酸、磷酸等]、有機酸[例如羧酸類(例如甲酸、乙酸、三氟乙酸等)、磺酸類(例如甲磺酸、三氟甲磺酸)]等}、磺酸酯類(例如三氟甲磺酸三甲基矽基等三氟甲磺酸酯類)、路易氏酸{例如硼錯體[例如三氟化硼錯體(例如三氟化硼二乙基醚錯體、三氟化硼單烷基胺錯體、三氟化硼水合物等)]等非金屬錯體；金屬烷氧基化物[例如鋁烷氧化物(三乙氧基鋁等)、鈦烷氧化物(四乙氧基鈦等)、鋯烷氧化物(四丁氧基鋯等)等]、金屬鹵化物(例如氯化鐵、氯化鋅、氯化鋁、四氯鈦)、金屬三氟甲磺酸酯、金屬乙醯丙酮根等金屬錯體(或金屬化合物)等}等。酸可為單獨或組合2種以上。 Examples of the acid include protic acids {for example, inorganic acids [for example, hydrogen halide (hydrogen chloride, hydrogen bromide, hydrogen iodide, etc.), sulfuric acid, nitric acid, phosphoric acid, etc.], organic acids [for example, carboxylic acids (for example, formic acid, acetic acid, three). Fluoroacetic acid, etc., sulfonic acid (for example, methanesulfonic acid, trifluoromethanesulfonic acid), etc., sulfonate (for example, trifluoromethanesulfonate such as trimethylsulfonyl trifluoromethanesulfonate), Louis Acid {e.g., boron complex (e.g., boron trifluoride complex (e.g., boron trifluoride diethyl ether complex, boron trifluoride monoalkylamine complex, boron trifluoride hydrate, etc.)] Metal complex; metal alkoxylate [such as aluminum alkoxide (triethoxy aluminum, etc.), titanium alkoxide (tetraethoxy titanium, etc.), zirconium alkoxide (tetrabutoxide) Zirconium, etc.), metal halides (such as ferric chloride, zinc chloride, aluminum chloride, titanium tetrachloride), metal triflate, metal acetoacetate, etc. (or metal compounds) )and many more. The acid may be used alone or in combination of two or more.

酸的使用比例可配合酸之種類等做適宜選擇，例如對於式(B)所示化合物(或式(C)所示化合物)1莫耳為0.001莫耳當量以上(例如0.001~2莫耳當量，較佳為0.005~1莫耳當量，更佳為0.01~0.5莫耳當量)，通常可為0.001~0.3莫耳當量(例如0.01~0.2莫耳當量)。 The ratio of use of the acid can be appropriately selected in accordance with the type of the acid, etc., for example, the compound represented by the formula (B) (or the compound represented by the formula (C)) has a molar amount of 0.001 mol or more (for example, 0.001 to 2 mol equivalents). Preferably, it is 0.005 to 1 mole equivalent, more preferably 0.01 to 0.5 mole equivalent, and usually 0.001 to 0.3 mole equivalent (e.g., 0.01 to 0.2 mole equivalent).

反應可在溶劑中進行。作為溶劑，若為不阻礙反應之溶劑即可，可使用前述例示之溶劑(例如鹵化烴類)等。 The reaction can be carried out in a solvent. As the solvent, a solvent (for example, a halogenated hydrocarbon) exemplified above may be used as long as it does not inhibit the reaction.

反應可在常溫(或室溫)下、冷卻下或加溫下進行。特別在本發明中，可使用酸觸媒，故在非加熱下(常溫或冷卻下)進行反應，亦可有效率地進行糖基化反應。因此，在本發明中，例如為40℃以下(例如-20℃~35℃)，較佳為30℃以下(例如-10℃~25℃)程度之反應溫度下可進行反應。 The reaction can be carried out at room temperature (or room temperature), under cooling or under heating. In particular, in the present invention, since an acid catalyst can be used, the reaction can be carried out under non-heating (at normal temperature or under cooling), and the glycosylation reaction can be carried out efficiently. Therefore, in the present invention, for example, the reaction can be carried out at a reaction temperature of, for example, 40 ° C or lower (for example, -20 ° C to 35 ° C), preferably 30 ° C or lower (for example, -10 ° C to 25 ° C).

反應時間雖無特別限定，例如1分鐘以上(例如2分鐘~48小時)，較佳為5分鐘以上(例如10分鐘~24小時)，更佳為20分鐘以上(例如30分鐘~12小時)程度。且可使用薄層層析法(TLC)等慣用方法，確認反應的進行。 The reaction time is not particularly limited, and is, for example, 1 minute or longer (for example, 2 minutes to 48 hours), preferably 5 minutes or longer (for example, 10 minutes to 24 hours), and more preferably 20 minutes or longer (for example, 30 minutes to 12 hours). . Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

如上述得到式(D)所示化合物。反應混合物(含有式(D)所示化合物之混合物)無須經分離(或回收)，可直接供給於後述反應，亦可經分離(或回收)。 The compound of the formula (D) is obtained as described above. The reaction mixture (mixture containing the compound of the formula (D)) is not required to be isolated (or recovered), and may be directly supplied to the reaction described later or may be isolated (or recovered).

特別欲除去糖苷反應之副產物(例如三氯乙醯胺等)，可將反應混合物進行鹼洗淨。 In particular, to remove by-products of the glycoside reaction (e.g., trichloroacetamide, etc.), the reaction mixture can be washed with an alkali.

又，在反應混合物含有未反應之對應脫離基X之化合物(例如三氯乙腈等)時，可藉由再結晶[例如在醇(甲醇等)中之再結晶]，分離(純化)生成物(式(D)所示化合物)。 Further, when the reaction mixture contains an unreacted compound corresponding to the leaving group X (for example, trichloroacetonitrile or the like), the product can be separated (purified) by recrystallization (for example, recrystallization in an alcohol (methanol or the like)] ( a compound of the formula (D)).

且，如前述，式(C)所示化合物可為α體、β體、這些之混合物中任一種，對於使用這些任一種時，通常可得到1,2-反式異構體之式(D)所示化合物。 Further, as described above, the compound represented by the formula (C) may be an α form, a β form, or a mixture of these, and when any of these is used, a formula of the 1,2-trans isomer is usually obtained (D). ) the compound shown.

作為代表性的式(D)所示化合物中含有下述式(D1)所示化合物、下述式(D2)所示化合物(即，ASu經醯化的D-葡萄糖或D-半乳糖之化合物)等。 The compound represented by the following formula (D) contains a compound represented by the following formula (D1) and a compound represented by the following formula (D2) (that is, a compound of D-glucose or D-galactose deuterated by ASu). )Wait.

<脫離步驟> <out step>

在脫離步驟，使式(D)所示化合物的基R¹及基R²脫離。脫離(脫離反應)中基R¹與基R²之脫離順序並無特別限定，將基R¹及基R²中任一方的基經脫離後，另一方的基亦可脫離，亦可將基R¹及R²同時(或同一反應系)脫離。 In the detachment step, the group R ¹ and the group R ^{2 of the} compound represented by the formula (D) are removed. The order of detachment of the group R ¹ from the group R ^{2 in} the detachment (desorption reaction) is not particularly limited, and when one of the groups R ¹ and R ² is removed, the other group may be detached or may be substituted. R ¹ and R ^{2 are} simultaneously (or the same reaction system) detached.

特別於脫離基R²後，亦可將基R¹脫離。以如此順序進行脫離後，可有效率地抑制副產物(或雜質)之生成等。 In particular, after the radical R ^{2 is} removed, the radical R ¹ can also be detached. After the detachment is performed in this order, the formation of by-products (or impurities) and the like can be efficiently suppressed.

[基R²的脫離(氫化處理步驟)] [Departing from the group R ² (step hydrogenation process)]

對於式(D)所示化合物，基R²之脫離方法雖無特別限定，例如可舉出將式(D)所示化合物進行氫化處理(氫化分解)之方法。 The method for removing the group R ² from the compound represented by the formula (D) is not particularly limited, and examples thereof include a method of subjecting the compound represented by the formula (D) to hydrogenation treatment (hydrogenation decomposition).

氫化處理可將式(D)所示化合物與氫(氫氣)進行反應(接觸)下進行。 Hydrogenation can introduce the compound of formula (D) with hydrogen (hydrogen) Perform the reaction (contact).

氫化處理可在觸媒之存在下進行。作為觸媒為金屬觸媒(或金屬錯體)，例如可舉出含有鈀、鎳、釕、銥、鉑、銠等過渡金屬之觸媒[特別為鈀/碳等貴金屬(特別為鉑族金屬)觸媒]等。 The hydrogenation treatment can be carried out in the presence of a catalyst. The catalyst is a metal catalyst (or a metal complex), and examples thereof include a catalyst containing a transition metal such as palladium, nickel, rhodium, ruthenium, platinum, or rhodium (particularly a noble metal such as palladium/carbon (particularly a platinum group metal). ) Catalyst] and so on.

又，氫化處理為欲促進反應，亦可在酸之存在下進行。作為酸，可舉出前述例示的酸，例如羧酸類(例如乙酸等)等。 Further, the hydrogenation treatment may be carried out in the presence of an acid in order to promote the reaction. Examples of the acid include the above-exemplified acids, for example, carboxylic acids (for example, acetic acid).

反應可在溶劑中進行。作為溶劑，若不阻礙反應之溶劑即可，並無特別限定，可使用前述例示之溶劑(例如醚類、醇類)等。 The reaction can be carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit the reaction, and the above-exemplified solvents (for example, ethers, alcohols) and the like can be used.

反應可在常溫(或室溫)下、冷卻下或加溫下進行。又，反應可在攪拌下進行。 The reaction can be carried out at room temperature (or room temperature), under cooling or under heating. Further, the reaction can be carried out under stirring.

反應時間雖無特別限定，例如10分鐘以上(例如30分鐘~10日)，較佳為1小時以上(例如2小時~5日)，更佳為3小時以上(例如5~36小時)程度。且可使用薄層層析法(TLC)等慣用方法，確認反應的進行。 The reaction time is not particularly limited, and is, for example, 10 minutes or longer (for example, 30 minutes to 10 days), preferably 1 hour or longer (for example, 2 hours to 5 days), and more preferably 3 hours or longer (for example, 5 to 36 hours). Further, the progress of the reaction can be confirmed by a conventional method such as thin layer chromatography (TLC).

如上述得到生成物。反應混合物(例如含有生成物之混合物)無須經分離(或回收)，可直接供給於後述反應，亦可經分離(或回收)。 The resultant was obtained as described above. The reaction mixture (for example, a mixture containing the product) may be directly supplied to the reaction described later or may be isolated (or recovered) without being separated (or recovered).

且，將基R¹的脫離比基R²的脫離更先進行時，作為生成物可得到下述式(E)所示化合物。 Further, when the detachment of the group R ¹ is performed earlier than the detachment of the group R ² , a compound represented by the following formula (E) can be obtained as a product.

(式中，R¹及ASu與前述相同)。 (wherein R ¹ and ASu are the same as described above).

特別作為代表性的式(E)所示化合物中，含有下述式(E1)所示化合物、下述式(E2)所示化合物(即，ASu為經醯化的D-葡萄糖或D-半乳糖之化合物)等。 Particularly, the compound represented by the formula (E) contains a compound represented by the following formula (E1) and a compound represented by the following formula (E2) (that is, ASu is deuterated D-glucose or D-half Lactose compounds) and the like.

(式中，R¹與前述相同)。 (wherein R ¹ is the same as described above).

[基R¹之脫離(脫醯化步驟)] [Separation of the base R ¹ (dissociation step)]

對於式(D)所示化合物(或式(E)所示化合物)，基R¹的脫離(脫醯化)方法雖無特別限定，例如可將式(D)所示化合物使用鹼進行脫醯化。 With respect to the compound represented by the formula (D) (or the compound represented by the formula (E)), the detachment (depurification) method of the group R ¹ is not particularly limited, and for example, the compound represented by the formula (D) can be desorbed using a base. Chemical.

作為鹼，例如弱酸之鹽(例如碳酸鹽(例如碳酸鉀等前述例示之碳酸鹽))、胺(前述例示之胺等)、氫氧化物(例如氫氧化鈉、氫氧化鉀等鹼或鹼土類金屬氫氧化物)等。鹼可單獨或組合2種以上使用。 As a base, such as a salt of a weak acid (such as a carbonate (such as carbonic acid) The above-exemplified carbonates such as potassium), amines (such as the above-exemplified amines), hydroxides (for example, alkali or alkaline earth metal hydroxides such as sodium hydroxide or potassium hydroxide), and the like. The base may be used singly or in combination of two or more.

脫醯化可在溶劑中進行。作為溶劑，若為不阻礙脫醯化之溶劑即可，並無特別限定，可使用前述例示之溶劑(例如醇等)等。 Depurination can be carried out in a solvent. The solvent is not particularly limited as long as it does not inhibit deodorization, and the solvent (for example, an alcohol or the like) exemplified above can be used.

如上述得到式(1)所示化合物。且，藉由使用的鹼之種類或純化方法，式(1)所示化合物有時可以鹽(例如鹼金屬鹽)等衍生物之形態獲得。 The compound represented by the formula (1) is obtained as described above. Further, the compound represented by the formula (1) may be obtained in the form of a derivative such as a salt (for example, an alkali metal salt) by the type of the base to be used or the purification method.

自反應混合物之式(1)所示化合物的分離(或純化)可利用慣用方法(例如過濾、萃取、濃縮、洗淨、吸著、膜分離、層析法等)。 The separation (or purification) of the compound represented by the formula (1) from the reaction mixture can be carried out by a conventional method (e.g., filtration, extraction, concentration, washing, adsorption, membrane separation, chromatography, etc.).

且，式(1)所示化合物的衍生物可藉由慣用方法獲得。例如鹽為可反應式(1)所示化合物與對應鹼[例如鹼或鹼土類金屬氫氧化物(氫氧化鈉等)、胺、氨等]後得到。又，醯化物可藉由將式(1)所示化合物與所對應的醯化劑(例如乙酸酐、丙酸酐等酸酐、酸鹵化物等)進行反應而得。 Further, a derivative of the compound represented by the formula (1) can be obtained by a conventional method. For example, the salt is obtained by reacting a compound represented by the formula (1) with a corresponding base [for example, an alkali or alkaline earth metal hydroxide (sodium hydroxide or the like), an amine, ammonia, or the like]. Further, the hydrazine compound can be obtained by reacting the compound represented by the formula (1) with the corresponding hydrazine. A chemical agent (for example, an acid anhydride such as acetic anhydride or propionic anhydride, or an acid halide) is obtained by a reaction.

<式(1)所示化合物(或其衍生物)之用途> <Use of the compound represented by the formula (1) (or a derivative thereof)>

本發明之配醣體(即，前述式(1)所示化合物或其衍生物)可利用於種種用途上。且配醣體亦可為藉由前述方法所製造者。 The glycoside of the present invention (i.e., the compound represented by the above formula (1) or a derivative thereof) can be utilized in various uses. The glycoside may also be produced by the aforementioned method.

如此配醣體可構成組成物。作為如此組成物(或配醣體)之用途，例如可舉出飲食物、醫藥、醫藥部外品、化妝品等。 Such a glycoside can constitute a composition. Examples of the use of the composition (or glycoside) include foods and drinks, medicines, pharmaceutical products, cosmetics, and the like.

作為飲食物(飲食品)，例如可舉出食品、飲料、調味料、功能食品(功能性食品)、健康食品、營養補助食品、特定保健用食品、補充劑等。 Examples of the foods and drinks (food and drink) include foods, beverages, seasonings, functional foods (functional foods), health foods, nutritional supplement foods, foods for specific health care, and supplements.

作為具體的飲食物，例如可舉出飴、片劑、口香糖、優格、霜淇淋、布丁、果凍、水羊羹、醇飲料、咖啡飲料、果汁、果實飲料、碳酸飲料、清涼飲料、牛乳、乳清飲料、乳酸菌飲料等，粉末[例如用時溶解用粉末(例如亦可為溶解於咖啡、紅茶、果汁、優格、湯等之粉末、混合於料理後使用的粉末等)]。 Specific foods and drinks include, for example, alfalfa, tablets, chewing gum, yogurt, cream, pudding, jelly, watery alpaca, alcoholic beverages, coffee drinks, fruit juices, fruit drinks, carbonated drinks, refreshing drinks, and milk. A whey drink, a lactic acid bacteria drink, or the like, and a powder (for example, a powder for dissolution in use (for example, a powder dissolved in coffee, black tea, fruit juice, yogurt, soup, or the like, mixed with a powder used after cooking, etc.)].

醫藥及醫藥部外品，例如可為經口劑(例如錠劑、膠囊劑、顆粒劑、散劑、糖漿劑、提取劑等)、外用劑或非經口劑(例如軟膏、眼軟膏、乳化劑、乳霜、貼付劑、塞劑、點眼劑、點鼻劑、注射劑等)等形態。外用劑可為皮膚用、非皮膚用中任一種，皮膚用外用劑例如含有洗顏料、石鹸、口腔用保養製品(洗口液、牙膏粉等)、洗髮精、潤髮精、護髮乳、髮乳霜、整髮料、髮水、育毛．羊毛料、化妝水、乳液、乳霜等。 The external products of the Ministry of Medicine and Medicine may be, for example, oral preparations (such as tablets, capsules, granules, powders, syrups, extractants, etc.), external preparations or parenteral preparations (such as ointments, eye ointments, emulsifiers). , creams, patches, plugs, eye drops, nose drops, injections, etc.). The external preparation may be either skin or non-skin, and the external preparation for skin contains, for example, Washing pigments, sarcophagi, oral maintenance products (washing liquid, toothpaste powder, etc.), shampoo, conditioner, hair care lotion, hair cream, hair styling, hair styling, hair growth. Wool, lotion, lotion, cream, etc.

且，組成物不限使用於人類，亦可使用於動物用組成物[例如動物用飲食品(例如寵物用飲食物、家畜用飼料等)等]。 Further, the composition is not limited to humans, and may be used for animal compositions (for example, animal foods and drinks (for example, pet foods, livestock feeds, etc.)).

作為組成物之構成成分[前述配醣體以外的成分(其他成分)]，可配合組成物之用途或形態做適宜選擇，例如可舉出糖類或甜味料(葡萄糖、果糖、蔗糖、麥芽糖、山梨醇、甜菊苷、甜茶苷、玉米糖漿、乳糖、甘露醇等)、酸味料(檸檬酸、酒石酸、蘋果酸、琥珀酸、乳酸等)、油脂(植物油、動物油等)、蠟(羊毛脂、蜂蠟等)、烴(或石蠟、白色凡士林等)、脂肪酸、脂質(神經醯胺等)、醇(乙醇等)、多元醇(丙二醇、1,3-丁二醇、聚乙二醇、甘油等)、高級醇、酯(甘油脂肪酸酯、聚甘油脂肪酸酯、蔗糖脂肪酸酯、山梨糖醇脂肪酸酯、丙二醇脂肪酸酯等)、胺基酸、肽或蛋白質質(膠原肽、彈力蛋白肽、蛋白多醣、酪蛋白、明膠等)、纖維素、纖維素衍生物(羧基甲基纖維素等纖維素醚類)、澱粉(玉米澱粉等)、澱粉加工物(糊精等)、礦物質成分(鈣鹽類等)、維他命類[維他命B類(菸鹼酸醯胺、泛酸鈣等)、L-抗壞血酸、dl-α-生育酚等]、海藻酸鹽(海藻酸鈉等)、***樹膠、卡拉膠、果膠、乳成分、果汁、咖啡萃取物、寒天、界面活性劑、保濕劑、美白劑、色素、著色劑、顏料、營養強化劑、香料、植物．動物萃取成分(例如由黃芩、月見草、甘蔗等植物原料所得之萃取物或粉碎物)、紫外線吸收劑、抗酸化劑(異抗壞血酸鈉等)、抗氧化劑、保存劑、防腐．殺菌劑、滑澤劑(硬脂酸鎂、棕櫚酸鎂等)、消臭成分[例如掩蔽劑、吸著劑、多孔質材料、消臭劑(例如抗酸化劑、脂氧合酶阻礙劑、抗菌劑、掩蔽．Harmonium Hivernage香料、乙醇胺等)等]、具有各種藥理作用之物質{例如具有自律神經調節作用之物質(交感神經作用物質、副交感神經作用物質等)、具有血壓降低作用之物質、具有抗肥胖作用之物質[具有食欲抑制系刺激作用之物質、對飽腹中樞具有作用之物質、與能量代謝相關的物質(例如β3受體作用物質、具有能量消費促進作用之物質)等]}等。 The constituent component of the composition [component (other component) other than the above-mentioned glycoside) can be appropriately selected depending on the use or form of the composition, and examples thereof include sugars or sweeteners (glucose, fructose, sucrose, maltose, and the like). Sorbitol, stevioside, sweet tea, corn syrup, lactose, mannitol, etc.), sour materials (citric acid, tartaric acid, malic acid, succinic acid, lactic acid, etc.), oils (vegetable oil, animal oil, etc.), wax (lanolin, Beeswax, etc., hydrocarbons (or paraffin, white petrolatum, etc.), fatty acids, lipids (neuroguanamine, etc.), alcohols (ethanol, etc.), polyols (propylene glycol, 1,3-butylene glycol, polyethylene glycol, glycerol, etc.) ), higher alcohols, esters (glycerol fatty acid esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitol fatty acid esters, propylene glycol fatty acid esters, etc.), amino acids, peptides or proteinaceous (collagen peptides, elastic Protein peptide, proteoglycan, casein, gelatin, etc.), cellulose, cellulose derivatives (cellulose ethers such as carboxymethyl cellulose), starch (corn starch, etc.), starch processed products (dextrin, etc.), ore Material composition (calcium salts, etc.), vitamins [vitamins] Class B (nicotinic acid amide, calcium pantothenate, etc.), L-ascorbic acid, dl-α-tocopherol, etc.], alginate (sodium alginate, etc.), gum arabic, carrageenan, pectin, milk ingredients, juice , coffee extract, cold weather, surfactants, moisturizers, whitening agents, pigments, colorants, pigments, nutritional supplements, spices, plants . Animal extract components (such as extracts or pulverized materials obtained from plant materials such as scutellaria, evening primrose, sugar cane), ultraviolet absorbers, acidulant (sodium erythorbate, etc.), antioxidants, preservatives, and antiseptic. A bactericide, a slip agent (magnesium stearate, magnesium palmitate, etc.), a deodorizing component [for example, a masking agent, a sorbent, a porous material, a deodorant (for example, an acid-proofing agent, a lipoxygenase inhibitor, Antibacterial agent, masking, Harmonium Hivernage, ethanolamine, etc.], substances having various pharmacological effects, such as substances having autonomic nervous regulation (sympathetic substances, parasympathetic substances, etc.), substances having a blood pressure lowering effect, A substance having an anti-obesity effect [a substance having an appetite suppressant stimulating effect, a substance having an effect on a satiety center, a substance related to energy metabolism (for example, a substance acting on a β3 receptor, a substance having an energy consumption promoting effect), etc.] Wait.

這些其他成分可為單獨或組合2種以上。 These other components may be used alone or in combination of two or more.

對於組成物，本發明之配醣體的比例可配合組成物之用途或形態做適宜選擇，例如以固體成分(或乾燥重量)換算下為0.0001~90重量%，較佳為0.0005~50重量%，更佳為0.001~10重量%程度。 For the composition, the ratio of the glycoside of the present invention can be appropriately selected in accordance with the use or form of the composition, for example, 0.0001 to 90% by weight, preferably 0.0005 to 50% by weight, based on the solid content (or dry weight). More preferably, it is 0.001 to 10% by weight.

且，組成物之用量可配合對象年齡、體重、健康狀態等做適宜選擇，例如本發明之配醣體的人類成人每1天的攝取量為1~5000mg，較佳為10~3000mg，更佳為30~1000mg程度。 Moreover, the amount of the composition can be appropriately selected according to the age, body weight, and health state of the subject. For example, the human adult of the glycoside of the present invention has an intake of 1 to 5000 mg per day, preferably 10 to 3000 mg, more preferably. It is 30~1000mg.

且，組成物可藉由前述配醣體與其他成分的混合而製造。又，與混合同時，亦可利用公知方法，成形為種種形態。 Further, the composition can be produced by mixing the aforementioned glycoside with other components. Further, it can be molded into various forms by a known method at the same time as mixing.

例如組成物的形態若為粉末時，亦可使用常用賦形劑(例如糊精、高分子澱粉水解物、高分子肽等)使其乾燥粉體化。 For example, when the form of the composition is a powder, it can be dried and powdered using a usual excipient (for example, dextrin, high molecular starch hydrolyzate, or polymer peptide).

又，調製醫藥品或醫藥部外品時，混合配醣體與其他成分，可作為各種劑形之醫藥品而調製。且，使用於各種劑形之調製的其他成分並無特別限定，可使用通常所使用者，作為該例子，可舉出澱粉、乳糖、白糖、甘露醇、羧基甲基纖維素、玉米澱粉、無機鹽等固體載體；蒸餾水、生理食鹽水、葡萄糖水溶液、乙醇等醇、丙二醇、聚乙二醇等液體載體；各種動植物油、白色凡士林、石蠟、蠟類等油性載體等。 Further, when a pharmaceutical product or a pharmaceutical product is prepared, the glycoside and other components are mixed, and it can be prepared as a pharmaceutical product of various dosage forms. Further, other components to be used in the preparation of various dosage forms are not particularly limited, and those which are usually used can be used. Examples of the examples include starch, lactose, white sugar, mannitol, carboxymethylcellulose, corn starch, and inorganic. A solid carrier such as a salt; a liquid carrier such as distilled water, physiological saline, aqueous dextrose or ethanol, propylene glycol or polyethylene glycol; or an oily carrier such as various animal and vegetable oils, white petrolatum, paraffin wax or wax.

且，混合配醣體與食用素材而加工成粉末、顆粒、顆粒、錠劑等形狀，或依據常法加工處理成前述例示之飲食品，或將混合這些之液狀物以明膠、海藻酸鈉、羧基甲基纖維素等被膜劑包被膜成形為膠囊，或加工成飲料(drink)之形態。 Further, the glycoside is mixed with the edible material to be processed into a shape such as a powder, a granule, a granule, a tablet, or the like, or processed into the above-exemplified food or drink according to a conventional method, or the liquid is mixed with gelatin or sodium alginate. A film coating film such as carboxymethyl cellulose is molded into a capsule or processed into a drink.

具體組成物的例子如以下所示。且，對於以下例子，作為配醣體，例如可使用前述式(1A)所示化合物或前述式(1B)所示化合物等。 Examples of specific compositions are shown below. In the following examples, as the glycoside, for example, a compound represented by the above formula (1A) or a compound represented by the above formula (1B) can be used.

且上述用時溶解用粉末若溶解在水、果汁或雞湯時，皆具有優良分散性，所得之飲料可適合作為用時溶解飲料使用。 Further, when the above-mentioned powder for dissolution is dissolved in water, juice or chicken soup, it has excellent dispersibility, and the obtained beverage can be suitably used as a dissolved beverage at the time of use.

又，於軟膠囊劑(由明膠60.0%、甘油30.0%、對羥基苯甲酸甲酯0.15%、對羥基苯甲酸丙酯0.51%、及適量水所成的劑)皮之中，將上述用時溶解用粉末藉由常法進行填充後得到軟膠囊。 Further, in the soft capsule (60.0% of gelatin, 30.0% of glycerin, 0.15% of methylparaben, 0.51% of propylparaben, and an appropriate amount of water), the above-mentioned time is used. The dissolution powder is filled in a usual manner to obtain a soft capsule.

且，上述錠劑為將上述所示配合之混合物依據常法造粒以及成型後得到。 Further, the above-mentioned tablet is obtained by granulating and molding the mixture as described above according to a usual method.

[實施例] [Examples]

以下將本發明依據實施例做更具體說明，但本發明並未限定於此等，多數變形為本發明之技術的思想內，且對於該領域中具有通常知識者皆可達成。 The invention will be more specifically described below based on the examples, but the invention is not limited thereto, and many of the modifications are within the spirit of the invention and can be achieved by those having ordinary knowledge in the field.

實施例1(2,5,6-三-O-乙醯-抗壞血酸之合成) Example 1 (Synthesis of 2,5,6-tri-O-acetamidine-ascorbic acid)

經由下述步驟，得到2,5,6-三-O-乙醯-抗壞血酸(化合物3)。 2,5,6-Tri-O-acetamidine-ascorbic acid (Compound 3) was obtained by the following procedure.

(式中，Ac表示乙醯基，Et表示乙基)。 (wherein Ac represents an ethyl group and Et represents an ethyl group).

將化合物1(抗壞血酸)(10.00g，57mmol)懸浮於乙酸酐(25mL，250mmol)中，在120℃進行加熱。因一邊激烈發熱會一邊溶解，故經溶解後再進行30分鐘加熱迴流。經冷卻加入甲醇5mL後使反應終了。將溶劑減壓餾去後，於殘渣加入甲苯，並進行減壓餾去之操作3次，得到油狀化合物2。 Compound 1 (ascorbic acid) (10.00 g, 57 mmol) was suspended in acetic anhydride (25 mL, 250 mmol) and heated at 120 °C. Since it dissolves while being heated intensely, it is heated and refluxed for 30 minutes after being dissolved. After 5 mL of methanol was added by cooling, the reaction was allowed to end. After the solvent was distilled off under reduced pressure, toluene was added to the residue, and the residue was evaporated to dryness three times.

(化合物2) (Compound 2)

¹H-NMR(CDCl₃)：2.06(3H，s)，2.09(3H，s)，2.26(3H，s)，2.28(3H，s)，4.31(1H，dd，J=7.3，11.6Hz)，4.40(1H，dd，J=5.6，11.6Hz)，5.39(1H，d，J=1.6Hz)，5.48(1H，ddd，J=1.6，5.6，7.3Hz)。 ¹ H-NMR (CDCl ₃ ): 2.06 (3H, s), 2.09 (3H, s), 2.26 (3H, s), 2.28 (3H, s), 4.31 (1H, dd, J = 7.3, 11.6 Hz) 4.40 (1H, dd, J = 5.6, 11.6 Hz), 5.39 (1H, d, J = 1.6 Hz), 5.48 (1H, ddd, J = 1.6, 5.6, 7.3 Hz).

¹³C-NMR(CDCl₃)：20.05，20.34，20.62，62.03，66.36，74.91，122.05，149.82，164.78，165.08，166.12，170.00，170.28。 ¹³ C-NMR (CDCl ₃ ): 20.05, 20.34, 20.62, 62.03, 66.36, 74.91, 122.05, 149.82, 164.78, 165.08, 166.12, 170.00, 170.28.

HRMS(ESI，M+H⁺)calcd for C₁₄H₁₇O₁₀ 345.0822，found 345.0813。 HRMS (ESI, M+H ⁺ ) calcd for C ₁₄ H ₁₇ O ₁₀ 345.0822, found 345.0813.

將所得之化合物2溶解於二氯甲烷80mL中，在室溫下將1-乙基哌嗪(7.2mL，57mmol)及二氯甲烷20mL經5分鐘滴入，再進行30分攪拌。以乙酸乙酯進行稀釋，再以1N鹽酸(1次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去後得到油狀化合物3(16.4g，95%)。 The obtained Compound 2 was dissolved in 80 mL of dichloromethane. 1-Ethylpiperazine (7.2 mL, 57 mmol) and 20 mL of dichloromethane were added dropwise at room temperature over 5 minutes, followed by stirring for 30 minutes. It was diluted with ethyl acetate, and washed with 1N hydrochloric acid (1 time) and saturated brine (2 times). The organic layer was dried (MgSO4), evaporated, evaporated

(化合物3) (Compound 3)

¹H-NMR(CDCl₃)：2.05(3H，s)，2.06(3H，s)，2.29(3H，s)，4.27(1H，dd，J=6.9，11.6Hz)，4.37(1H，dd，J=5.4，11.6Hz)，4.99(1H，d，J=1.6Hz)，5.46(1H，ddd，J=1.6，5.4，6.9Hz)。 ¹ H-NMR (CDCl ₃ ): 2.05 (3H, s), 2.06 (3H, s), 2.29 (3H, s), 4.27 (1H, dd, J = 6.9, 11.6 Hz), 4.37 (1H, dd, J = 5.4, 11.6 Hz), 4.99 (1H, d, J = 1.6 Hz), 5.46 (1H, ddd, J = 1.6, 5.4, 6.9 Hz).

¹³C-NMR(CDCl₃)：20.30，20.42，20.58，61.94，67.29，74.12，114.78，157.13，166.87，169.74，169.88，170.68。 ¹³ C-NMR (CDCl ₃ ): 20.30, 20.42, 20.58, 61.94, 67.29, 74.12, 114.78, 157.13, 166.87, 169.74, 169.88, 170.68.

HRMS(ESI，M+H⁺)calcd for C₁₂H₁₅O₉ 303.0716，found 303.0708。 HRMS (ESI, M+H ⁺ ) calcd for C ₁₂ H ₁₅ O ₉ 303.0716, found 303.0708.

實施例2(3-O-苯甲基-5,6-二-O-乙醯-抗壞血酸之合成) Example 2 (Synthesis of 3-O-benzyl-5,6-di-O-acetyl-ascorbic acid)

經過下述步驟，得到3-O-苯甲基-5,6-二-O-乙醯-抗壞血酸(化合物5)。 After the following procedure, 3-O-benzyl-5,6-di-O-acetyl-ascorbic acid (Compound 5) was obtained.

(式中，Ac表示乙醯基，Bn表示苯甲基，Et表示乙基)。 (In the formula, Ac represents an ethyl group, Bn represents a benzyl group, and Et represents an ethyl group).

將實施例1所得之化合物3(9.32g，30mmol)溶解在二甲基甲醯胺(DMF)90mL，在氬環境下加入亞硫酸氫鈉(13.1g，75mmol)，碳酸鉀(7.45g，54mmol)並使其懸浮。在室溫下加入溴化苯甲基(5.34mL，45mmol)，在油浴中以60℃加熱20分鐘(化合物4之生成)。化合物4之生成可由TLC(乙酸乙酯/己烷=1/1)確認。 Compound 3 (9.32 g, 30 mmol) obtained in Example 1 was dissolved in 90 mL of dimethylformamide (DMF), and sodium hydrogensulfite (13.1 g, 75 mmol), potassium carbonate (7.45 g, 54 mmol) was added under argon. ) and let it float. Benzyl bromide (5.34 mL, 45 mmol) was added at room temperature and heated at 60 ° C for 20 minutes in an oil bath (formation of compound 4). The formation of Compound 4 was confirmed by TLC (ethyl acetate /hexane = 1 / 1).

(化合物4) (Compound 4)

¹H-NMR(CDCl₃)：2.04(3H，s)，2.07(3H，s)，2.22(3H，s)，4.28(1H，dd，J=7.0，11.5Hz)，4.33(1H，dd，J=6.0，11.5Hz)，4.91(1H，d，J=1.5Hz)，5.15(1H，d，J=11.1Hz)，5.26(1H，d，J=11.1Hz)，5.43(1H，ddd，J=1.5，6.0，7.0Hz)，7.33-7.42(5H，m)。 ¹ H-NMR (CDCl ₃ ): 2.04 (3H, s), 2.07 (3H, s), 2.22 (3H, s), 4.28 (1H, dd, J = 7.0, 11.5 Hz), 4.33 (1H, dd, J = 6.0, 11.5 Hz), 4.91 (1H, d, J = 1.5 Hz), 5.15 (1H, d, J = 11.1 Hz), 5.26 (1H, d, J = 11.1 Hz), 5.43 (1H, ddd, J = 1.5, 6.0, 7.0 Hz), 7.33 - 7.42 (5H, m).

冷卻至室溫，加入1-乙基哌嗪(5.7mL，45mmol)並進行1小時攪拌。將不溶物以矽藻土過濾，將濾液以乙酸乙酯稀釋，再以1N鹽酸(1次)、飽和食鹽水(2次)洗淨，將有機層以硫酸鎂進行乾燥。將溶劑經減壓餾去所得之油狀殘渣經矽膠管柱(乙酸乙酯/己烷=1/2~1/1) 進行純化後得到黃色油狀化合物5(6.05g，58%)。 After cooling to room temperature, 1-ethylpiperazine (5.7 mL, 45 mmol) was added and stirred for 1 hour. The insoluble material was filtered through celite, and the filtrate was diluted with ethyl acetate and washed with 1N hydrochloric acid (1 time) and brine (2 times), and the organic layer was dried over magnesium sulfate. The oily residue obtained by distilling off the solvent under reduced pressure was passed through a cartridge column (ethyl acetate/hexane = 1/2 to 1/1). After purification, compound 5 (6.05 g, 58%) was obtained.

(化合物5) (Compound 5)

¹H-NMR(CDCl₃)：1.94(3H，s)，2.04(3H，s)，4.24(1H，dd，J=6.8，11.6Hz)，4.33(1H，dd，J=5.4，11.6Hz)，4.84(1H，d，J=2.4Hz)，5.37(1H，ddd，J=2.4，5.4，6.8Hz)，5.42(1H，d，J=11.6Hz)，5.45(1H，d，J=11.6Hz)，6.35(1H，bs)，7.35-7.43(5H，m)。 ¹ H-NMR (CDCl ₃ ): 1.94 (3H, s), 2.04 (3H, s), 4.24 (1H, dd, J = 6.8, 11.6 Hz), 4.33 (1H, dd, J = 5.4, 11.6 Hz) , 4.84 (1H, d, J = 2.4 Hz), 5.37 (1H, ddd, J = 2.4, 5.4, 6.8 Hz), 5.42 (1H, d, J = 11.6 Hz), 5.45 (1H, d, J = 11.6) Hz), 6.35 (1H, bs), 7.35-7.43 (5H, m).

¹³C-NMR(CDCl₃)：20.39，20.59，62.05，67.56，73.48，74.47，119.50，128.39，128.64，128.81，135.34，147.59，169.54，170.44，170.87。 ¹³ C-NMR (CDCl ₃ ): 20.39, 20.59, 62.05, 67.56, 73.48, 74.47, 119.50, 128.39, 128.64, 128.81, 135.34, 147.59, 169.54, 170.44, 170.87.

HRMS(ESI，M+H⁺)calcd for C₁₇H₁₉O₈ 341.1080，found 351.1076。 HRMS (ESI, M+H ⁺ ) calcd for C ₁₇ H ₁₉ O ₈ 341. 1080, found 351.1076.

實施例3(葡萄糖五乙酸酯之合成) Example 3 (Synthesis of Glucose Pentaacetate)

經下述步驟，得到D-葡萄糖五乙酸酯(化合物7)。 D-glucose pentaacetate (compound 7) was obtained by the following procedure.

(式中，Ac表示乙醯基)。 (wherein Ac represents an ethyl group).

於乙酸酐(25mL，264mmol)懸浮乙酸鈉(1.14g，13.9mmol)，緩緩地進行加熱迴流。將D-葡萄糖(α體/β體的混合物)(化合物6)(5.00g，27.8mmol)經15分鐘以段階式加入。加入結束後，進一步經15分鐘加熱迴流後，冷卻至室溫。加入冰片使反應淬火後，將溶劑減壓餾去。將所得之白色固體殘渣溶解於乙酸乙酯，以飽和碳酸氫鈉水(1次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去後得到白色固體之化合物7(10.42g，96%)。化合物7之生成可由NMR確認。 Sodium acetate (1.14 g, 13.9 mmol) was suspended in acetic anhydride (25 mL, 264 mmol) and slowly refluxed with stirring. D-glucose (mixture of alpha/beta bodies) (compound 6) (5.00 g, 27.8 mmol) by 15 minutes The clock is added in steps. After the completion of the addition, the mixture was further heated under reflux for 15 minutes, and then cooled to room temperature. After the borneol was added to quench the reaction, the solvent was distilled off under reduced pressure. The obtained white solid residue was dissolved in ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate (1 time) and brine (2 times). The organic layer was dried (MgSO4). The formation of Compound 7 was confirmed by NMR.

實施例4(葡萄糖四乙酸酯及其亞胺酸酯體之合成) Example 4 (Synthesis of Glucose Tetraacetate and Its Imidate)

經由下述步驟，得到D-葡萄糖四乙酸酯(化合物8)及其亞胺酸酯體。 D-glucose tetraacetate (compound 8) and its imidate body were obtained by the following procedure.

(式中，Ac表示乙醯基)。 (wherein Ac represents an ethyl group).

於以實施例3所得之葡萄糖五乙酸酯(化合物7)(11.7g，30mmol)的二氯甲烷溶液(60mL)以冰冷下加入1-乙基哌嗪(5.7mL，45mmol)後，在室溫下進行一晚攪拌。以乙酸乙酯稀釋後以2N鹽酸(1次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑減壓餾去所得之化合物8(以TLC(乙酸乙酯/己烷=1/1)確認生成)溶解於二氯甲烷溶液(60mL)，在室溫加入碳酸鉀(2.07g，15mmol)與三氯乙腈(6.45g，45mmol)，並經一晚攪拌。過濾不溶物，將濾液以乙酸乙酯稀釋並以飽和食鹽水(2次) 洗淨。將有機層以硫酸鎂乾燥，將溶劑減壓餾去後得到黃色油狀之亞胺酸酯體(化合物9)(13.8g，93%、α體及β體之混合物)。 After adding 1-ethylpiperazine (5.7 mL, 45 mmol) to the solution of glucose pentaacetate (Compound 7) (11.7 g, 30 mmol) obtained in Example 3 in dichloromethane (60 mL), Stir for one night under warm conditions. After diluting with ethyl acetate, it was washed with 2N hydrochloric acid (1 time) and saturated brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated to dryness crystals (yield from EtOAc (hexane/hexane = 1/1)). Potassium carbonate (2.07 g, 15 mmol) and trichloroacetonitrile (6.45 g, 45 mmol) were stirred overnight. Insoluble material was filtered, and the filtrate was diluted with ethyl acetate and brine (2 times) Wash. The organic layer was dried over magnesium sulfate, and the solvent was evaporated to dryness to give the title compound (yield: 9 g, 93%, mixture of ??

(化合物9) (Compound 9)

¹H-NMR(CDCl₃)：(使用於異構物之6：1混合物的主要異構物)2.01(3H，s)，2.02(3H，s)，2.04(3H，s)，2.07(3H，s)，4.12(1H，dd，J=1.9，12.4Hz)，4.20(1H，ddd，J=1.9，4.0，10.2Hz)，4.27(1H，dd，J=4.0，12.3Hz)，5.13(1H，dd，J=3.7，10.2Hz)，5.18(1H，dd，J=9.9，9.9Hz)，5.56(1H，dd，J=9.9，9.9Hz)，6.55(1H，d，J=3.7Hz)，8.69(1H，s)。 ¹ H-NMR (CDCl ₃ ): (the main isomer used in the 6:1 mixture of isomers) 2.01 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.07 (3H , s), 4.12 (1H, dd, J = 1.9, 12.4 Hz), 4.20 (1H, ddd, J = 1.9, 4.0, 10.2 Hz), 4.27 (1H, dd, J = 4.0, 12.3 Hz), 5.13 ( 1H, dd, J = 3.7, 10.2 Hz), 5.18 (1H, dd, J = 9.9, 9.9 Hz), 5.56 (1H, dd, J = 9.9, 9.9 Hz), 6.55 (1H, d, J = 3.7 Hz) ), 8.69 (1H, s).

¹³C-NMR(CDCl₃)：20.40，20.54，20.63，61.53，67.73，69.67，69.82，69.96，92.85，160.74，169.46，169.81，169.96，170.52。 ¹³ C-NMR (CDCl ₃ ): 20.40, 20.54, 20.63, 61.53, 67.73, 69.67, 69.82, 69.96, 92.85, 160.74, 169.46, 169.81, 169.96, 170.52.

實施例5(糖基化) Example 5 (glycosylation)

如下述步驟，進行化合物5與化合物9之反應(糖基化反應)。 The reaction of the compound 5 with the compound 9 (glycosylation reaction) is carried out as follows.

混合以實施例2所得之化合物5(保護抗壞血酸)(6.0g，17mmol)的二氯甲烷溶液(20mL)、與以實施例4所得之化合物9(亞胺酸酯體)(11.0g，22mmol)的二氯甲烷溶液(20mL)，在冰冷下加入三氟化硼二乙基醚錯體(122mL，0.86mmol)，並進行2小時攪拌。且，反應的進行以薄層層析法(TLC)(乙酸乙酯/己烷=1/1)確認。加入飽和碳酸氫鈉水(2mL)並淬火，再以乙酸乙酯稀釋，以飽和淬火(2次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去後所得之油狀殘渣中加入甲醇並再度餾去溶劑後得到固體之化合物10(僅β體)。自甲醇進行再結晶，得到淡黃色結晶(9.22g，80%)。 A solution of the compound 5 (protected ascorbic acid) obtained in Example 2 (6.0 g, 17 mmol) in dichloromethane (20 mL), and the compound 9 obtained from Example 4 (the imidate) (11.0 g, 22 mmol) A solution of methylene chloride (20 mL) was added EtOAc (EtOAc m. Further, the progress of the reaction was confirmed by thin layer chromatography (TLC) (ethyl acetate /hexane = 1 / 1). Saturated sodium bicarbonate water (2 mL) was added and quenched, and then diluted with ethyl acetate and washed with saturated quenching (2 times) and saturated brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated to dryness. Recrystallization from methanol gave pale yellow crystals (9.22 g, 80%).

(化合物10) (Compound 10)

¹H-NMR(CDCl₃)：1.93(3H，s)，1.997(3H，s)， 2.001(3H，s)，2.015(3H，s)，2.020(3H，s)，2.11(3H，s)，3.76(1H，ddd，J=2.2，4.2，10.0Hz)，4.14(1H，dd，J=2.0，12.2Hz)，4.21(1H，dd，J=6.7，11.7Hz)，4.26-4.33(2H，m)，4.84(1H，d，J=2.2Hz)，5.12(1H，dd，J=9.7，9.7Hz)，5.16(1H，dd，8.2，9.4Hz)，5.25-5.36(4H，m)，5.48(1H，d，J=11.5Hz)，7.35(5H，m)。 ¹ H-NMR (CDCl ₃ ): 1.93 (3H, s), 1.997 (3H, s), 2.001 (3H, s), 2.015 (3H, s), 2.020 (3H, s), 2.11 (3H, s) , 3.76 (1H, ddd, J = 2.2, 4.2, 10.0 Hz), 4.14 (1H, dd, J = 2.0, 12.2 Hz), 4.21 (1H, dd, J = 6.7, 11.7 Hz), 4.26 - 4.33 (2H , m), 4.84 (1H, d, J = 2.2 Hz), 5.12 (1H, dd, J = 9.7, 9.7 Hz), 5.16 (1H, dd, 8.2, 9.4 Hz), 5.25-5.36 (4H, m) , 5.48 (1H, d, J = 11.5 Hz), 7.35 (5H, m).

¹³C-NMR(CDCl₃)：20.38，20.49，20.54，20.67，61.28，61.77，67.55，67.95，70.89，72.16，72.31，73.75，74.39，98.71，118.11，128.43，128.65，128.94，134.73，157.67，167.40，169.34，169.39，169.86，170.16，170.36。 ¹³ C-NMR (CDCl ₃ ): 20.38, 20.49, 20.54, 20.67, 61.28, 61.77, 67.55, 67.95, 70.89, 72.16, 72.31, 73.75, 74.39, 98.71, 118.11, 128.43, 128.65, 128.94, 134.73, 157.67, 167.40 , 169.34, 169.39, 169.86, 170.16, 170.36.

HRMS(ESI，M+H⁺)calcd for C₃₁H₃₇O₁₇ 681.2031，found 681.2034。 HRMS (ESI, M+H ⁺ ) calcd for C ₃₁ H ₃₇ O ₁₇ 681.2031, found 681.2034.

實施例6(脫苯甲基化) Example 6 (debenzylation)

如下述步驟所示，進行化合物10的脫苯甲基化(氫化分解)。 Debenzylation (hydrogenation decomposition) of Compound 10 was carried out as shown in the following procedure.

(式中，Ac表示乙醯基，Bn表示苯甲基)。 (wherein Ac represents an ethyl group and Bn represents a benzyl group).

於以實施例5所得之化合物10(配醣體)(200mg，0.29mmol)的四氫呋喃(THF)溶液(5mL)中加入乙酸0.5mL與10%Pd碳(20mg)，在1氣壓的氫環境下，在室溫進行3小時攪拌。濾去觸媒，將濾液減壓濃縮後得到化合物11。 To a solution of the compound 10 (glycoside) (200 mg, 0.29 mmol) obtained in Example 5 in tetrahydrofuran (THF) (5 mL) was added 0.5 mL of acetic acid and 10% Pd carbon (20 mg) in a hydrogen atmosphere of 1 atmosphere. Stir at room temperature for 3 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give Compound 11.

(化合物11) (Compound 11)

¹H-NMR(CDCl₃)：1.98(3H，s)，2.02(3H，s)，2.05(3H，s)，2.09(3H，s)，2.096(3H，s)，2.101(3H，s)，3.85(1H，m)，4.21-4.24(2H，m)，4.26(1H，dd，J=7.0，11.6Hz)，4.37(1H，d，J=5.3，11.6Hz)，4.91(1H，d，J=2.7Hz)，5.01-5.10(3H，m)，5.24(1H，dd，J=9.2，9.2Hz)，5.39(1H，m)。 ¹ H-NMR (CDCl ₃ ): 1.98 (3H, s), 2.02 (3H, s), 2.05 (3H, s), 2.09 (3H, s), 2.096 (3H, s), 2.101 (3H, s) , 3.85 (1H, m), 4.21-4.24 (2H, m), 4.26 (1H, dd, J = 7.0, 11.6 Hz), 4.37 (1H, d, J = 5.3, 11.6 Hz), 4.91 (1H, d , J = 2.7 Hz), 5.01-5.10 (3H, m), 5.24 (1H, dd, J = 9.2, 9.2 Hz), 5.39 (1H, m).

HRMS(ESI，M+H⁺)calcd for C₂₄H₃₁O₁₇ 591.1561，found 591.1552。 HRMS (ESI, M+H ⁺ ) calcd for C ₂₄ H ₃₁ O ₁₇ 591.1561, found 591.1552.

實施例7(脫乙醯化) Example 7 (deacetylation)

如下述步驟所示，進行化合物11的脫乙醯化。 Deacetylation of Compound 11 was carried out as shown in the following procedure.

(式中，Ac表示乙醯基，Me表示甲基)。 (wherein Ac represents an ethyl group and Me represents a methyl group).

於以實施例6所得之化合物11(脫苯甲基體)的甲醇溶液(3mL)中將1MNaOH水溶液(2.24mL)在室溫下滴入，經一晚攪拌。將陽離子交換樹脂(Dow．化學公司製之Dowex 50Wx8(H⁺ form))慢慢加入，調整至pH3。過濾樹脂後，以50%甲醇-水洗淨。將濾液經減壓濃縮，除去甲醇後，經冷凍乾燥所得之殘渣通過陽離子交換樹脂(有機公司製之Amberlite FPC3500(Na⁺ form))，經水溶離。將溶離液經冷凍乾燥後得到化合物12(104mg、98%)之淡黃色非晶質。 A 1 M aqueous NaOH solution (2.24 mL) was added dropwise to a solution of the compound 11 (debenzylidene) obtained in Example 6 (3 mL). A cation exchange resin (Dowex 50Wx8 (H ⁺ form) manufactured by Dow. Chemical Co., Ltd.) was slowly added and adjusted to pH 3. After filtering the resin, it was washed with 50% methanol-water. The filtrate was concentrated under reduced pressure to remove methanol, and the residue obtained by lyophilization was passed through a cation exchange resin (Amberlite FPC3500 (Na ⁺ form), manufactured by Organic Corporation), and dissolved in water. The eluate was freeze-dried to give a pale yellow amorphous compound 12 (104 mg, 98%).

(化合物12) (Compound 12)

¹H-NMR(100mM磷酸緩衝液/D₂O，pH7.0)：3.38-3.58(4H，m)，3.69-3.79(3H，m)，3.86(1H，m)，4.03(1H，m)，4.56(1H，d，1.9Hz)，4.72(1H，d，J=7.8Hz)。 ¹ H-NMR (100 mM phosphate buffer / D ₂ O, pH 7.0): 3.38-3.58 (4H, m), 3.69-3.79 (3H, m), 3.86 (1H, m), 4.03 (1H, m) , 4.56 (1H, d, 1.9 Hz), 4.72 (1H, d, J = 7.8 Hz).

¹³C-NMR(100mM磷酸緩衝液/D₂O，pH7.0)：60.38，62.30，69.23，69.44，72.78，75.37，76.12，78.39，103.13，114.60，176.92，179.27。 ¹³ C-NMR (100 mM phosphate buffer / D ₂ O, pH 7.0): 60.38, 62.30, 69.23, 69.44, 72.78, 75.37, 76.12, 78.39, 103.13, 114.60, 176.92, 179.27.

HRMS(ESI，M+H⁺)calcd for C₁₂H₁₈O₁₁Na 361.0747，found 361.0722。 HRMS (ESI, M+H ⁺ ) calcd for C ₁₂ H ₁₈ O ₁₁ Na 361.0747, found 361.0722.

實施例8(化合物5之無分離的糖苷化) Example 8 (no isolated glycosidation of compound 5)

在實施例5，反應經分離的化合物5與化合物9，但如以下所示，自化合物3所合成的化合物5無須分離(純化)，可供給於與化合物9之反應。 In Example 5, the isolated compound 5 and the compound 9 were reacted, but as shown below, the compound 5 synthesized from the compound 3 was supplied to the reaction with the compound 9 without isolation (purification).

將實施例1所得之化合物3(1.50g，5.0mmol)溶解於二甲基甲醯胺(DMF)8mL，在氬環境下加入碳酸鉀(1.25g，9.0mmol)並使其懸浮。在室溫加入溴化苯甲基(0.90mL，7.5mmol)，進行1小時攪拌。進一步在室溫加入1-乙基哌嗪(1.2mL，75mmol)並進行30分鐘攪拌。將不溶物以矽藻土過濾，並將濾液以乙酸乙酯稀釋，以1N鹽酸(1次)、飽和食鹽水(2次)洗淨，將有機層以硫酸鎂進行乾燥。將溶劑經減壓餾去所得之油狀殘渣溶解於氯仿中，供給於覆蓋矽膠15g之玻璃濾器，以乙酸乙酯/己烷(1/1混合液、100mL)溶離。濃縮濾液，欲使DMF餾去，加入甲苯並在55℃進行減壓濃縮之操作重複3次。 The compound 3 (1.50 g, 5.0 mmol) obtained in Example 1 was dissolved in 8 mL of dimethylformamide (DMF), and potassium carbonate (1.25 g, 9.0 mmol) was added and suspended in an argon atmosphere. Benzyl bromide (0.90 mL, 7.5 mmol) was added at room temperature and stirred for 1 hour. Further, 1-ethylpiperazine (1.2 mL, 75 mmol) was added at room temperature and stirred for 30 minutes. The insoluble material was filtered through celite, and the filtrate was diluted with ethyl acetate, and washed with 1N hydrochloric acid (1 time) and brine (2 times), and the organic layer was dried over magnesium sulfate. The oily residue obtained by distilling off the solvent in vacuo was dissolved in chloroform, and was applied to a glass filter covered with 15 g of phthalocyanine, and dissolved in ethyl acetate/hexane (1/1 mixture, 100 mL). The filtrate was concentrated, and the DMF was distilled off, and toluene was added thereto, and the operation under reduced pressure at 55 ° C was repeated three times.

混合所得之殘渣的二氯甲烷溶液(2mL)與以實施例4所得之化合物9(亞胺酸酯體的二氯甲烷溶液(2mL)，在冰冷下加入三氟化硼二乙基醚錯體(30mL)進行1小時攪拌。加入飽和碳酸氫鈉水(2mL)使其淬火，以乙酸乙酯稀釋，再以飽和碳酸氫鈉水(2次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去所得之油狀殘渣中加入甲醇，得到淡黃色結晶(1.10g、33%)之化合物10。濃縮母液，再度自甲醇使其結晶化，並再回收化合物10(0.24g、7%)(即，合計為1.24g、40%)。 The obtained residue was mixed with a dichloromethane solution (2 mL) and the compound 9 obtained in Example 4 (diamine ester solution in dichloromethane (2 mL), and boron trifluoride diethyl ether was added under ice cooling. (30 mL) was stirred for 1 hour, and it was quenched by adding saturated sodium hydrogencarbonate water (2 mL), diluted with ethyl acetate, and washed with saturated sodium hydrogen carbonate (2 times) and brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Methanol was added to the obtained oily residue to obtain Compound 10 as pale yellow crystals (1.10 g, 33%). The mother liquid was concentrated, crystallized again from methanol, and Compound 10 (0.24 g, 7%) was further recovered (i.e., 1.24 g, 40% in total).

對於葡萄糖以外的糖亦必須確認得到配醣體，故進行以下實驗。 The glycoside was also confirmed for sugars other than glucose, so the following experiment was carried out.

實施例9(半乳糖四乙酸酯及其亞胺酸酯體之合成) Example 9 (Synthesis of galactose tetraacetate and its imidate)

經由下述步驟，得到D-半乳糖四乙酸酯(化合物14)及其亞胺酸酯體。 D-galactose tetraacetate (compound 14) and its imidate body were obtained by the following procedure.

(式中，Ac表示乙醯基)。 (wherein Ac represents an ethyl group).

對於實施例3，取代D-葡萄糖使用D-半乳糖以外為相同，得到半乳糖五乙酸酯(化合物13)。 In Example 3, the substitution D-glucose was the same except that D-galactose was used, and galactose pentaacetate (Compound 13) was obtained.

於所得之半乳糖五乙酸酯(化合物13)(2.0g，5.0mmol)之二氯甲烷溶液(20mL)中在冰冷下加入1-乙基哌嗪(760μL，6.0mmol)後，在室溫進行一晚攪拌。以乙酸乙酯稀釋，並以2N鹽酸(1次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去所得之化合物14(以TLC(乙酸乙酯/己烷=1/1)確認生成)溶解於二氯甲烷溶液(20mL)，在室溫加入碳酸鉀(345mg，2.5mmol)與三氯乙腈(1.1mL，7.5mmol)，進行一晚攪拌。過濾不溶物，將濾液以乙酸乙酯稀釋後以飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑減壓餾去後得到黃色油狀亞胺酸酯體(化合物15)(1.98g，80%、α體/β體=約2/1之混合物)。 After adding 1-ethylpiperazine (760 μL, 6.0 mmol) to ice-cold in a dichloromethane solution (20 mL) of galactose pentaacetate (Compound 13) (2.0 g, 5.0 mmol), at room temperature Stir for one night. It was diluted with ethyl acetate and washed with 2N hydrochloric acid (1 time) and saturated brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated evaporated evaporated. Potassium carbonate (345 mg, 2.5 mmol) and trichloroacetonitrile (1.1 mL, 7.5 mmol) were added and stirred overnight. Filter insoluble matter, filter The solution was diluted with ethyl acetate and washed with saturated brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated to dryness to give crystals (yield: y.

(化合物15) (Compound 15)

¹H-NMR(CDCl₃)：1.99-2.04(9H，m)，2.16(3Hx2/3，s)，2.18(3Hx1/3，s)，4.04-4.45(3H，m)，5.10-5.57(3H，m)，5.83(1Hx1/3，d，J=8.2Hz)，6.59(1Hx2/3，d，J=3.4Hz)，8.66(1Hx2/3，s)，8.71(1Hx1/3，s)。 ¹ H-NMR (CDCl ₃ ): 1.99-2.04 (9H, m), 2.16 (3Hx2/3, s), 2.18 (3Hx1/3, s), 4.04-4.45 (3H, m), 5.10-5.57 (3H m), 5.83 (1Hx1/3, d, J = 8.2 Hz), 6.59 (1Hx2/3, d, J = 3.4 Hz), 8.66 (1Hx2/3, s), 8.71 (1Hx1/3, s).

實施例10(糖基化) Example 10 (glycosylation)

如下述步驟所示，進行化合物5與化合物15之反應(糖基化反應)。 The reaction of the compound 5 with the compound 15 (glycosylation reaction) is carried out as shown in the following step.

混合實施例2所得之化合物5(保護抗壞血酸)(700mg，2.0mmol)之二氯甲烷溶液(10mL)與以實施例9所得之化合物15(亞胺酸酯體)(1.08g，2.2mmol)的二氯甲烷溶液(10mL)，冰冷下加入三氟化硼二乙基醚錯體(30mL，0.1mmol)並進行1小時攪拌。且，反應的進行以薄層層析法(TLC)(甲醇/氯仿=1/20)確認。加入飽和碳酸氫鈉水(2mL)並淬火，以乙酸乙酯稀釋，以飽和碳酸氫鈉水(2次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去所得之油狀殘渣經矽膠管柱層析法(甲醇/氯仿=1/20)進行純化，得到淡黃色結晶(1.10g，81%)之化合物16。 The compound 5 (protected ascorbic acid) obtained in Example 2 (700 mg, 2.0 mmol) in methylene chloride (10 mL) and the compound 15 (ylidene ester) obtained in Example 9 (1.08 g, 2.2 mmol) A dichloromethane solution (10 mL) was added, and boron trifluoride diethyl ether (30 mL, 0.1 mmol) was added under ice cooling and stirred for 1 hour. Further, the progress of the reaction was confirmed by thin layer chromatography (TLC) (methanol / chloroform = 1/20). Saturated sodium bicarbonate water (2 mL) was added and the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate (2 times) and brine (2 times). The organic layer was dried over MgSO4, EtOAc (EtOAc) Compound 16.

(化合物16) (Compound 16)

¹H-NMR(CDCl₃)：1.94(3H，s)，2.00(3H，s)，2.033(3H，s)，2.036(3H，s)，2.14(3H，s)，2.15(3H，s)，3.98(1H，ddd，J=0.9，6.6，6.6Hz)，4.12(1H，dd，J=6.5，11.3Hz)，4.19(1H，dd，J=6.6，11.3Hz)，4.23(1H，dd，J=6.8，11，6Hz)，4.32(1H，dd，J=5.6，11.6Hz)，4.85(1H，d，J=2.3Hz)，5.10(1H，dd，J=3.5，10.3Hz)，5.27(1H，d，J=8.0Hz)，5.31-5.38(2H，m)，5.39(1H，d，J=11.5Hz)，5.44(1H，dd，J=0.9，3.3Hz)，5.52(1H，d，J=11.5Hz)，5.39(5H，m)。 ¹ H-NMR (CDCl ₃ ): 1.94 (3H, s), 2.00 (3H, s), 2.033 (3H, s), 2.036 (3H, s), 2.14 (3H, s), 2.15 (3H, s) , 3.98 (1H, ddd, J = 0.9, 6.6, 6.6 Hz), 4.12 (1H, dd, J = 6.5, 11.3 Hz), 4.19 (1H, dd, J = 6.6, 11.3 Hz), 4.23 (1H, dd , J = 6.8, 11, 6 Hz), 4.32 (1H, dd, J = 5.6, 11.6 Hz), 4.85 (1H, d, J = 2.3 Hz), 5.10 (1H, dd, J = 3.5, 10.3 Hz), 5.27 (1H, d, J = 8.0 Hz), 5.31-5.38 (2H, m), 5.39 (1H, d, J = 11.5 Hz), 5.44 (1H, dd, J = 0.9, 3.3 Hz), 5.52 (1H) , d, J = 11.5 Hz), 5.39 (5H, m).

¹³C-NMR(CDCl₃)：20.43，20.51，20.62，20.86，60.83，61.86，66.75，67.62，68.44，70.50，71.37， 73.78，74.46，99.47，118.30，128.01，128.75，129.04，134.86，157.64，167.51，169.41，169.87，169.97，170.04，170.25，170.30。 ¹³ C-NMR (CDCl ₃ ): 20.43, 20.51, 20.62, 20.86, 60.83, 61.86, 66.75, 67.62, 68.44, 70.50, 71.37, 73.78, 74.46, 99.47, 118.30, 128.01, 128.75, 129.04, 134.86, 157.64, 167.51 , 169.41, 169.87, 169.97, 170.04, 170.25, 170.30.

HRMS(ESI，M+H⁺)calcd for C₃₁H₃₇O₁₇ 681.2031，found 681.2068。 HRMS (ESI, M+H ⁺ ) calcd for C ₃₁ H ₃₇ O ₁₇ 681.2031, found 681.2068.

實施例11(脫苯甲基化) Example 11 (debenzylation)

如下述步驟所示，進行化合物16的脫苯甲基化(氫化分解)。 Debenzylation (hydrogenation decomposition) of Compound 16 was carried out as shown in the following procedure.

於以實施例10所得之化合物16(配醣體)(1.10g，1.6mmol)的四氫呋喃(THF)溶液(20mL)中加入乙酸1mL與10%Pd碳(50mg)，在1氣壓之氫環境下，在室溫進行2小時攪拌。濾去觸媒，將濾液減壓濃縮後得到白色非晶質之化合物17(840mg、88%)。 To a solution of the compound 16 (glycoside) obtained in Example 10 (1.10 g, 1.6 mmol) in tetrahydrofuran (THF) (20 mL) was added 1 mL of acetic acid and 10% Pd carbon (50 mg) under 1 atmosphere of hydrogen atmosphere. Stir at room temperature for 2 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give white crystals of compound 17 (840 mg, 88%).

(化合物17) (Compound 17)

¹H-NMR(CDCl₃)：2.00(3H，s)，2.07(3H，s)，2.09(3H，s)，2.10(3H，s)，2.15(3H，s)，2.18(3H，s)，4.09(1H，dd，J=5.8，6.4Hz)，4.19-4.23(2H)，4.29(1H，dd，J=6.8，11.6Hz)，4.40(1H，dd，J=5.2，11.6Hz)，4.93(1H，d，J=2.8Hz)，4.94(1H，d，J=8.3Hz)，5.08(1H，dd，J=3.4，10.5Hz)，5.34(1H，dd，J=8.2，10.5Hz)，5.42-5.47(2H，m)，8.76(1H，bs)。 ¹ H-NMR (CDCl ₃ ): 2.00 (3H, s), 2.07 (3H, s), 2.09 (3H, s), 2.10 (3H, s), 2.15 (3H, s), 2.18 (3H, s) , 4.09 (1H, dd, J = 5.8, 6.4 Hz), 4.19 - 4.23 (2H), 4.29 (1H, dd, J = 6.8, 11.6 Hz), 4.40 (1H, dd, J = 5.2, 11.6 Hz), 4.93 (1H, d, J = 2.8 Hz), 4.94 (1H, d, J = 8.3 Hz), 5.08 (1H, dd, J = 3.4, 10.5 Hz), 5.34 (1H, dd, J = 8.2, 10.5 Hz) ), 5.42 - 5.47 (2H, m), 8.76 (1H, bs).

¹³C-NMR(CDCl₃)：20.28，20.46，20.49，20.57，66.76，66.95，67.34，70.09，72.47，73.40，101.33，119.11，156.91，166.57，169.68，169.72，169.78，170.35。 ¹³ C-NMR (CDCl ₃ ): 20.28, 20.46, 20.49, 20.57, 66.76, 66.95, 67.34, 70.09, 72.47, 73.40, 101.33, 119.11, 156.91, 166.57, 169.68, 169.72, 169.78, 170.35.

HRMS(ESI，M+H⁺)calcd for C₂₄H₃₁O₁₇ 591.1561，found 591.1585。 HRMS (ESI, M+H ⁺ ) calcd for C ₂₄ H ₃₁ O ₁₇ 591.1561, found 591.1585.

實施例12(脫乙醯化) Example 12 (deacetylation)

如下述步驟所示，進行化合物17的脫乙醯化。 Deacetylation of compound 17 was carried out as shown in the following procedure.

於以實施例11所得之化合物17(脫苯甲基體)(500mg、0.85mmol)之甲醇溶液(10mL)將1MNaOH水溶液(6.8mL)在室溫下滴入，經一晚攪拌。慢慢加入陽離子交換樹脂(Dow．化學公司製之Dowex 50Wx8(H⁺ form))，調整至pH3。過濾樹脂，以50%甲醇-水洗淨。將濾液減壓濃縮，除去甲醇後冷凍乾燥，得到化合物18(205mg、71%)之淡黃色非晶質。 A 1 M aqueous NaOH solution (6.8 mL) was added dropwise to a methanol solution (10 mL) of Compound 17 (de-benzylidene) (500 mg, 0.85 mmol) obtained in Example 11 at room temperature, and stirred overnight. A cation exchange resin (Dowex 50Wx8 (H ⁺ form) manufactured by Dow. Chemical Co., Ltd.) was slowly added thereto, and adjusted to pH 3. The resin was filtered and washed with 50% methanol-water. The filtrate was concentrated under reduced pressure, and then methanol was evaporated, and then evaporated to dryness to afford compound 18 (205 mg, 71%) as pale yellow amorphous.

(化合物18) (Compound 18)

¹H-NMR(100mM磷酸緩衝液/D₂O，pH7.0)：3.62-3.82(7H，m)，3.92(1H，bs)，4.04(1H，dd，J=6.3，6.3Hz)，4.56(1H，bs)，4.67(1H，d，J=6.8Hz)。 ¹ H-NMR (100 mM phosphate buffer / D ₂ O, pH 7.0): 3.62-3.82 (7H, m), 3.92 (1H, bs), 4.04 (1H, dd, J = 6.3, 6.3 Hz), 4.56 (1H, bs), 4.67 (1H, d, J = 6.8 Hz).

¹³C-NMR(100mM磷酸緩衝液/D₂O，pH7.0)：60.89，62.30，68.50，69.42，70.59，72.47，75.44，78.38，103.73，114.73，176.95，179.16。 ¹³ C-NMR (100 mM phosphate buffer / D ₂ O, pH 7.0): 60.89, 62.30, 68.50, 69.42, 70.59, 72.47, 75.44, 78.38, 103.73, 114.73, 176.95, 179.16.

HRMS(ESI，M+H⁺)calcd for C₁₂H₁₉O₁₁ 339.0927，found 361.0903。 HRMS (ESI, M+H ⁺ ) calcd for C ₁₂ H ₁₉ O ₁₁ 339.0927, found 361.0903.

實施例13(藉由碳酸鉀之化合物2的脫醯化) Example 13 (depurification of compound 2 by potassium carbonate)

將實施例1所得之化合物2(345mg)溶解於二甲基甲醯胺(DMF)7mL，在室溫加入碳酸鉀(166mg，1.2mmol)並進行1.5小時攪拌。濾去不溶物後，以乙酸乙酯稀釋，以1N鹽酸(1次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑減壓餾去後得到油狀化合物3(260mg， 86%)。 The compound 2 (345 mg) obtained in Example 1 was dissolved in 7 mL of dimethylformamide (DMF), and potassium carbonate (166 mg, 1.2 mmol) was added at room temperature and stirred for 1.5 hours. After the insoluble material was filtered off, it was diluted with ethyl acetate and washed with 1N hydrochloric acid (1 time) and brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated evaporated evaporated. 86%).

實施例14(化合物3之第3位配醣化) Example 14 (the third position of compound 3 is glycosylated)

如下述所示，進行化合物3的第3位之配醣化。 The glycosidation of the third position of the compound 3 was carried out as shown below.

混合以實施例1所得之化合物3(保護抗壞血酸)(350mg，1.16mmol)之二氯甲烷溶液(20mL)與以實施例4所得之化合物9(亞胺酸酯體)(680mg，1.39mmol)的二氯甲烷溶液(20mL)，在冰冷下加入三氟化硼二乙基醚錯體(18μL，0.06mmol)之二氯甲烷溶液1mL並進行2小時攪拌。且反應的進行以薄層層析法(TLC)(乙酸乙酯/己烷=1/1)確認。加入飽和碳酸氫鈉水(2mL)使其淬火，以乙酸乙酯稀釋，以飽和碳酸氫鈉水(2次)、飽和食鹽水(2次)洗淨。將有機層以硫酸鎂乾燥，將溶劑經減壓餾去所得之油狀殘渣經矽膠管柱層析法(乙酸乙酯/己烷=1/3)進行純化後得到化合物19(391mg，62%)。 A solution of the compound 3 (protected ascorbic acid) (350 mg, 1.16 mmol) obtained in Example 1 in dichloromethane (20 mL) and the compound 9 (ylidene ester) obtained in Example 4 (680 mg, 1.39 mmol) A dichloromethane solution (20 mL) was added, and 1 mL of a solution of boron trifluoride diethyl ether (18 μL, 0.06 mmol) in dichloromethane was added under ice cooling and stirred for 2 hours. The progress of the reaction was confirmed by thin layer chromatography (TLC) (ethyl acetate /hexane = 1 / 1). The mixture was quenched with saturated aqueous sodium hydrogencarbonate (2 mL), diluted with ethyl acetate, and washed with saturated sodium hydrogen carbonate (2 times) and brine (2 times). The organic layer was dried over magnesium sulfate, and the solvent was evaporated to ethylamine. Compound 19 (391 mg, 62%) was obtained.

(化合物19) (Compound 19)

¹H-NMR(CDCl₃)：1.97(3H，s)，1.98(3H，s)，2.01(3H，s)，2.02(3H，s)，2.03(3H，s)，2.05(3H，s)，2.25(3H，s)，3.75(1H，ddd，J=3.2，5.7，8.1Hz)，4.03(1H，dd，J=2.3，12.4Hz)，4.22-4.27(3H，m)，4.93(1H，d，J=1.4Hz)，5.04(1H，dd，J=9.4，9.6Hz)，5.10(1H，dd，J=7.6，9.4Hz)，5.17-5.27(3H，m)。 ¹ H-NMR (CDCl ₃ ): 1.97 (3H, s), 1.98 (3H, s), 2.01 (3H, s), 2.02 (3H, s), 2.03 (3H, s), 2.05 (3H, s) , 2.25 (3H, s), 3.75 (1H, ddd, J = 3.2, 5.7, 8.1 Hz), 4.03 (1H, dd, J = 2.3, 12.4 Hz), 4.22-4.27 (3H, m), 4.93 (1H , d, J = 1.4 Hz), 5.04 (1H, dd, J = 9.4, 9.6 Hz), 5.10 (1H, dd, J = 7.6, 9.4 Hz), 5.17-5.27 (3H, m).

¹³C-NMR(CDCl₃)：19.93，20.16，20.32，20.33，20.34.20.46，20.47，61.54，61.60，66.32，67.80，70.06，71.64，72.54，73.91，98.21，115.99，155.15，165.49，166.72，169.15，169.28，169.38，169.84，170.03，170.35。 ¹³ C-NMR (CDCl ₃ ): 19.93, 20.16, 20.32, 20.33, 20.34.20.46, 20.47, 61.54, 61.60, 66.32, 67.80, 70.06, 71.64, 72.54, 73.91, 98.21, 115.99, 155.15, 165.49, 166.72, 169.15 , 169.28, 169.38, 169.84, 170.03, 170.35.

[產業上可利用性] [Industrial availability]

本發明中可有效率地製造出將抗壞血酸作為糖苷配基之配醣體。又，本發明中提供作為維生素原C等有用的新穎配醣體。 In the present invention, a glycoside having ascorbic acid as an aglycone can be efficiently produced. Further, in the present invention, a novel glycoside which is useful as provitamin C or the like is provided.

Claims

一種化合物，其特徵為下述式(A) (式中，R¹表示醯基)所示化合物。 a compound characterized by the following formula (A) (wherein R ¹ represents a fluorenyl group) is a compound shown.

一種式(A)所示化合物之製造方法，其特徵為使用鹼，使下述式(A’) (式中，R¹與前述相同)所示化合物進行脫醯化處理者。 A method for producing a compound of the formula (A), characterized in that a base is used to give the following formula (A') The compound represented by the formula (wherein R ¹ is the same as defined above) is subjected to depurination treatment.

如請求項2之製造方法，其中鹼為第2級胺。 The production method of claim 2, wherein the base is a second-order amine.

如請求項2或3之製造方法，其中鹼為N-單取代哌嗪。 The process of claim 2 or 3 wherein the base is N-monosubstituted piperazine.

如請求項2~4中任一項之製造方法，其中對於式(A’)所示化合物而言，使用0.8~1.2莫耳當量之鹼。 The production method according to any one of claims 2 to 4, wherein, for the compound of the formula (A'), a base of 0.8 to 1.2 moles is used.

一種下述式(1)所示化合物或其衍生物的製造方法 (式中，Su表示自糖除去糖苷性羥基之基)，其特徵為含有使下述式(B) (式中，R²表示芳基甲基，R¹與前述相同)所示化合物與下述式(C)【化5】ASu-X (C)(式中，ASu表示自經醯化的糖除去糖苷性羥基之基，X表示脫離基)所示化合物進行反應，得到下述式(D) (式中，R¹、R²及ASu與前述相同)所示化合物之糖基化步驟，與使式(D)所示化合物的基R¹及基R²脫離之脫離步驟。 Method for producing a compound represented by the following formula (1) or a derivative thereof (In the formula, Su represents a group from which a glycosidic hydroxyl group is removed from a sugar), and is characterized by containing the following formula (B) (wherein R ² represents an arylmethyl group, and R ¹ is the same as defined above) and a compound of the following formula (C) [Chem. 5] ASu-X (C) (wherein ASu represents a deuterated sugar) The compound represented by the glycosidic hydroxyl group is removed, and the compound represented by X represents a leaving group), and the following formula (D) is obtained. The glycosylation step of the compound of the formula (wherein R ¹ , R ² and ASu are the same as defined above) is carried out in a detachment step from the group R ¹ and the group R ^{2 of the} compound of the formula (D).

如請求項6之製造方法，其中進一步含有將前述式 (A)所示化合物與芳基甲基鹵化物進行反應後，使用鹼進行脫醯化處理，製造出式(B)所示化合物之步驟。 The manufacturing method of claim 6, which further comprises the aforementioned formula After the compound of the formula (A) is reacted with an arylmethyl halide, the mixture is treated with a base to produce a compound of the formula (B).

如請求項6或7之製造方法，其中式(C)所示化合物為α體與β體之混合物。 The production method according to claim 6 or 7, wherein the compound represented by the formula (C) is a mixture of an α body and a β body.

如請求項6~8中任一項之製造方法，其中式(C)中之X為亞胺酸酯基。 The production method according to any one of claims 6 to 8, wherein X in the formula (C) is an urinate group.

如請求項6~9中任一項之製造方法，其中進一步含有使用鹼使下述式(C’)【化7】ASu-OR¹ (C')(式中，R¹及ASu與前述相同)所示化合物進行脫醯化處理，得到下述式(C”)【化8】ASu-OH (C")(式中，ASu與前述相同)所示化合物之步驟、及使前述式(C”)所示化合物與對應脫離基X之化合物進行反應，得到前述式(C)所示化合物之步驟。 The production method according to any one of claims 6 to 9, which further comprises the following formula (C') using the base: ASu-OR ¹ (C') (wherein R ¹ and ASu are the same as the above) The compound shown is subjected to a depurination treatment to obtain a step of the compound of the following formula (C") (A8), ASu-OH (C") (wherein ASu is the same as defined above), and the above formula (C) The compound shown in the formula () is reacted with a compound corresponding to the leaving group X to obtain a compound of the above formula (C).

如請求項10之製造方法，其中式(C’)所示化合物為α體與β體之混合物。 The method of claim 10, wherein the compound of the formula (C') is a mixture of an alpha body and a beta body.

如請求項10或11之製造方法，其中鹼為第2級胺。 The method of producing the item 10 or 11, wherein the base is a second-order amine.

如請求項10~12中任一項之製造方法，其中鹼為N-單取代哌嗪。 The process of any one of claims 10 to 12, wherein the base is an N-monosubstituted piperazine.

如請求項6~13中任一項之製造方法，其中在酸的存在下，使式(B)所示化合物與式(C)所示化合物進行反應。 The production method according to any one of claims 6 to 13, wherein the compound of the formula (B) is reacted with the compound of the formula (C) in the presence of an acid. should.

如請求項6~14中任一項之製造方法，其中使式(B)所示化合物與式(C)所示化合物之反應在非加熱下進行。 The production method according to any one of claims 6 to 14, wherein the reaction of the compound of the formula (B) with the compound of the formula (C) is carried out without heating.

如請求項6~15中任一項之製造方法，其中脫離步驟為含有將式(D)所示化合物經氫化處理，得到下述式(E) (式中，R¹及ASu與前述相同)所示化合物之步驟、及將式(E)所示化合物進行脫醯化處理，得到式(1)所示化合物之步驟。 The production method according to any one of claims 6 to 15, wherein the detaching step comprises subjecting the compound represented by the formula (D) to a hydrogenation treatment to obtain the following formula (E): The step of (wherein, R ¹ and ASu are the same as defined above) and the step of subjecting the compound of the formula (E) to depurination to obtain a compound of the formula (1).

如請求項6~16中任一項之製造方法，其中糖為單糖。 The method of any one of claims 6 to 16, wherein the sugar is a monosaccharide.

如請求項6~17中任一項之製造方法，其中糖為己糖。 The method of any one of claims 6 to 17, wherein the sugar is hexose.

一種化合物或衍生物，其特徵為下述式(1B) 所示化合物或其衍生物。 a compound or derivative characterized by the following formula (1B) A compound or derivative thereof.

一種化合物或衍生物，其特徵為藉由如請求項6~18中任一項之方法所得之前述式(1)所示化合物或其衍生物。 A compound or a derivative thereof, which is a compound represented by the above formula (1) or a derivative thereof obtained by the method according to any one of claims 6 to 18.

一種組成物，其特徵為含有如請求項20之化合物或其衍生物。 A composition comprising a compound of claim 20 or a derivative thereof.

一種如請求項21之組成物的製造方法，其特徵為混合如請求項20之化合物或其衍生物與組成物之構成成分。 A method of producing a composition according to claim 21, characterized by mixing a compound of claim 20 or a derivative thereof and a constituent of the composition.