JPH07188247A - Production of thiophane derivative - Google Patents
Production of thiophane derivativeInfo
- Publication number
- JPH07188247A JPH07188247A JP33157993A JP33157993A JPH07188247A JP H07188247 A JPH07188247 A JP H07188247A JP 33157993 A JP33157993 A JP 33157993A JP 33157993 A JP33157993 A JP 33157993A JP H07188247 A JPH07188247 A JP H07188247A
- Authority
- JP
- Japan
- Prior art keywords
- dibenzyl
- formula
- thieno
- oxohexahydro
- imidazole
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明はチオファン誘導体の製造
法に関するものである。さらに詳しくはビオチン（ビタ
ミンＨ）の中間体として有用なチオファン誘導体の製造
法に関する。TECHNICAL FIELD The present invention relates to a method for producing a thiophane derivative. More specifically, it relates to a method for producing a thiophane derivative useful as an intermediate for biotin (vitamin H).
【０００２】[0002]
【従来の技術】従来、チオファン誘導体の製造法とし
て、テトラヒドロフラン中で反応させる方法（特開昭６
１−１５１１９４号公報）が知られている。2. Description of the Related Art Conventionally, as a method for producing a thiophane derivative, a method of reacting in tetrahydrofuran (Japanese Patent Application Laid-Open No. 6-58242)
No. 1-151194) is known.
【０００３】[0003]
【発明が解決しようとする課題】しかし、上記の方法で
は二酸化炭素との反応中に反応系内の粘度が高くなり、
操作性が悪くかつ反応収率も充分とは言えず、工業的製
造法としては必ずしも満足できるものとは言い難かっ
た。However, in the above method, the viscosity in the reaction system increases during the reaction with carbon dioxide,
The operability was poor and the reaction yield was not sufficient, and it was difficult to say that the method was industrially satisfactory.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、上記課題
を解決するため鋭意検討した結果、ビオチンの中間体と
して重要なチオファン誘導体の工業的有利な製造法を見
出し本発明に至った。すなわち、本発明は、式（１） で示される４，６−ジベンジル−１，５−ジオキソヘキ
サヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾールと
１，４−ジハロゲノマグネシウムブタンとをテトラヒド
ロフランと芳香族系溶媒とからなる混合溶媒中、３級ア
ミンの存在下に反応させ、次いで二酸化炭素を反応させ
ることを特徴とする式（２） で示される５−（４，６−ジベンジル−１−ヒドロキシ
−５−オキソヘキサヒドロ−１Ｈ−チエノ［３，４−
ｄ］イミダゾール−１−イル）ペンタン酸の製造法、お
よび上記で得られる式（２）で示される化合物を脱水す
ることにより式（３） で示される５−（４，６−ジベンジル−５−オキソヘキ
サヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾール−
１−イリデン）ペンタン酸を得る製造法、および上記で
得られる式（３）で示される化合物を還元することによ
り式（４） で示される５−（４，６−ジベンジル−５−オキソヘキ
サヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾール−
１−イル）ペンタン酸を得る製造法を提供するものであ
る。上記で得られる式（４）で示されるチオファン誘導
体は、例えば特公昭６３−８９５４号公報に記載の方法
に準じて、メタンスルホン酸と反応させることにより容
易にビオチンとすることができる。Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found an industrially advantageous method for producing a thiophane derivative which is important as an intermediate of biotin, and arrived at the present invention. That is, the present invention provides the formula (1) A mixture of 4,6-dibenzyl-1,5-dioxohexahydro-1H-thieno [3,4-d] imidazole represented by and 1,4-dihalogenomagnesium butane consisting of tetrahydrofuran and an aromatic solvent. Formula (2) characterized by reacting in a solvent in the presence of a tertiary amine, and then reacting with carbon dioxide 5- (4,6-dibenzyl-1-hydroxy-5-oxohexahydro-1H-thieno [3,4-
d] a method for producing imidazol-1-yl) pentanoic acid, and a compound represented by the formula (3) by dehydrating the compound represented by the formula (2) obtained above. 5- (4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazole-
1-ylidene) pentanoic acid, and a compound of formula (4) by reducing the compound of formula (3) obtained above. 5- (4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazole-
1-yl) pentanoic acid is provided. The thiophane derivative represented by the formula (4) obtained above can be easily converted into biotin by reacting it with methanesulfonic acid according to the method described in JP-B-63-8954.
【０００５】以下、本発明について詳細に説明する。本
発明の出発化合物である式（１）で示されるチオファン
誘導体は、光学活性体、ラセミ体のいずれでもよい。ま
ず、チオファン誘導体（１）からチオファン誘導体
（２）を得る反応（工程）は、１，４−ジクロロもし
くはジブロモ等のジハロゲノブタンと金属マグネシウム
より調整される１，４−ジハロゲノジマグネシウムブタ
ンとテトラヒドロフラン（以下、ＴＨＦと略す。）溶液
に３級アミンを加え、これとＴＨＦ／芳香族系溶媒より
なる混合溶液に溶かしたチオファン誘導体（１）とを反
応させ、次いで反応溶液中に二酸化炭素を吹き込んで反
応させ、次いで中性条件で常法により加水分解すること
により行われる。The present invention will be described in detail below. The thiophane derivative represented by the formula (1), which is the starting compound of the present invention, may be an optically active substance or a racemic body. First, the reaction (step) of obtaining the thiophane derivative (2) from the thiophane derivative (1) is performed by dihalogenobutane such as 1,4-dichloro or dibromo and 1,4-dihalogenodimagnesium butane prepared from metal magnesium and tetrahydrofuran ( (Hereinafter, abbreviated as THF)) A tertiary amine is added to the solution, and this is reacted with a thiophane derivative (1) dissolved in a mixed solution of a THF / aromatic solvent, and then carbon dioxide is blown into the reaction solution. It is carried out by reacting and then hydrolyzing by a conventional method under neutral conditions.
【０００６】本発明で用いる３級アミンとしては、例え
ば、トリエチルアミン、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメ
チルエチレンジアミン、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラエ
チルエチレンジアミン、Ｎ，Ｎ，Ｎ’，Ｎ’−テトラメ
チル−１，３−プロパンジアミン、Ｎ，Ｎ−ジメチルア
ニリン、１，８−ビス（ジメチルアミノ）ナフタレン等
があげられ、特にＮ，Ｎ，Ｎ’，Ｎ’−テトラメチルエ
チレンジアミンが好ましく用いられる。３級アミンの使
用量は、チオファン誘導体（１）に対して、通常は０．
０５〜１０モルパーセント、好ましくは０．２〜２モル
パーセントである。Examples of the tertiary amine used in the present invention include triethylamine, N, N, N ', N'-tetramethylethylenediamine, N, N, N', N'-tetraethylethylenediamine, N, N, N '. , N'-tetramethyl-1,3-propanediamine, N, N-dimethylaniline, 1,8-bis (dimethylamino) naphthalene, and the like, particularly N, N, N ', N'-tetramethylethylenediamine. Is preferably used. The amount of the tertiary amine used is usually 0. 0 with respect to the thiophane derivative (1).
It is from 05 to 10 mole percent, preferably from 0.2 to 2 mole percent.
【０００７】上記反応において、二酸化炭素を反応させ
るときの溶媒としては、テトラヒドロフランと芳香族系
溶媒の混合溶媒が用いられる。特に芳香族系溶媒の存在
が重要であり、芳香族系溶媒が存在しない場合には溶液
粘度が高くなり、撹拌不良を引き起こす。芳香族系溶媒
としては、例えばベンゼン、トルエン、ｐ−キシレン、
ｏ−キシレン、ｍ−キシレン、混合キシレン、エチルベ
ンゼン、クメン、シメン、トリメチルベンゼン、クロロ
ベンゼン、クロロトルエン、ジクロロベンゼン、アニソ
ール等が挙げられるが、特にベンゼン、トルエン、ｐ−
キシレン、ｏ−キシレン、ｍ−キシレン、混合キシレン
が好ましく用いられる。芳香族系溶媒とＴＨＦとの重量
比（芳香族系溶媒／ＴＨＦ）は、通常０．０１〜０．
５、好ましくは０．０２〜０．２５の範囲である。使用
量は特に限定されない。上記反応に用いる二酸化炭素の
使用量は、チオファン誘導体に対して通常、１〜２０当
量、好ましくは３〜８当量である。In the above reaction, a mixed solvent of tetrahydrofuran and an aromatic solvent is used as a solvent for reacting carbon dioxide. Particularly, the presence of the aromatic solvent is important, and when the aromatic solvent is not present, the solution viscosity becomes high, which causes poor stirring. Examples of aromatic solvents include benzene, toluene, p-xylene,
Examples thereof include o-xylene, m-xylene, mixed xylene, ethylbenzene, cumene, cymene, trimethylbenzene, chlorobenzene, chlorotoluene, dichlorobenzene, anisole and the like, but especially benzene, toluene and p-.
Xylene, o-xylene, m-xylene and mixed xylene are preferably used. The weight ratio of aromatic solvent and THF (aromatic solvent / THF) is usually 0.01 to 0.
5, preferably in the range of 0.02 to 0.25. The amount used is not particularly limited. The amount of carbon dioxide used in the above reaction is usually 1 to 20 equivalents, preferably 3 to 8 equivalents, relative to the thiophane derivative.
【０００８】上記反応の反応温度は、通常−７８〜１０
℃、好ましくは、−５０〜−２０℃の範囲である。The reaction temperature for the above reaction is usually -78 to 10
C., preferably in the range of -50 to -20.degree.
【０００９】こうして得られたチオファン誘導体（２）
からチオファン誘導体（３）を得る反応（工程）は、
チオファン誘導体（２）を前記工程で用いた混合溶媒
中または、キシレン、トルエン、ベンゼン等の溶媒中、
硫酸、酢酸、ｐ−トルエンスルホン酸等の酸性触媒存在
下、加熱、脱水することにより行われる。上記反応に用
いる酸性触媒の使用量は、チオファン誘導体（２）に対
し通常、0.01〜１当量であり、好ましくは0.02〜0.3 当
量である。反応温度は通常、10〜120 ℃、好ましくは、
20〜80℃である。尚、本反応は、通常、前記工程に於
いてチオファン誘導体（２）を単離せずに、二酸化炭素
を反応させた後の反応マスに酸性触媒を添加し加熱、脱
水することにより行われる。The thiophane derivative (2) thus obtained
The reaction (step) for obtaining the thiophane derivative (3) from
The thiophane derivative (2) in the mixed solvent used in the above step or in a solvent such as xylene, toluene or benzene,
It is carried out by heating and dehydration in the presence of an acidic catalyst such as sulfuric acid, acetic acid or p-toluenesulfonic acid. The amount of the acidic catalyst used in the above reaction is usually 0.01 to 1 equivalent, preferably 0.02 to 0.3 equivalent, based on the thiophane derivative (2). The reaction temperature is usually 10 to 120 ° C., preferably
20 to 80 ° C. In addition, this reaction is usually performed by adding an acidic catalyst to the reaction mass after reacting carbon dioxide and heating and dehydrating it without isolating the thiophane derivative (2) in the above step.
【００１０】更に、チオファン誘導体（３）を還元して
チオファン誘導体（４）を得る反応（工程）は、チオ
ファン誘導体（３）を酸化パラジウム、パラジウム−活
性炭、酢酸パラジウム、ニッケル−ケイソウ土等の触媒
を用いて還元することにより行われる。上記反応に用い
る反応溶媒は、通常、メタノール、エタノール、２−プ
ロパノール等のアルコール類、またはこれらと水との混
合溶媒が挙げられる。反応に用いる触媒の使用量は、チ
オファン誘導体（３）に対し通常、0.05モル％以上、好
ましくは0.4 モル％であり、上限については反応に悪影
響を及ぼさない量であればよい。反応温度は通常、０〜
100 ℃、好ましくは、30〜70℃である。Further, in the reaction (step) of reducing the thiophane derivative (3) to obtain the thiophane derivative (4), the thiophane derivative (3) is catalyzed by palladium oxide, palladium-activated carbon, palladium acetate, nickel-diatomaceous earth or the like. Is carried out by reduction. Examples of the reaction solvent used in the above reaction include alcohols such as methanol, ethanol and 2-propanol, or a mixed solvent of these with water. The amount of the catalyst used in the reaction is usually 0.05 mol% or more, preferably 0.4 mol% with respect to the thiophane derivative (3), and the upper limit may be an amount that does not adversely affect the reaction. The reaction temperature is usually 0 to
The temperature is 100 ° C, preferably 30 to 70 ° C.
【００１１】[0011]
【発明の効果】本発明の製造法によれば、ビオチンの中
間体として有用な式（２）、（３）および（４）で示さ
れるチオファン誘導体を操作性よく工業的有利に製造す
ることができる。Industrial Applicability According to the production method of the present invention, the thiophane derivatives represented by the formulas (2), (3) and (4) useful as intermediates for biotin can be produced with good operability and industrially. it can.
【００１２】[0012]
【実施例】以下、実施例により本発明をさらに詳細に説
明するが、本発明はこれにより限定されるものではな
い。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
【００１３】実施例１ マグネシウム６．９ｇ、テトラヒドロフラン８０ｇの懸
濁液に１，４−ジクロロブタン３ｇ、次いでヨウ素０．
１ｇ、テトラヒドロフラン２ｇからなる溶液を５０℃で
適下した。この溶液にテトラヒドロフラン６５ｇを加
え、次いで１，４−ジクロロブタン１４．２ｇを環流下
適下し、適下終了後６０〜６５℃で３時間撹拌した。こ
の反応液にＮ，Ｎ，Ｎ’，Ｎ’−テトラメチルエチレン
ジアミン５．２ｇ及びテトラヒドロフラン３１ｇを加え
た後−４０〜−５０℃に冷却し、これに（３ａＳ，６ａ
Ｒ）−４，６−ジベンジル−１，５−ジオキソヘキサヒ
ドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾール２５．
４ｇ、テトラヒドロフラン１３７ｇ、ｐ−キシレン３６
ｇからなる溶液を同温で滴下した。滴下後同温で０．５
時間撹拌後、炭酸ガス（６当量）を導入した。この反応
液を１５％硫酸中に注加し、１時間撹拌した後、水層を
を分離した。この溶液にｐ−キシレン１６０ｇを加え減
圧濃縮した。残渣に５％水酸化ナトリウムを加え、約ｐ
Ｈ１０に調製し、撹拌、分液した後、水層にトルエンを
加え３０％硫酸でｐＨ６．５に調製し、分液した。有機
層を濃縮し、５−（（３ａＳ，６ａＲ）−４，６−ジベ
ンジル−５−オキソヘキサヒドロ−１Ｈ−チエノ［３，
４−ｄ］イミダゾール−１−イリデン）ペンタン酸を油
状物質として得た。ＬＣ分析により純度換算したところ
純収量は２８．５ｇであった。これを２−プロパノール
とヘキサンにより再結晶することにより、融点８４−８
５℃；旋光度［α］D 20２３６．２゜（Ｃ＝１．０、メ
タノール）の物性を示した。Example 1 3 g of 1,4-dichlorobutane was added to a suspension of 6.9 g of magnesium and 80 g of tetrahydrofuran, and then iodine of 0.
A solution consisting of 1 g and 2 g of tetrahydrofuran was appropriately applied at 50 ° C. To this solution, 65 g of tetrahydrofuran was added, and then 14.2 g of 1,4-dichlorobutane was appropriately added under reflux, and after completion of the application, the mixture was stirred at 60 to 65 ° C. for 3 hours. After adding 5.2 g of N, N, N ′, N′-tetramethylethylenediamine and 31 g of tetrahydrofuran to the reaction solution, the reaction solution was cooled to −40 to −50 ° C., and added to (3aS, 6a
R) -4,6-Dibenzyl-1,5-dioxohexahydro-1H-thieno [3,4-d] imidazole 25.
4 g, tetrahydrofuran 137 g, p-xylene 36
A solution of g was added dropwise at the same temperature. 0.5 at the same temperature after dropping
After stirring for an hour, carbon dioxide gas (6 equivalents) was introduced. The reaction solution was poured into 15% sulfuric acid and stirred for 1 hour, and then the aqueous layer was separated. To this solution, 160 g of p-xylene was added and concentrated under reduced pressure. Add 5% sodium hydroxide to the residue,
After adjusting to H10, stirring and separating the layers, toluene was added to the aqueous layer to adjust the pH to 6.5 with 30% sulfuric acid, and the layers were separated. The organic layer was concentrated to give 5-((3aS, 6aR) -4,6-dibenzyl-5-oxohexahydro-1H-thieno [3.
4-d] imidazole-1-ylidene) pentanoic acid was obtained as an oily substance. When converted into purity by LC analysis, the pure yield was 28.5 g. This was recrystallized from 2-propanol and hexane to give a melting point of 84-8.
5 ° C .; optical property [α] D 20 236.2 ° (C = 1.0, methanol).
【００１４】実施例２ 実施例１のｐ−キシレンの代わりに、トルエンを用いた
以外は実施例１と同様に反応および後処理を行い、５−
（（３ａＳ，６ａＲ）−４，６−ジベンジル−５−オキ
ソヘキサヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾ
ール−１−イリデン）ペンタン酸を油状物質として得
た。ＬＣ分析により純度換算したところ純収量は２８．
５ｇであった。Example 2 The reaction and post-treatment were carried out in the same manner as in Example 1 except that toluene was used instead of p-xylene of Example 1, and
((3aS, 6aR) -4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-ylidene) pentanoic acid was obtained as an oily substance. When converted into purity by LC analysis, the pure yield was 28.
It was 5 g.
【００１５】実施例３ ５−（（３ａＳ，６ａＲ）−４，６−ジベンジル−５−
オキソヘキサヒドロ−１Ｈ−チエノ［３，４−ｄ］イミ
ダゾール−１−イリデン）ペンタン酸１３２ｇを２−プ
ロパノール４５０ｇ、水２００ｇの溶液に溶解し、酢酸
パラジウム１ｇ（１．４モルパーセント）を用いて水素
圧２０ｋｇ／ｃｍ2 、７０℃で３時間接触還元した。反
応後反応液にヘキサン１０００ｇ、活性炭２０ｇを加
え、触媒を除去しろ過した。ろ液を減圧濃縮し、５−
（（１Ｒ，３ａＳ，６ａＲ）−４，６−ジベンジル−５
−オキソヘキサヒドロ−１Ｈ−チエノ［３，４−ｄ］イ
ミダゾール−１−イル）ペンタン酸を油状物として得
た。ＬＣ分析により純度換算したところ純収量は１３１
ｇであった。これを冷蔵庫で一夜放置することにより結
晶化させ、２−プロパノールとヘキサンにより再結晶す
ることにより、融点９１−９２℃；旋光度［α］D 23−
２６．８゜（Ｃ＝１．０、メタノール）の物性を示し
た。Example 3 5-((3aS, 6aR) -4,6-dibenzyl-5-
132 g of oxohexahydro-1H-thieno [3,4-d] imidazol-1-ylidene) pentanoic acid were dissolved in a solution of 450 g of 2-propanol and 200 g of water, and 1 g of palladium acetate (1.4 mol percent) was used. Catalytic reduction was carried out at 70 ° C. for 3 hours under a hydrogen pressure of 20 kg / cm 2. After the reaction, 1000 g of hexane and 20 g of activated carbon were added to the reaction solution to remove the catalyst, and the mixture was filtered. The filtrate is concentrated under reduced pressure, and 5-
((1R, 3aS, 6aR) -4,6-dibenzyl-5
-Oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid was obtained as an oil. When the purity was converted by LC analysis, the pure yield was 131.
It was g. This was crystallized by allowing to stand overnight in a refrigerator, and recrystallized with 2-propanol and hexane, mp 91-92 ° C.; optical rotation [α] D 23 -
It showed a physical property of 26.8 ° (C = 1.0, methanol).
───────────────────────────────────────────────────── フロントページの続き (72)発明者 高橋 寿也 大阪府高槻市塚原２丁目10番１号 住友化 学工業株式会社内 (72)発明者 水野 正 大阪府高槻市塚原２丁目10番１号 住友化 学工業株式会社内 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Toshiya Takahashi 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Kagaku Kogyo Co., Ltd. (72) Inventor Tadashi Mizuno 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture No. Sumitomo Chemical Industry Co., Ltd.
Claims (4)
サヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾールと
１，４−ジハロゲノマグネシウムブタンとをテトラヒド
ロフランと芳香族系溶媒とからなる混合溶媒中、３級ア
ミンの存在下に反応させ、次いで二酸化炭素を反応させ
ることを特徴とする式（２） で示される５−（４，６−ジベンジル−１−ヒドロキシ
−５−オキソヘキサヒドロ−１Ｈ−チエノ［３，４−
ｄ］イミダゾール−１−イル）ペンタン酸の製造法。1. A formula (1) A mixture of 4,6-dibenzyl-1,5-dioxohexahydro-1H-thieno [3,4-d] imidazole represented by and 1,4-dihalogenomagnesium butane consisting of tetrahydrofuran and an aromatic solvent. Formula (2) characterized by reacting in a solvent in the presence of a tertiary amine, and then reacting with carbon dioxide 5- (4,6-dibenzyl-1-hydroxy-5-oxohexahydro-1H-thieno [3,4-
d] A method for producing imidazol-1-yl) pentanoic acid.
１，５−ジオキソヘキサヒドロ−１Ｈ−チエノ［３，４
−ｄ］イミダゾールと１，４−ジハロゲノマグネシウム
ブタンとをテトラヒドロフランと芳香族系溶媒との混合
溶媒中、３級アミンの存在下に反応させ、次いで二酸化
炭素を反応させて式（２）で示される５−（４，６−ジ
ベンジル−１−ヒドロキシ−５−オキソヘキサヒドロ−
１Ｈ−チエノ［３，４−ｄ］イミダゾール−１−イル）
ペンタン酸を得て、次いでこれを脱水することを特徴と
する式（３） で示される５−（４，６−ジベンジル−５−オキソヘキ
サヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾール−
１−イリデン）ペンタン酸の製造法。2. A 6,6-dibenzyl group represented by the formula (1):
1,5-dioxohexahydro-1H-thieno [3,4
-D] Imidazole and 1,4-dihalogenomagnesium butane are reacted in a mixed solvent of tetrahydrofuran and an aromatic solvent in the presence of a tertiary amine, and then reacted with carbon dioxide to give a compound represented by the formula (2). 5- (4,6-dibenzyl-1-hydroxy-5-oxohexahydro-
1H-thieno [3,4-d] imidazol-1-yl)
Formula (3) characterized in that pentanoic acid is obtained and then dehydrated 5- (4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazole-
Method for producing 1-ylidene) pentanoic acid.
１，５−ジオキソヘキサヒドロ−１Ｈ−チエノ［３，４
−ｄ］イミダゾールと１，４−ジハロゲノマグネシウム
ブタンとをテトラヒドロフランと芳香族系溶媒との混合
溶媒中、３級アミンの存在下に反応させ、次いで二酸化
炭素を反応させて式（２）で示される５−（４，６−ジ
ベンジル−１−ヒドロキシ−５−オキソヘキサヒドロ−
１Ｈ−チエノ［３，４−ｄ］イミダゾール−１−イル）
ペンタン酸を得て、次いでこれを脱水し、式（３）で示
される５−（４，６−ジベンジル−５−オキソヘキサヒ
ドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾール−１−
イリデン）ペンタン酸を得て、更にこれを還元すること
を特徴とする式（４） で示される５−（４，６−ジベンジル−５−オキソヘキ
サヒドロ−１Ｈ−チエノ［３，４−ｄ］イミダゾール−
１−イル）ペンタン酸の製造法。3. A 6,6-dibenzyl group represented by the formula (1):
1,5-dioxohexahydro-1H-thieno [3,4
-D] Imidazole and 1,4-dihalogenomagnesium butane are reacted in a mixed solvent of tetrahydrofuran and an aromatic solvent in the presence of a tertiary amine, and then reacted with carbon dioxide to give a compound represented by the formula (2). 5- (4,6-dibenzyl-1-hydroxy-5-oxohexahydro-
1H-thieno [3,4-d] imidazol-1-yl)
Pentanoic acid was obtained and then dehydrated to give 5- (4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazole-1-of formula (3).
Ylidene) pentanoic acid is obtained and further reduced by the formula (4). 5- (4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazole-
1-yl) A method for producing pentanoic acid.
キシレン、ｏ−キシレン、ｍ−キシレンまたは混合キシ
レンであり、３級アミンがＮ，Ｎ，Ｎ’，Ｎ’−テトラ
メチルエチレンジアミンである請求項１、２または３に
記載の製造法。4. The aromatic solvent is benzene, toluene, p-
The production method according to claim 1, 2 or 3, wherein xylene, o-xylene, m-xylene or mixed xylene and the tertiary amine is N, N, N ′, N′-tetramethylethylenediamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33157993A JP3561938B2 (en) | 1993-12-27 | 1993-12-27 | Method for producing thiophane derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP33157993A JP3561938B2 (en) | 1993-12-27 | 1993-12-27 | Method for producing thiophane derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07188247A true JPH07188247A (en) | 1995-07-25 |
| JP3561938B2 JP3561938B2 (en) | 2004-09-08 |
Family
ID=18245236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP33157993A Expired - Fee Related JP3561938B2 (en) | 1993-12-27 | 1993-12-27 | Method for producing thiophane derivatives |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3561938B2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0781775A3 (en) * | 1995-12-26 | 1998-02-04 | Sumitomo Chemical Company, Limited | Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid |
| US7098344B2 (en) * | 2000-01-14 | 2006-08-29 | Merck Patent Gmbh | Reaction of carbonyl compounds with organometallic reagents |
| CN107973806A (en) * | 2016-10-21 | 2018-05-01 | 大丰海嘉诺药业有限公司 | A kind of method for preparing D-Biotin bromide intermediate |
| CN114891019A (en) * | 2022-02-25 | 2022-08-12 | 复旦大学 | Continuous flow preparation method of vinyl thioether compound |
-
1993
- 1993-12-27 JP JP33157993A patent/JP3561938B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0781775A3 (en) * | 1995-12-26 | 1998-02-04 | Sumitomo Chemical Company, Limited | Process for producing 1-hydroxythienoimidazole carboxylic acid and thienoimidazole carboxylic acid |
| US7098344B2 (en) * | 2000-01-14 | 2006-08-29 | Merck Patent Gmbh | Reaction of carbonyl compounds with organometallic reagents |
| CN107973806A (en) * | 2016-10-21 | 2018-05-01 | 大丰海嘉诺药业有限公司 | A kind of method for preparing D-Biotin bromide intermediate |
| CN114891019A (en) * | 2022-02-25 | 2022-08-12 | 复旦大学 | Continuous flow preparation method of vinyl thioether compound |
Also Published As
| Publication number | Publication date |
|---|---|
| JP3561938B2 (en) | 2004-09-08 |
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