JP2005320310A - Method for producing 3-o-alkylascorbic acid - Google Patents
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本発明は、３−Ｏ−アルキルアスコルビン酸の製造において、一般にはアスコルビン酸の５，６位の水酸基を保護してから３−Ｏ−アルキル化し、次いで脱保護する３工程を要する反応をアスコルビン酸そのものから１工程で目的の３−Ｏ−アルキルアスコルビン酸を得る製造法に関する。 In the production of 3-O-alkylascorbic acid, the present invention generally comprises a reaction that requires three steps of 3-O-alkylation after protecting the hydroxyl groups at positions 5 and 6 of ascorbic acid and then deprotecting the ascorbic acid. The present invention relates to a production process for obtaining the desired 3-O-alkylascorbic acid from itself in one step.
アスコルビン酸は抗酸化剤、ラジカル捕縛剤としてよく知られている。しかし、アスコルビン酸自体は脂溶性が少ない為、脂溶性と安定性が増加したアスコルビン酸誘導体、特に３−Ｏ−アルキルアスコルビン酸が注目を集めている。
これまでの３−Ｏ−アルキルアスコルビン酸の製造は５、６位の水酸基をイソプロピリデンで保護して３−Ｏ−アルキル化し最後に保護基を除去する方法が取られている（特許文献１〜４、非特許文献１〜６）。しかし、この方法では３工程を要し時間的、労力的、コスト的にみてよい方法とは思えない。Ascorbic acid is well known as an antioxidant and radical scavenger. However, since ascorbic acid itself has low fat solubility, ascorbic acid derivatives having increased fat solubility and stability, particularly 3-O-alkylascorbic acid, have attracted attention.
The production of 3-O-alkylascorbic acid so far employs a method in which the hydroxyl groups at the 5- and 6-positions are protected with isopropylidene to form 3-O-alkyl and finally the protective group is removed (Patent Documents 1 to 3). 4, non-patent documents 1 to 6). However, this method requires three steps and does not seem to be a method that can be seen in terms of time, labor, and cost.
アスコルビン酸を直接３−Ｏ−アルキル化する方法は文献的には二つあり（非特許文献７、８）、一つはＤＭＳＯ溶媒中２．５倍のアスコルビン酸及び３．５倍のＮａＨＣＯ３を使用しており、もう一つは−７８℃でＤＭＦ中アルコールとジエチル ジアゾジカルボキシレートを用いて光延反応を行っている。双方ともアスコルビン酸を溶解させるために沸点の高い特殊な溶媒を使用している。工業的には大量のＤＭＳＯ溶媒は沸点が高く、発がん性の問題もあるので避けたい溶媒であり、−７８℃の条件も反応操作上できれば改善したい条件である。There are two literature methods for direct 3-O-alkylation of ascorbic acid (Non-patent Documents 7 and 8). One is 2.5 times ascorbic acid and 3.5 times NaHCO 3 in DMSO solvent. The other is Mitsunobu reaction using alcohol and diethyl diazodicarboxylate in DMF at -78 ° C. Both use special solvents with high boiling points to dissolve ascorbic acid. Industrially, a large amount of DMSO solvent has a high boiling point and has a carcinogenic problem, so it is a solvent that should be avoided. A condition of −78 ° C. is a condition that should be improved if the reaction operation can be performed.
アスコルビン酸の水酸基を保護することなく、直接、しかも選択的に３−Ｏ−アルキル化する方法で、取り扱いやすい溶媒及び試薬を用いて、簡単な操作で３−Ｏ−アルキルアスコルビン酸が製造できれば、特に大量合成を必要とする企業にとって産業上極めて有用な方法となるであろう。
本発明はアスコルビン酸のアルキル化により３−Ｏ−アルキルアスコルビン酸を製造する方法を提供することを目的とする。Without protecting the hydroxyl group of ascorbic acid, if 3-O-alkylascorbic acid can be produced by a simple operation using a solvent and a reagent that are easy to handle by direct and selective 3-O-alkylation, This will be an extremely useful industrial method especially for companies that require mass synthesis.
An object of the present invention is to provide a method for producing 3-O-alkylascorbic acid by alkylation of ascorbic acid.
本発明は上記を目的に検討した結果、３級アミンの存在下、アルキル スルフォナート又はジアルキル硫酸をアルキル化剤として用いることによりアスコルビン酸から１工程で３−Ｏ−アルキルアスコルビン酸を製造することに成功した。すなわち、本発明は下記式（Ｉ） As a result of studying the present invention, the present invention succeeded in producing 3-O-alkylascorbic acid from ascorbic acid in one step by using alkyl sulfonate or dialkyl sulfuric acid as an alkylating agent in the presence of a tertiary amine. did. That is, the present invention provides the following formula (I)
で表されるＬ−アスコルビン酸を３級アミンの存在下式
Ｒ２ＳＯ３Ｒ１ （ＩＩＩ） 又は Ｒ１ＯＳＯ３Ｒ１ （ＩＶ）
（式中、Ｒ１は炭素数１〜２２のアルキル基を示し、Ｒ２はアリール基又はアルキル基を示す。）で表されるスルホン酸化合物と反応させることを特徴とする式（ＩＩ）L-ascorbic acid represented by the formula R 2 SO 3 R 1 (III) or R 1 OSO 3 R 1 (IV) in the presence of a tertiary amine
(Wherein R 1 represents an alkyl group having 1 to 22 carbon atoms, and R 2 represents an aryl group or an alkyl group), and is reacted with a sulfonic acid compound represented by formula (II)
（式中、Ｒ１は前記と同意義である。）で表される３−Ｏ−アルキルアスコルビン酸の製造方法である。(Wherein R 1 has the same meaning as described above), and is a method for producing 3-O-alkylascorbic acid.
本発明において、Ｒ１で示される炭素数１〜２２のアルキル基は直鎖状、分岐状又は環状のいずれであってもよく、その例としてはメチル基、エチル基、イソプロピル基、ｔｅｒｔ−ブチル基、シクロペンチル基、シクロヘキシル基などが挙げられる。
本発明において、３級アミンとはトリエチルアミン、Ｎ−メチルピペリジン、Ｎ−メチルモルホリンなど脂肪族アミン及びパラジメチルアミノピリジン、Ｎ，Ｎ−ジメチルアニリンなどの芳香族アミンを指す。In the present invention, the alkyl group having 1 to 22 carbon atoms represented by R 1 may be linear, branched or cyclic, and examples thereof include a methyl group, an ethyl group, an isopropyl group, and tert-butyl. Group, cyclopentyl group, cyclohexyl group and the like.
In the present invention, tertiary amine refers to aliphatic amines such as triethylamine, N-methylpiperidine and N-methylmorpholine, and aromatic amines such as paradimethylaminopyridine and N, N-dimethylaniline.
本発明において、式ＩＩＩで示されるアルキル スルフォナートとは芳香族及び脂肪族スルフォナートを指し、例えばパラトルエンスルフォナート及びメタンスルフォナートなどを指す。式ＩＶで示されるジアルキル硫酸はジメチル硫酸、ジエチル硫酸など硫酸の水素原子がアルキル置換されたものを指す。 In the present invention, the alkyl sulfonate represented by the formula III refers to aromatic and aliphatic sulfonates such as para-toluene sulfonate and methane sulfonate. The dialkyl sulfuric acid represented by the formula IV refers to an alkyl-substituted hydrogen atom of sulfuric acid such as dimethyl sulfuric acid and diethyl sulfuric acid.
本発明により、アスコルビン酸の水酸基を保護することなく、直接、しかも選択的に３−Ｏ−アルキル化する方法を提供することができた。 According to the present invention, it was possible to provide a method for 3-O-alkylation directly and selectively without protecting the hydroxyl group of ascorbic acid.
本発明の製造方法は、有害な溶媒を使用することなく、試薬はほぼ当モル用い１〜２時間の還流という簡便な操作で行うことができる。反応は通常有機溶媒中で行われるが、極性溶媒が好ましく、メタノール、エタノール等のアルコール類、アセトニトリル、ニトロメタン等が好ましい。アスコルビン酸自体はアルコール類には溶けにくいが、３級アミンを添加すると容易に溶解する。 The production method of the present invention can be carried out by a simple operation of using an approximately equimolar amount of reflux and refluxing for 1 to 2 hours without using a harmful solvent. The reaction is usually carried out in an organic solvent, but a polar solvent is preferred, and alcohols such as methanol and ethanol, acetonitrile, nitromethane and the like are preferred. Ascorbic acid itself is hardly soluble in alcohols, but easily dissolves when a tertiary amine is added.
以下、実施例を挙げて本発明を具体的に説明する。
［実施例１］ ３−Ｏ−メチルアスコルビン酸の合成
アスコルビン酸（３２５ｍｇ，２ｍｍｏｌ）のメタノール（４ｍｌ）溶液にトリエチルアミン（２２３ｍｇ，２．２ｍｍｏｌ）を加え攪拌した。アスコルビン酸はトリエチルアミン塩となって溶解した。次いで、メチル メタンスルフォナート（２４２ｍｇ，２．２ｍｍｏｌ）を加え２時間加熱還流した。反応後メタノールを減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：ＡｃＯＥｔ−ＭｅＯＨ＝５：１）に付し標記化合物（２２６ｍｇ，５９％）を得た。
Ｍｐ １２５−１２７℃（ＡｃＯＥｔ）［α］Ｄ ２２＋２７．９（ｃ＝１．１，ＭｅＯＨ）
ＩＲ（ＫＢｒ）３３５０，３１５０，１７４０，１６８０ｃｍ−１
１Ｈ ＮＭＲ（ＣＤ３ＯＤ）δ３．６４（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．８０−３．８５（ｍ，１Ｈ），４．１８（ｓ，３Ｈ），４．７７（ｓ，１Ｈ）
ＥＩ−ＭＳ ｍ／ｚ １９０（Ｍ＋，８．３５），１３０（１００）Hereinafter, the present invention will be specifically described with reference to examples.
[Example 1] Synthesis of 3-O-methylascorbic acid To a solution of ascorbic acid (325 mg, 2 mmol) in methanol (4 ml), triethylamine (223 mg, 2.2 mmol) was added and stirred. Ascorbic acid dissolved as a triethylamine salt. Subsequently, methyl methanesulfonate (242 mg, 2.2 mmol) was added and heated under reflux for 2 hours. After the reaction, methanol was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: AcOEt-MeOH = 5: 1) to obtain the title compound (226 mg, 59%).
Mp 125-127 ° C. (AcOEt) [α] D 22 +27.9 (c = 1.1, MeOH)
IR (KBr) 3350, 3150, 1740, 1680 cm −1
1 H NMR (CD 3 OD) δ 3.64 (d, J = 6.8 Hz, 2H), 3.80-3.85 (m, 1H), 4.18 (s, 3H), 4.77 (s , 1H)
EI-MS m / z 190 (M + , 8.35), 130 (100)
［実施例２］ ３−Ｏ−エチルアスコルビン酸の合成
アスコルビン酸（１７，６ｇ，０．１ｍｏｌ）のエタノール（１４０ｍｌ）溶液にトリエチルアミン（１１．１ｇ，０．１１ｍｏｌ）を加え攪拌した。アスコルビン酸はトリエチルアミン塩となってすぐ溶解した。次いで、エチル メタンスルフォナート（１３．９ｇ，０．１１ｍｏｌ）を加え１時間加熱還流した。反応後エタノールを減圧留去し残渣に水（３０ｍｌ）を加え酢酸エチル（６０ｍｌｘ４）で抽出した。酢酸エチル層は水洗することなく無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムを濾過し濾液を減圧留去すると標記化合物（９．１７ｇ）を得た。水層をさらに酢酸エチルで約８時間連続抽出し、同様の操作により標記化合物（４．３４ｇ）を得た。総収率，１３．５１ｇ，６６％．
Ｍｐ １１６−１１７．５℃（ＡｃＯＥｔ）［α］Ｄ ２３＋４１．６（ｃ＝１．０，ＭｅＯＨ）
ＩＲ（ＫＢｒ）３３００，１７４０，１６７５ｃｍ−１
１Ｈ ＮＭＲ（ＣＤ３ＯＤ）δ１．３７（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），３．６４（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．８１−３．８７（ｍ，２Ｈ），４．７６（ｓ，１Ｈ）
ＥＩ−ＭＳ ｍ／ｚ ２０４（Ｍ＋，２０．４９），１４４（１００）Example 2 Synthesis of 3-O-ethylascorbic acid Triethylamine (11.1 g, 0.11 mol) was added to an ethanol (140 ml) solution of ascorbic acid (17,6 g, 0.1 mol) and stirred. Ascorbic acid dissolved immediately as a triethylamine salt. Next, ethyl methanesulfonate (13.9 g, 0.11 mol) was added and the mixture was heated to reflux for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, water (30 ml) was added to the residue, and the mixture was extracted with ethyl acetate (60 ml × 4). The ethyl acetate layer was dried over anhydrous sodium sulfate without washing with water. Anhydrous sodium sulfate was filtered and the filtrate was distilled off under reduced pressure to obtain the title compound (9.17 g). The aqueous layer was further continuously extracted with ethyl acetate for about 8 hours, and the title compound (4.34 g) was obtained by the same operation. Total yield, 13.51 g, 66%.
Mp 116-117.5 ℃ (AcOEt) [α ] D 23 +41.6 (c = 1.0, MeOH)
IR (KBr) 3300, 1740, 1675 cm −1
1 H NMR (CD 3 OD) δ 1.37 (t, J = 7.3 Hz, 3H), 3.64 (d, J = 6.8 Hz, 2H), 3.81-3.87 (m, 2H) , 4.76 (s, 1H)
EI-MS m / z 204 (M + , 20.49), 144 (100)
［実施例３］ ３−Ｏ−エチルアスコルビン酸の合成
アスコルビン酸（３２５ｍｇ，２ｍｍｏｌ）のアセトニトリル（５ｍｌ）溶液にトリエチルアミン（２２３ｍｇ，２．２ｍｍｏｌ）を加え攪拌する。アスコルビン酸はトリエチルアミン塩となって溶解する。次いで、エチル メタンスルフォナート（２７３ｍｇ，２．２ｍｍｏｌ）を加え１時間加熱還流する。反応後アセトニトリルを減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：ＡｃＯＥｔ−ＭｅＯＨ＝５：１）に付し標記化合物（２３５ｍｇ，５８％）を得た。[Example 3] Synthesis of 3-O-ethylascorbic acid To a solution of ascorbic acid (325 mg, 2 mmol) in acetonitrile (5 ml), triethylamine (223 mg, 2.2 mmol) is added and stirred. Ascorbic acid dissolves as a triethylamine salt. Next, ethyl methanesulfonate (273 mg, 2.2 mmol) is added and heated to reflux for 1 hour. After the reaction, acetonitrile was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: AcOEt-MeOH = 5: 1) to obtain the title compound (235 mg, 58%).
［実施例４］ ３−Ｏ−エチルアスコルビン酸の合成
アスコルビン酸（３２５ｍｇ，２ｍｍｏｌ）のエタノール（４ｍｌ）溶液にトリエチルアミン（２２３ｍｇ，２．２ｍｍｏｌ）を加え攪拌した。アスコルビン酸はトリエチルアミン塩となって溶解した。次いで、ジエチル硫酸（３３９ｍｇ，２．２ｍｍｏｌ）を加え１時間加熱還流した。反応後エタノールを減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：ＡｃＯＥｔ−ＭｅＯＨ＝５：１）に付し標記化合物（２６７ｍｇ，６５％）を得た。Example 4 Synthesis of 3-O-ethylascorbic acid To a solution of ascorbic acid (325 mg, 2 mmol) in ethanol (4 ml) was added triethylamine (223 mg, 2.2 mmol) and stirred. Ascorbic acid dissolved as a triethylamine salt. Next, diethylsulfuric acid (339 mg, 2.2 mmol) was added and heated to reflux for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: AcOEt-MeOH = 5: 1) to obtain the title compound (267 mg, 65%).
［実施例５］ ３−Ｏ−エチル−スコルビン酸の合成
アスコルビン酸（１．７６ｇ，０．０１ｍｏｌ）のエタノール（１４ｍｌ）溶液にトリエチルアミン（１．１１ｇ，０．０１１ｍｏｌ）を加え攪拌した。アスコルビン酸はトリエチルアミン塩となってすぐ溶解した。次いで、ジエチル硫酸（１．７ｇ，０．０１１ｍｏｌ）を加え１時間加熱還流した。反応後エタノールを減圧留去し残渣に水（５ｍｌ）を加え酢酸エチル（２０ｍｌ×４）で抽出した。酢酸エチル層は水洗することなく無水硫酸ナトリウムで乾燥する。無水硫酸ナトリウムを濾過し濾液を減圧留去すると標記化合物（１．１６ｇ，５７％）を得た。Example 5 Synthesis of 3-O-ethyl-scorbic acid Triethylamine (1.11 g, 0.011 mol) was added to an ethanol (14 ml) solution of ascorbic acid (1.76 g, 0.01 mol) and stirred. Ascorbic acid dissolved immediately as a triethylamine salt. Next, diethylsulfate (1.7 g, 0.011 mol) was added, and the mixture was heated to reflux for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, water (5 ml) was added to the residue, and the mixture was extracted with ethyl acetate (20 ml × 4). The ethyl acetate layer is dried over anhydrous sodium sulfate without washing with water. Anhydrous sodium sulfate was filtered and the filtrate was distilled off under reduced pressure to obtain the title compound (1.16 g, 57%).
［実施例６］ ３−Ｏ−ヘプチルアスコルビン酸の合成
アスコルビン酸（３２５ｍｇ，２ｍｍｏｌ）のエタノール（４ｍｌ）溶液にトリエチルアミン（２２３ｍｇ，２．２ｍｍｏｌ）を加え攪拌した。アスコルビン酸はトリエチルアミン塩となって溶解した。次いで、ヘプチル メタンスルフォナート（４２７ｍｇ，２．２ｍｍｏｌ）を加え１時間加熱還流した。反応後エタノールを減圧留去し、残渣をシリカゲルカラムクロマトグラフィー（展開溶媒：ＡｃＯＥｔ−ＭｅＯＨ＝５：１）に付し標記化合物（３１４ｍｇ，５７％）を得た。
Ｍｐ ８８−８９℃（ＡｃＯＥｔ／Ｈｅｘａｎｅ）［α］Ｄ ２２＋３６．９（ｃ＝１．０，ＭｅＯＨ）
ＩＲ（ＫＢｒ）３４３０，３３００，３１７０，１７６０，１７００ｃｍ−１
１Ｈ ＮＭＲ（ＣＤ３ＯＤ）δ０．８０−０．９５（ｍ，３Ｈ），１．２５−１．５０（ｍ，８Ｈ），１．７０−１．８０（ｍ，２Ｈ），３．６６（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．８０−３．９０（ｍ，１Ｈ），４．４０−４．５０（ｍ，２Ｈ），４．７８（ｓ，１Ｈ）
ＥＩ−ＭＳ ｍ／ｚ ２７４（Ｍ＋，１０．０１），１１６（１００）[Example 6] Synthesis of 3-O-heptylascorbic acid Triethylamine (223 mg, 2.2 mmol) was added to an ethanol (4 ml) solution of ascorbic acid (325 mg, 2 mmol) and stirred. Ascorbic acid dissolved as a triethylamine salt. Subsequently, heptyl methanesulfonate (427 mg, 2.2 mmol) was added and heated under reflux for 1 hour. After the reaction, ethanol was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: AcOEt-MeOH = 5: 1) to obtain the title compound (314 mg, 57%).
Mp 88-89 ° C. (AcOEt / Hexane) [α] D 22 +36.9 (c = 1.0, MeOH)
IR (KBr) 3430, 3300, 3170, 1760, 1700 cm −1
1 H NMR (CD 3 OD) δ 0.80-0.95 (m, 3H), 1.25-1.50 (m, 8H), 1.70-1.80 (m, 2H), 3.66 (D, J = 6.8 Hz, 2H), 3.80-3.90 (m, 1H), 4.40-4.50 (m, 2H), 4.78 (s, 1H)
EI-MS m / z 274 (M + , 10.01), 116 (100)
本発明は、アスコルビン酸の水酸基を保護することなく、直接、しかも選択的に３−Ｏ−アルキル化する方法で、取り扱いやすい溶媒及び試薬を用いて、簡単な操作で３−Ｏ−アルキルアスコルビン酸を製造することができ、特に大量合成を必要とする企業にとって産業上極めて有用な方法を提供するものである。 The present invention is a method for directly and selectively 3-O-alkylating without protecting the hydroxyl group of ascorbic acid, and using a solvent and a reagent that are easy to handle, with a simple operation, 3-O-alkylascorbic acid. The present invention provides a method that is extremely useful industrially, particularly for companies that require mass synthesis.
Claims (1)
Ｒ２ＳＯ３Ｒ１ （ＩＩＩ） 又は Ｒ１ＯＳＯ３Ｒ１ （ＩＶ）
（式中、Ｒ１は炭素数１〜２２のアルキル基を示し、Ｒ２はアリール基又はアルキル基を示す。）で表されるスルホン酸化合物と反応させることを特徴とする式（ＩＩ）
(Wherein R 1 represents an alkyl group having 1 to 22 carbon atoms, and R 2 represents an aryl group or an alkyl group), and is reacted with a sulfonic acid compound represented by formula (II)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009286735A (en) * | 2008-05-29 | 2009-12-10 | Shiseido Co Ltd | Skin care preparation |
| CN113527537A (en) * | 2021-07-14 | 2021-10-22 | 润辉生物技术（威海）有限公司 | Levo-vitamin C hyaluronic acid ester derivative and preparation method and application thereof |
| WO2023125957A1 (en) * | 2021-12-31 | 2023-07-06 | 华熙生物科技股份有限公司 | Reduced hyaluronate and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2004307383A (en) * | 2003-04-04 | 2004-11-04 | Shiseido Co Ltd | Method for producing ascorbic acid derivative |
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| JP2004307383A (en) * | 2003-04-04 | 2004-11-04 | Shiseido Co Ltd | Method for producing ascorbic acid derivative |
Non-Patent Citations (2)
| Title |
|---|
| JPN6010032479, Ｔｅｔｒａｈｅｄｒｏｎ, 2000, ５６（３）, ３５７−３６１ * |
| JPN6010032481, Ｔｅｔｒａｈｅｄｒｏｎ, 1996, ５２（４）, １２９３−３０２ * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009286735A (en) * | 2008-05-29 | 2009-12-10 | Shiseido Co Ltd | Skin care preparation |
| CN113527537A (en) * | 2021-07-14 | 2021-10-22 | 润辉生物技术（威海）有限公司 | Levo-vitamin C hyaluronic acid ester derivative and preparation method and application thereof |
| WO2023125957A1 (en) * | 2021-12-31 | 2023-07-06 | 华熙生物科技股份有限公司 | Reduced hyaluronate and preparation method therefor |
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