JPS638954B2 - - Google Patents
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- Publication number
- JPS638954B2 JPS638954B2 JP1175879A JP1175879A JPS638954B2 JP S638954 B2 JPS638954 B2 JP S638954B2 JP 1175879 A JP1175879 A JP 1175879A JP 1175879 A JP1175879 A JP 1175879A JP S638954 B2 JPS638954 B2 JP S638954B2
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- Japan
- Prior art keywords
- acid
- biotin
- reaction
- water
- crystals
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Description
【発明の詳細な説明】
本発明はシス−テトラハイドロ−２−オキソチ
エノ〔３，４−ｄ〕−イミダゾリン−４−吉草酸、
たとえばｄ−ビオチン、dl−ビオチン（以下これ
らをビオチンと称する。）の製法に関するもので
あり、更に詳しくは、
一般式
〔式中、R1、R2は水素原子またはベンジル基で
ある。但し、R1、R2は同時に水素原子となるこ
とはない。R3は水素原子またはカルボキシル基
である。〕
で示される化合物あるいはこれらの混合物をアル
カンスルホン酸類で加熱処理することを特徴とす
るビオチンの製造方法である。DETAILED DESCRIPTION OF THE INVENTION The present invention provides cis-tetrahydro-2-oxothieno[3,4-d]-imidazoline-4-valeric acid,
For example, it relates to the production method of d-biotin and dl-biotin (hereinafter referred to as biotin), and more specifically, the general formula [In the formula, R 1 and R 2 are a hydrogen atom or a benzyl group. However, R 1 and R 2 do not become hydrogen atoms at the same time. R 3 is a hydrogen atom or a carboxyl group. ] This is a method for producing biotin, which is characterized by heat-treating a compound represented by the following or a mixture thereof with an alkanesulfonic acid.
本発明により得られるビオチンはビタミンＨと
も呼ばれ成長促進、皮膚疾患予防治療効果等をも
つ有効な化合物である。 Biotin obtained by the present invention is also called vitamin H, and is an effective compound that has growth promoting, skin disease preventive and therapeutic effects, etc.
従来ビオチンを得る方法としては３，4′−（1′，
3′−ジベンジル−2′−ケトイミダゾリド）−２−
（ω−カルボキシブチル）チオフアンを48％臭化
水素酸中で還流下処理し、脱ベンジル化反応を行
なう製法（特公昭53−27279号公報）が知られて
いるが反応による目的物の収率が低く、また使用
する試剤等が非常に刺激性及び臭気が強く、取扱
い操作に大きな注意を払わねばならない難点があ
る。 The conventional method for obtaining biotin is 3,4'-(1',
3′-dibenzyl-2′-ketoimidazolide)-2-
There is a known production method (Japanese Patent Publication No. 53-27279) in which (ω-carboxybutyl)thiophane is treated under reflux in 48% hydrobromic acid to perform a debenzylation reaction, but the yield of the target product due to the reaction is Moreover, the reagents used are very irritating and have a strong odor, and great care must be taken when handling them.
本発明者らは上述した従来の欠点を克服すべく
鋭意研究努力を重ねた結果、経済的で工業的に容
易な操作で本発明の目的化合物であるdl−ビオチ
ン又は光学的に活性なｄ−ビオチンを高収率にし
かも高品質で製造する方法を発明するに至つた。 The present inventors have made intensive research efforts to overcome the above-mentioned conventional drawbacks, and as a result, we have found that the target compound of the present invention, dl-biotin or optically active d- We have now invented a method for producing biotin in high yield and quality.
本発明方法の実施について説明すると、前記一
般式で示される原料に、原料の重量に対して１〜
100倍重量好ましくは３〜50倍重量のアルカンス
ルホン酸を加え反応温度80〜180℃、好ましくは
110゜〜150℃の範囲で10分〜20時間、好ましくは
30分〜10時間反応を続けた後、反応液を冷却後、
冷水にて処理し、析出する結晶を取して粗結晶
を得、さらに水より再結晶することにより精製し
たビオチンを得ることができる。この反応に際
し、反応系にクロルベンゼン、トルエン、キシレ
ン、オクタン、デカン、アニソール等の沸点100
℃以上の炭化水素系溶媒及び又は酢酸、プロピオ
ン酸等のC2〜C4のカルボン酸類の添加使用が可
能であり、これにより副生成物の抑制及び温度調
節の簡易化に効果を発現する。また本発明の実施
は次のような態様も包含する。 To explain the implementation of the method of the present invention, the raw material represented by the above general formula is
100 times the weight, preferably 3 to 50 times the weight of alkanesulfonic acid is added, and the reaction temperature is 80 to 180°C, preferably
10 minutes to 20 hours at a temperature of 110° to 150°C, preferably
After continuing the reaction for 30 minutes to 10 hours, cool the reaction solution,
Purified biotin can be obtained by treatment with cold water, removing precipitated crystals to obtain crude crystals, and further recrystallizing from water. During this reaction, chlorobenzene, toluene, xylene, octane, decane, anisole, etc. with a boiling point of 100% are added to the reaction system.
It is possible to add a hydrocarbon solvent at a temperature of 0.degree. C. or higher and/or a C2 to C4 carboxylic acid such as acetic acid or propionic acid, which is effective in suppressing by-products and simplifying temperature control. The implementation of the present invention also includes the following aspects.
すなわち、前記一般式の化合物は通常３，４−
（1′，3′−ジベンジル−2′−ケトイミダゾリド）−
２−（ω，ω−ジアルコキシカルボニルブチル）
チオフアンをケン化することにより、またはさら
に脱炭酸、あるいはまた部分的に脱ベンジル化す
ることにより得られるが、その際このジアルコキ
シカルボニル化合物を含水アルカンスルホン酸
（含水率40重量％以下）あるいは又C1〜C3の脂肪
族カルボン酸を含むアルカンスルホン酸中、40゜
〜100℃好ましくは70〜95℃で２〜20時間加熱処
理することによりケン化し、３，４−（1′，3′−
ジベンジル−2′−ケトイミダゾリド）−２−（ω，
ω−ジカルボキシブチル）チオフアンとする。こ
のものを取り出すことなく、更に100〜180℃好ま
しくは110〜150℃で１〜20時間加熱を続け、反応
系の水分、アルコール、あるいはカルボン酸エス
テル等の低沸点物質を留去しながら脱炭酸および
脱ベンジル化反応を行ない、ビオチンを含む反応
液を得る。この反応液を前述と同様に処理して精
製ビオチンを得る。 That is, the compound of the above general formula usually has 3,4-
(1′,3′-dibenzyl-2′-ketoimidazolide)-
2-(ω,ω-dialkoxycarbonylbutyl)
It can be obtained by saponifying thiophane, or by further decarboxylation, or partial debenzylation, and in this case, the dialkoxycarbonyl compound is treated with hydrous alkanesulfonic acid (water content of 40% by weight or less) or 3,4-( 1 ', 3 ′−
dibenzyl-2'-ketoimidazolide)-2-(ω,
ω-dicarboxybutyl) thiophane. Without taking this product out, it is further heated at 100-180°C, preferably 110-150°C, for 1-20 hours to decarboxylate while distilling off low-boiling substances such as water, alcohol, or carboxylic acid esters in the reaction system. and debenzylation reaction to obtain a reaction solution containing biotin. This reaction solution is treated in the same manner as described above to obtain purified biotin.
前記説明のうち３，４−（1′，3′−ジベンジル
−2′−ケトイミダゾリド）−２−（ω，ω−ジアル
コキシカルボニルブチル）チオフアンとあるが、
この（ω，ω−ジアルコキシカルボニルブチル）
の例としては（ω，ω−ジエトキシカルボニルブ
チル）、（ω，ω−ジメトキシカルボニルブチル）、
〔（ω，ω−メトキシカルボニル、エトキシカルボ
ニル）−ブチル〕、及びこれらの混合物を指す。 In the above description, 3,4-(1',3'-dibenzyl-2'-ketoimidazolide)-2-(ω,ω-dialkoxycarbonylbutyl)thiophane is mentioned,
This (ω,ω-dialkoxycarbonylbutyl)
Examples include (ω,ω-diethoxycarbonylbutyl), (ω,ω-dimethoxycarbonylbutyl),
[(ω,ω-methoxycarbonyl, ethoxycarbonyl)-butyl], and mixtures thereof.
またアルカンスルホン酸の例としてはメタンス
ルホン酸、エタンスルホン酸及びプロパンスルホ
ン酸を指すものである。 Examples of alkanesulfonic acids include methanesulfonic acid, ethanesulfonic acid, and propanesulfonic acid.
以上の如き反応により目的化合物であるビオチ
ンを高収率にて得ることができる。また本発明方
法によれば化学的に純度の高いビオチンが得られ
るのみならず、出発物質として光学活性体を使用
した場合、各反応過程でこの光学活性は保持さ
れ、光学純度の高いビオチンが得られることが大
きな特徴であり、特に生理活性の大きなｄ−ビオ
チンを含成する場合極めて重要かつ、有利な方法
を提供するものである。 By the reaction as described above, biotin, which is the target compound, can be obtained in high yield. Furthermore, according to the method of the present invention, not only biotin with high chemical purity can be obtained, but when an optically active substance is used as a starting material, this optical activity is retained in each reaction process, and biotin with high optical purity can be obtained. This is a major feature, and provides an extremely important and advantageous method especially when d-biotin, which has a large physiological activity, is contained.
次に実施例を具体的に示して本発明方法の態様
を例示するが、本発明は実施例により限定される
ものではない。 Next, embodiments of the method of the present invention will be illustrated with specific examples, but the present invention is not limited by the examples.
実施例 １
ｄ−モノベンジルビオチン1.0ｇ及び試薬メタ
ンスルホン酸3.0ｇを10mlナス型フラスコに加え
てマグネチツクスターラーにて撹拌しながら反応
温度130℃に調整された油浴中で６時間反応を続
けた。反応液を室温まで冷却した後、これを10ml
の氷水中に注加し、よく撹拌し、析出する結晶を
取した。Example 1 1.0 g of d-monobenzylbiotin and 3.0 g of the reagent methanesulfonic acid were added to a 10 ml eggplant-shaped flask, and the reaction was continued for 6 hours in an oil bath adjusted to a reaction temperature of 130°C while stirring with a magnetic stirrer. Ta. After cooling the reaction solution to room temperature, add 10 ml of this
The mixture was poured into ice water, stirred well, and precipitated crystals were collected.
こうして得られた粗ビオチン結晶を水より再結
晶することにより白色針状結晶としてｄ−ビオチ
ンを0.58ｇを得た。収率79％、融点230℃、〔α〕
20 D＋91゜（Ｃ＝１、0.1％苛性ソーダ水溶液中）
実施例 ２
80℃に加熱したトルエン200ml中のナトリウム
メチラート11ｇの懸濁液にマロン酸ジエチルエス
テル45.0ｇを滴下した。この混合物を上記温度で
１時間撹拌した後、50℃まで冷却しｌ−（−）−
３，４−（1′，3′−ジベンジル−2′−ケトイミダゾ
リド）−１，２−トリメチレンチオフアニウムブ
ロマイド30.0ｇを加え、次にこの混合物を還流下
４時間加熱した。これを室温に冷却し、これに水
270ｇ加え、相を分離した。有機相を更に水250ｇ
で洗浄した後乾燥し、真空下に溶媒を留去して得
られた残留物〔主としてｌ−（−）３，４−（1′，
3′−ジベンジル−2′−ケトイミダゾリド）−２−
（ω，ω−ジエトキシカルボニルブチル）チオフ
アンを含む〕にKOH（24.1重量％）のエタノール
溶液160ｇを加え還流下１時間反応させた後、真
空下に溶媒を留去して得られた残留物に水300ｇ
を加え更に濃塩酸で中和した後酢酸エチルで有機
物を抽出し、これを乾燥し、真空下に溶媒を留去
すると主としてｌ−（−）−３，４−（1′，3′−ジ
ベンジル−2′−ケトイミダゾリド−２−（ω，ω
−ジカルボキシブチル）チオフアンを含む残留物
が得られた。 The crude biotin crystals thus obtained were recrystallized from water to obtain 0.58 g of d-biotin as white needle-like crystals. Yield 79%, melting point 230℃, [α]
20 D +91° (C=1, in 0.1% caustic soda aqueous solution) Example 2 45.0 g of malonic acid diethyl ester were added dropwise to a suspension of 11 g of sodium methylate in 200 ml of toluene heated to 80°C. This mixture was stirred at the above temperature for 1 hour, then cooled to 50°C and l-(-)-
30.0 g of 3,4-(1',3'-dibenzyl-2'-ketoimidazolide)-1,2-trimethylenethiophanium bromide were added and the mixture was then heated under reflux for 4 hours. Cool this to room temperature and add water to it.
270g was added and the phases were separated. Add 250g of water to the organic phase.
After washing with
3′-dibenzyl-2′-ketoimidazolide)-2-
(containing ω, ω-diethoxycarbonylbutyl)thiophane] was added with 160 g of an ethanol solution of KOH (24.1% by weight), reacted under reflux for 1 hour, and the solvent was distilled off under vacuum to obtain a residue. 300g of water
After neutralization with concentrated hydrochloric acid, the organic matter was extracted with ethyl acetate, dried, and the solvent was distilled off under vacuum. -2′-ketoimidazolide-2-(ω,ω
-dicarboxybutyl)thiophane was obtained.
この残留物にメタンスルホン酸90.0ｇを加え、
130℃に調整した油浴中にて５時間加熱撹拌した
後、これを室温まで冷却し、これに270ｇの氷冷
水を滴下した。得られたスラリー液を吸引過に
より結晶を得、この結晶を水からの再結晶により
白色針状結晶としてｄ−ビオチンを12.6ｇを得
た。〔収率77％、〔α〕20 D＝＋91゜（Ｃ＝１、0.1％
NaOH水溶液）〕
実施例 ３
実施例２と同じ反応で得られたｌ−（−）−３，
４−（1′，3′−ジベンジル−2′−ケトイミダゾリ
ド）−２−（ω，ω−ジエトキシカルボニルブチ
ル）チオフアンを含む残留物にギ酸75ｇとメタン
スルホン酸10.0ｇを加え、90℃で４時間撹拌しな
がら反応したのち、油浴温度を150℃まで上昇さ
せ低沸点物質を留去した後100℃まで冷却し、こ
れに150ｇのメタンスルホン酸を追加して140℃で
４時間加熱撹拌した。反応液を冷却した後これに
氷水500ｇを加えて得られたスラリー液を実施例
２と同様の処理をすることによりｄ−ビオチンを
12.3ｇ（収率75.1％）得た。 Add 90.0g of methanesulfonic acid to this residue,
After heating and stirring for 5 hours in an oil bath adjusted to 130°C, this was cooled to room temperature, and 270 g of ice-cold water was added dropwise thereto. The obtained slurry liquid was filtered under suction to obtain crystals, and the crystals were recrystallized from water to obtain 12.6 g of d-biotin as white needle-shaped crystals. [Yield 77%, [α] 20 D = +91° (C = 1, 0.1%
NaOH aqueous solution] Example 3 l-(-)-3 obtained by the same reaction as Example 2,
75 g of formic acid and 10.0 g of methanesulfonic acid were added to the residue containing 4-(1',3'-dibenzyl-2'-ketoimidazolide)-2-(ω,ω-diethoxycarbonylbutyl)thiophane, and the After reacting with stirring for an hour, the oil bath temperature was raised to 150°C, low-boiling substances were distilled off, and then cooled to 100°C. 150g of methanesulfonic acid was added thereto, and the mixture was heated and stirred at 140°C for 4 hours. . After cooling the reaction solution, 500 g of ice water was added to it, and the resulting slurry was treated in the same manner as in Example 2 to obtain d-biotin.
12.3g (yield 75.1%) was obtained.
実施例 ４
粗製のＮ，Ｎ−ジベンジルビオチン20.0ｇとメ
タンスルホン酸200.0ｇを四ツ口フラスコに入れ
140℃で６時間加熱撹拌した後、反応液を10〜15
℃まで冷却し、これを１の氷水中によく撹拌し
つつ注加し、得られた結晶を取した後、これを
水より再結晶し、精製を実施した結果白色針状晶
としてｄ−ビオチンを8.30ｇを得た。（収率72.0
％）
実施例 ５
原料としてｌ−（−）３，４−（1′，3′−ジベン
ジル−2′−ケトイミダゾリド）−１，２−トリメ
チレンチオフアニウムブロマイドの代りにｄ，ｌ
−３，４−（1′，3′−ジベンジル−2′−ケトイミダ
ゾリド）−１，２−トリメチレンチオフアニウム、
ｄ−カンフアスルホネートを39.9ｇ用いた以外は
実施例２と全く同様の反応で得られたｄ，ｌ−
３，４−（1′，3′−ジベンジル−2′−ケトイミダゾ
リド）−２−（ω，ω−ジエトキシカルボニルブチ
ル）チオフアンを含む残留物にメタンスルホン酸
120ｇ、約40％の水を含む含水酢酸50mlを加えた
後撹拌しながら93〜95℃にて６時間加熱した。そ
の後油浴温度を140℃まで上昇させ留出物を除去
した後これにキシレン100mlを加え還流下８時間
反応を行つた。この間約30mlのキシレン含有還流
液を系外に除去した。その後反応液を室温まで冷
却した後キシレン相を分離除去した反応液を400
mlの氷水中に注加し、得られた結晶を単離した
後、水からの再結晶により精製を行ない、白色結
晶としてｄ，ｌ−ビオチンを11.5ｇ得た。（融点
233〜235℃）。Example 4 20.0 g of crude N,N-dibenzylbiotin and 200.0 g of methanesulfonic acid were placed in a four-necked flask.
After heating and stirring at 140℃ for 6 hours, the reaction solution was heated to 10~15℃.
It was cooled to ℃ and poured into ice water in step 1 with good stirring. The obtained crystals were collected and then recrystallized from water. As a result of purification, d-biotin was obtained as white needle-like crystals. 8.30g of was obtained. (Yield 72.0
%) Example 5 d,l instead of l-(-)3,4-(1',3'-dibenzyl-2'-ketoimidazolide)-1,2-trimethylenethiophanium bromide as a raw material
-3,4-(1',3'-dibenzyl-2'-ketoimidazolide)-1,2-trimethylenethiophanium,
d,l- obtained by the same reaction as in Example 2 except that 39.9g of d-camphorsulfonate was used.
Methanesulfonic acid was added to the residue containing 3,4-(1',3'-dibenzyl-2'-ketoimidazolide)-2-(ω,ω-diethoxycarbonylbutyl)thiophane.
After adding 120 g of hydrous acetic acid (50 ml) containing about 40% water, the mixture was heated at 93-95° C. for 6 hours with stirring. Thereafter, the oil bath temperature was raised to 140°C and the distillate was removed, after which 100 ml of xylene was added and the reaction was carried out under reflux for 8 hours. During this time, about 30 ml of xylene-containing reflux liquid was removed from the system. After that, the reaction solution was cooled to room temperature, and the xylene phase was separated and removed.
ml of ice water, and the obtained crystals were isolated and purified by recrystallization from water to obtain 11.5 g of d,l-biotin as white crystals. (melting point
233-235℃).
Claims (1)
ある。但し、R1、R2が同時に水素原子となるこ
とはない。R3は水素原子またはカルボキシル基
である。〕 で示される化合物をアルカンスルホン酸類で処理
することを特徴とするシス−テトラハイドロ−２
−オキソチエノ〔３，４−ｄ〕−イミダゾリン−
４−吉草酸の製法。 ２ R1またはR2の１つがベンジル基である特許
請求の範囲第１項記載の製法。 ３ R3が水素原子である特許請求の範囲第１ま
たは２項記載の製法。 ４ アルカンスルホン酸類が、メタンスルホン
酸、エタンスルホン酸またはプロパンスルホン酸
である特許請求の範囲第１、２または３項記載の
製法。 ５ アルカンスルホン酸類がメタンスルホン酸で
ある特許請求の範囲第４項記載の製法。 ６ 反応温度が110〜150℃である特許請求の範囲
第１、２、３、４または５項記載の製法。[Claims] 1. General formula [In the formula, R 1 and R 2 are a hydrogen atom or a benzyl group. However, R 1 and R 2 do not become hydrogen atoms at the same time. R 3 is a hydrogen atom or a carboxyl group. ] Cis-tetrahydro-2, characterized in that the compound represented by is treated with an alkanesulfonic acid.
-Oxothieno[3,4-d]-imidazoline-
4-Production method of valeric acid. 2. The method according to claim 1, wherein one of R 1 or R 2 is a benzyl group. 3. The manufacturing method according to claim 1 or 2, wherein R 3 is a hydrogen atom. 4. The production method according to claim 1, 2 or 3, wherein the alkanesulfonic acid is methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid. 5. The manufacturing method according to claim 4, wherein the alkanesulfonic acid is methanesulfonic acid. 6. The manufacturing method according to claim 1, 2, 3, 4 or 5, wherein the reaction temperature is 110 to 150°C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1175879A JPS55104286A (en) | 1979-02-02 | 1979-02-02 | Preparation of thienoimidazoline compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1175879A JPS55104286A (en) | 1979-02-02 | 1979-02-02 | Preparation of thienoimidazoline compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS55104286A JPS55104286A (en) | 1980-08-09 |
| JPS638954B2 true JPS638954B2 (en) | 1988-02-25 |
Family
ID=11786875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1175879A Granted JPS55104286A (en) | 1979-02-02 | 1979-02-02 | Preparation of thienoimidazoline compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS55104286A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02136996U (en) * | 1989-04-18 | 1990-11-15 | ||
| JPH037824A (en) * | 1989-06-02 | 1991-01-16 | Sanyo Electric Co Ltd | Heat exchanging unit |
| EP0780392A1 (en) | 1995-12-20 | 1997-06-25 | Sumitomo Chemical Company Limited | Process for preparing imidazole derivatives |
| EP0781775A2 (en) | 1995-12-26 | 1997-07-02 | Sumitomo Chemical Company, Limited | Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid |
| US6333417B1 (en) | 1998-12-24 | 2001-12-25 | Sumitomo Chemical Company, Limited | Method for producing hexahydro-2-OXO-1H-thieno[3,4-D]imidazole-4-pentanoic acid |
-
1979
- 1979-02-02 JP JP1175879A patent/JPS55104286A/en active Granted
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02136996U (en) * | 1989-04-18 | 1990-11-15 | ||
| JPH037824A (en) * | 1989-06-02 | 1991-01-16 | Sanyo Electric Co Ltd | Heat exchanging unit |
| EP0780392A1 (en) | 1995-12-20 | 1997-06-25 | Sumitomo Chemical Company Limited | Process for preparing imidazole derivatives |
| EP0781775A2 (en) | 1995-12-26 | 1997-07-02 | Sumitomo Chemical Company, Limited | Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid |
| US6333417B1 (en) | 1998-12-24 | 2001-12-25 | Sumitomo Chemical Company, Limited | Method for producing hexahydro-2-OXO-1H-thieno[3,4-D]imidazole-4-pentanoic acid |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS55104286A (en) | 1980-08-09 |
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