WO1991017990A1 - Process for producing l-ascorbic acid derivative - Google Patents

Process for producing l-ascorbic acid derivative Download PDF

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Publication number
WO1991017990A1
WO1991017990A1 PCT/JP1991/000701 JP9100701W WO9117990A1 WO 1991017990 A1 WO1991017990 A1 WO 1991017990A1 JP 9100701 W JP9100701 W JP 9100701W WO 9117990 A1 WO9117990 A1 WO 9117990A1
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WO
WIPO (PCT)
Prior art keywords
ascorbic acid
acid
isopropylidene
producing
reaction
Prior art date
Application number
PCT/JP1991/000701
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French (fr)
Japanese (ja)
Inventor
Masashi Toyoda
Yoshio Mishima
Masahiro Tsuji
Original Assignee
Nisshin Flour Milling Co., Ltd.
Senju Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Nisshin Flour Milling Co., Ltd., Senju Pharmaceutical Co., Ltd. filed Critical Nisshin Flour Milling Co., Ltd.
Publication of WO1991017990A1 publication Critical patent/WO1991017990A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for producing 5,6-O-isopropylidene-L-ascorbic acid.
  • an industrially advantageous method not only has a good yield, but also uses a reagent that is inexpensive and easy to handle, and the amount of the reagent used is as small as possible.
  • the method is required to have advantages such as a short time and easy reaction operation and post-treatment, however, the above-mentioned method satisfies all of them.
  • the catalyst is copper sulfate, use sulfuric acid with an O / w ratio of at least 6 times that of L-ascorbic acid.
  • the catalyst is zinc chloride, use an O / w ratio of at least 2 times that of L-ascorbic acid.
  • the cost is also higher because of the use of 30% (v / w ratio) of L-ascorbic acid.
  • post-processing becomes difficult.
  • the yield is satisfactory, but it is difficult to say that these reagents are irritating and are not necessarily industrially easy to handle.
  • the present inventors have conducted intensive studies to overcome the drawbacks of the conventional method, and as a result, by reacting L-ascorbic acid and acetone in the presence of sulfuric acid, 5,6-0-a
  • the present invention has been completed on the basis of a completely new finding that isopropylidene-L-ascorbic acid can be obtained easily and in a high yield.
  • the present invention provides a method for reacting L-ascorbic acid and acetone in the presence of sulfuric acid as a catalyst, and comprises 5,6-0-isopropylidene L-type. This is a method for producing asconolevic acid.
  • the amount of acetone used in the present invention is about 5 10 times by volume / weight ratio (v / w) with respect to L-ascorbic acid, but it is sufficient to use 5 times the amount.
  • the sulfuric acid used as a catalyst in the present invention is concentrated sulfuric acid.
  • the amount used is 10 to 40% by weight / weight ratio (w / w) with respect to L-ascorbic acid. Preferably, about 20% is used.
  • the reaction is carried out at a temperature ranging from 0 ° C to 50 ° C, preferably from 5 to 20 ° C.
  • the reaction time is about 1 to 10 hours, preferably about 2 hours.
  • Acetone 1000 * was added to L-ascorbic acid 2009, and then 80 g of concentrated sulfuric acid was added dropwise at 5-10 ° C with stirring over 2 hours. Thereafter, the temperature is returned to room temperature, and the crystals which have been obtained are filtered, washed with water and dried under vacuum, and 216 g (yield 88%) of 5,6--0_isopropylidene L —Ascorbic acid was obtained. 210 ° C (decomposition)
  • L-ascorbic acid and acetone are reacted in the presence of sulfuric acid, and 5,6-0-isopropylidene-L-asconolevin is provided.
  • An industrially advantageous process for the production of acids is provided.
  • the acetonidation reaction of the present invention is industrially easy to handle and inexpensive in sulfuric acid in about 5 times the amount (v / w ratio) of L-ascorbic acid. Can be used as a catalyst and can proceed under mild reaction conditions in a relatively short time, for example, not exceeding 2 hours. Isolation of the resulting 5,6-0-isopropylidene-L-asconolevinic acid is extremely easy and in high yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

5,6-O-Isopropylidene-L-ascorbic acid is produced by the reaction of L-ascorbic acid with acetone in the presence of sulfuric acid.

Description

明 細 書 L ーァ スコルビン酸誘導体の製造法  Description L-Scorbic acid derivative production method
(産業上の利用分野） (Industrial applications)
本発明は 5， 6— O— イ ソ プ ロ ピ リ デ ン ー L ー ァ ス コ ル ビン酸の製造法に関する。  The present invention relates to a process for producing 5,6-O-isopropylidene-L-ascorbic acid.
(従来技術）  (Prior art)
5， 6— 0—イ ソプロ ピ リ デンー L 一ァス コノレビン酸は ァス コルビン酸様の薬理作用が期待されるのみな らず、 抗凝血剤、 抗止血剤並びに L ーァス コルビン酸の安定化 誘導体と して知 られる L —ァス コルビン酸一 2 —硫酸ェ ステルおよび L ーァス コルビン酸一 2 —燐酸エステルで 代表される有用化合物の合成中間体と して公知であ り 、 従っ て 5， 6— 0—イ ソ プロ ピ リ デンー L — ァ ス コルビ ン 酸を効率よ く 製造す.る こ と には産業上きわめて大き い意 味があ る。  5, 6-0-Isopropylidene-L-asconolevic acid is not only expected to have an ascorbic acid-like pharmacological action, but also has an anticoagulant, anti-hemostatic agent and stability of L-ascorbic acid It is known as an intermediate for synthesizing useful compounds represented by L-ascorbic acid 12-sulfate and L-ascorbic acid 12-phosphate known as chlorinated derivatives. , 6—0—Isopropylidene L—Ascorbic acid has a significant industrial significance in producing it efficiently.
L —ァス コルビン酸とァセ ト ン との脱水縮合反応によ る 5， 6— O— イ ソ プロ ピ リ デン一 L —ァス コルビン酸の 製造法は、 これまでに種々 の方法が知 られている。 例え ば大量の硫酸銅を触媒とする F. Micheelらの「Chem. Ber.， 69B, 879頁 （1936)」 および J. S. Brimacomboらの rCarbohydrate Res.， 45巻， 45頁 （ 1975)」に言己載の方法、 p - トルエンスノレホ ン酸を用いる E. Cutloらの 「Gazz. Chim. Ital.， 91巻， 964頁 （1961 )」に記載の方法、 過剰の 塩ィ匕水素を用いるし · L. Salomonの 厂 Expe r i en t i a . 619頁 (1963) J および R- C Hummaらの 厂 Carbohyrate. Res.， 19卷 . 127頁（1971)」に記載の方法、 塩化ァセチルを用いる K. G. A. Jac - ksonらの「Can丄 Chem.， 47巻， 2498頁（1969)」 お よび M. E. Jungらの 「J. Am. Chem. Soc.， 102卷， 6304頁 (1980)」 に記載の方法、 塩化亜鉛を用いる特開昭 58— 131978号公報に記載の方法およびヨ ウ化水素、 五塩化ァ ンチモ ンま たは五フ ッ化ア ンチモ ンを用 い る特開昭 60— 69079号公報に記載の方法な どが知 られてい る 。 Various methods have been used to produce 5,6-O-isopropylidene-L-ascorbic acid by the dehydration condensation reaction between L-ascorbic acid and acetone. Are known. For example, F. Micheel et al., “Chem. Ber., 69B, p. 879 (1936)” and rCarbohydrate Res., JS Brimacombo et al. The method described in E. Cutlo et al., Gazz. Chim. Ital., Vol. 91, p. 964 (1961) using p-toluene sulphonic acid. The method described in L. Salomon's Factory Experimentia. Page 619 (1963) J and R-C Humma et al., Factory Carbohyrate. Res., Vol. 19, page 127 (1971) Kac Jac-kson et al., “Can. Chem., 47, 2498 (1969)” and ME Jung et al., “J. Am. Chem. Soc., 102, 6304 (1980) using acetyl chloride. The method described in JP-A-58-131978 using zinc chloride and the method described in JP-A-58-131978 using hydrogen iodide, antimony pentachloride or antimony pentafluoride. A method described in Japanese Patent Application Laid-Open No. 60-69079 is known.
(発明が解決しょ う とする課題）  (Problems to be solved by the invention)
と こ ろで工業的な製法を考える場合、 工業的に有利な 方法とは収率がよいばかり でな く 、 使用する試薬が安価 で取扱いやす く 、 その使用量はでき るだけ少な く 、 反応 時間は短 く 、 また反応操作および後処理は容易であ る こ とな どの利点を具備する ものであ る こ とが求め られる しか しながら前記 した方法はそれらすベてを満足する も のではな く 、 少量規模の場合は実施可能であ っ て も、 こ れを工業的規模で実施する場合には有利な方法とは言い 難い ものが多い。 例えば触媒が硫酸銅の場合 L 一ァスコ ルビ ン酸の 6 倍以上 O/w比） の硫酸鋦を使用 し、 塩化亜 鉛の場合は L —ァスコ ルビン酸の 2倍以上 O/w比） の塩 化亜鉛を使用 し、 p — ト ルエンスルホ ン酸の場合は L 一 ァ ス コ ノレ ビ ン酸の 25% (w/w比） の p — ト ノレエ ン ス ゾレホ ン 酸を使用 し、 アセ ト ン も L ーァス コ ルビン酸に対 して 30 倍（v/w比） 程度使用するためそれだけ コ ス 卜が高 く な る し、 また後処理も困難になる。 一方、 塩化水素や塩化ァ セチルの場合、 収率的には満足 し得るが、 こ れらの試薬 は刺激性があ り工業的に必ずし も取 り扱いやすい と は言 い難い。 同様に、 ヨ ウ化水素、 五塩化ア ンチモ ンまたは 五フ ッ化ア ンチモ ンの場合 も収率的には満足 し得るが、 L — ァ ス コ ル ビ ン酸に対 して 15倍量（v /w比 ) の アセ ト ン を使用 し、 必要に応 じてさ らにモ レキュラ ー 'シーブス ' 3 Aで脱水操作を施さなければな らず、 これ らの従来方 法は必ず し も工業的製法 と して優れてい る と は言い難 い。 However, when considering an industrial production method, an industrially advantageous method not only has a good yield, but also uses a reagent that is inexpensive and easy to handle, and the amount of the reagent used is as small as possible. The method is required to have advantages such as a short time and easy reaction operation and post-treatment, however, the above-mentioned method satisfies all of them. In addition, even if it can be carried out on a small scale, it is difficult to say that it is an advantageous method when it is carried out on an industrial scale. For example, if the catalyst is copper sulfate, use sulfuric acid with an O / w ratio of at least 6 times that of L-ascorbic acid. If the catalyst is zinc chloride, use an O / w ratio of at least 2 times that of L-ascorbic acid. Use zinc chloride, and in the case of p-toluenesulphonic acid, use 25% (w / w ratio) of p-toluenesolefonic acid, and use p-toluenesolefonic acid for acetate. The cost is also higher because of the use of 30% (v / w ratio) of L-ascorbic acid. Also, post-processing becomes difficult. On the other hand, in the case of hydrogen chloride or acetyl chloride, the yield is satisfactory, but it is difficult to say that these reagents are irritating and are not necessarily industrially easy to handle. Similarly, in the case of hydrogen iodide, antimony pentachloride or antimony pentafluoride, the yield is satisfactory, but the amount is 15 times that of L-ascorbic acid. (V / w ratio) of acetonitrile and, if necessary, a further dehydration operation with Molecular 'Sieves' 3 A. These conventional methods must be used. However, it is difficult to say that these are also excellent as industrial manufacturing methods.
(課題を解決するための手段）  (Means for solving the problem)
本発明者らは従来法の欠点を克服するため鋭意研究を 重ねた結果、 L ーァス コルビン酸とアセ ト ン とを硫酸の 存在下に反応させる こ と によ り 、 5 , 6— 0 —イ ソ プロ ピ リ デン一 L ーァス コルビン酸が容易にかつ高収率で得 ら れる とい う 全 く 新 しい知見に基づいて本発明を完成させ ο  The present inventors have conducted intensive studies to overcome the drawbacks of the conventional method, and as a result, by reacting L-ascorbic acid and acetone in the presence of sulfuric acid, 5,6-0-a The present invention has been completed on the basis of a completely new finding that isopropylidene-L-ascorbic acid can be obtained easily and in a high yield.
すなわち、 本発明は、 L —ァス コルビン酸とア セ ト ン とを触媒と しての硫酸の存在下に反応させる こ とを特徴 とする 5 , 6— 0 —イ ソプロ ピ リ デンー L 一ァス コ ノレビン 酸の製造法であ る。  That is, the present invention provides a method for reacting L-ascorbic acid and acetone in the presence of sulfuric acid as a catalyst, and comprises 5,6-0-isopropylidene L-type. This is a method for producing asconolevic acid.
本発明において用い られる アセ ト ンの量は、 L — ァ ス コルビン酸に対 して容量 重量比（v / w )で 5 1 0倍程度 であ るが、 5 倍量用いれば十分である。  The amount of acetone used in the present invention is about 5 10 times by volume / weight ratio (v / w) with respect to L-ascorbic acid, but it is sufficient to use 5 times the amount.
本発明において触媒と して用い られる硫酸は濃硫酸で、 その使用量は L ーァスコルビン酸に対 して重量ノ重量比 (w/w)で 10〜40%量である。 好ま し く は 20%量程度用い られる。 The sulfuric acid used as a catalyst in the present invention is concentrated sulfuric acid. The amount used is 10 to 40% by weight / weight ratio (w / w) with respect to L-ascorbic acid. Preferably, about 20% is used.
反応温度は 0 °Cない し 50°Cの温度範囲で行われるが、 好ま し く は 5 ~ 20°Cの範囲である。  The reaction is carried out at a temperature ranging from 0 ° C to 50 ° C, preferably from 5 to 20 ° C.
反応時間は 1〜 10時間程度であ り 、 好ま し く は 2時間 程度であ る。  The reaction time is about 1 to 10 hours, preferably about 2 hours.
か く して得 られた 5 , 6— 0 —イ ソプロ ピ リ デン _ L — ァス コルビン酸を反応系から単離する には反応終了後に 反応液中に柝出 している結晶を炉取するだけでよ く 、 通 常の精製手段を全 く 施す こ と な く 十分な純度を有する 5， 6— 0 —イ ソプロ ピ リ デンー L —ァス コルビン酸が容 易に得 られる。  In order to isolate the thus obtained 5, 6-0—isopropylidene_L—ascorbic acid from the reaction system, the crystals that have been crystallized out of the reaction solution after the completion of the reaction are taken out of the reactor. Thus, 5,6-0-isopropylidene-L-ascorbic acid having sufficient purity can be easily obtained without performing any ordinary purification means.
(実施例）  (Example)
以下、 本発明を実施例にてさ らに詳 し く 説明するが、 これらは本発明を限定する ものではない。  Hereinafter, the present invention will be described in more detail with reference to Examples, but these do not limit the present invention.
実施例 1 Example 1
L —ァス コルビン酸 2009にァセ ト ン 1000* を加え、 次 いで 5〜 10 °Cにて撹拌下に濃硫酸 80 gを 2時間で滴下 し た。 その後室温に戻 し、 柝出 している結晶を炉別 し、 Ύ セ ト ンで洗浄 しそ して真空乾燥 して 216g (収率 88% ) の 5, 6— 0 _ イ ソプロ ピ リ デンー L —ァ ス コ ルビン酸を得 た。 融点 210°C (分解）  Acetone 1000 * was added to L-ascorbic acid 2009, and then 80 g of concentrated sulfuric acid was added dropwise at 5-10 ° C with stirring over 2 hours. Thereafter, the temperature is returned to room temperature, and the crystals which have been obtained are filtered, washed with water and dried under vacuum, and 216 g (yield 88%) of 5,6--0_isopropylidene L —Ascorbic acid was obtained. 210 ° C (decomposition)
赤外線スぺク ト ル ：  Infrared spectrum:
レ max3200〜 3600、 〗 760、 1670cit-' 実施例 2 Les max 3200-3600,〗 760, 1670cit- ' Example 2
(5)  (Five)
L ー ァ ス コ ル ビ ン酸 10も g、 ア セ ト ン 6(U、 濃硫酸 2も 9 を用いて実施例 1 と同様に して反応を行う こ と によ り 10 も (収率 82% ) の 5， 6— 0— イ ソ プロ ピ リ デンー L —ァ ス コルビン酸を得た。 融点 210°C (分解）。  The reaction was carried out in the same manner as in Example 1 using 10 g of L-ascorbic acid and 9 g of acetate 6 (U and 9 of concentrated sulfuric acid 2). 82%) of 5, 6-0-isopropylidene L-ascorbic acid, melting point 210 ° C (decomposition).
(発明の効果）  (The invention's effect)
本発明によれば、 L —ァス コルビン酸とァセ ト ン とを 硫酸の存在下に反応させる こ とを特徴とする 5， 6 - 0 - イ ソ プロ ピ リ デン一 L — ァス コノレビン酸の工業的に有利 な製造法が提供される。  According to the present invention, L-ascorbic acid and acetone are reacted in the presence of sulfuric acid, and 5,6-0-isopropylidene-L-asconolevin is provided. An industrially advantageous process for the production of acids is provided.
本発明のァセ トナイ ド化反応は L— ァス コルビン酸に 対 して 5倍量程度（v/w比） のア セ ト ン中にて工業的に取 り 扱いやす く かつ安価な硫酸を触媒と して用いて温和な 反応条件下に比較的短時間例えば 2時間を越えない時間 で進行させる こ とができ る。 そ して生成 した 5, 6— 0— イ ソプロ ピ リ デン一 L 一ァ ス コノレビ ン酸の単離は極めて 容易で しかも高収率である。  The acetonidation reaction of the present invention is industrially easy to handle and inexpensive in sulfuric acid in about 5 times the amount (v / w ratio) of L-ascorbic acid. Can be used as a catalyst and can proceed under mild reaction conditions in a relatively short time, for example, not exceeding 2 hours. Isolation of the resulting 5,6-0-isopropylidene-L-asconolevinic acid is extremely easy and in high yield.

Claims

請 求 の 範 囲 The scope of the claims
1. L ーァスコルビン酸とアセ ト ンとを硫酸の存在下に 反応させる こ とを特徴とする 5， 6— 0 — イ ソプロ ピ リ デン一 L ーァス コルビン酸の製造法。 1. A process for producing 5,6-0-isopropylidene-L-ascorbic acid, which comprises reacting L-ascorbic acid with acetone in the presence of sulfuric acid.
PCT/JP1991/000701 1990-05-24 1991-05-24 Process for producing l-ascorbic acid derivative WO1991017990A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/132738 1990-05-24
JP13273890A JPH0429989A (en) 1990-05-24 1990-05-24 Production of l-ascorbic acid derivative

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WO1991017990A1 true WO1991017990A1 (en) 1991-11-28

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* Cited by examiner, † Cited by third party
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US20090170932A1 (en) * 2007-12-31 2009-07-02 Tyco Healthcare Group Lp Disinfectant compositions, methods and systems

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5064267A (en) * 1973-10-18 1975-05-31
JPS50116467A (en) * 1974-02-28 1975-09-11
JPS58131978A (en) * 1982-01-15 1983-08-06 イ−ライ・リリ−・アンド・カンパニ− Ascorbic acid ether and related compounds
JPS6069079A (en) * 1983-09-27 1985-04-19 Takeda Chem Ind Ltd Production of l-ascorbic acid and d-erythorbic acid ketal

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5064267A (en) * 1973-10-18 1975-05-31
JPS50116467A (en) * 1974-02-28 1975-09-11
JPS58131978A (en) * 1982-01-15 1983-08-06 イ−ライ・リリ−・アンド・カンパニ− Ascorbic acid ether and related compounds
JPS6069079A (en) * 1983-09-27 1985-04-19 Takeda Chem Ind Ltd Production of l-ascorbic acid and d-erythorbic acid ketal

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