JP2006193480A - Method for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid - Google Patents
Method for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid Download PDFInfo
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本発明は、１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を製造する方法に関する。このジカルボン酸は次式で示され、ビオチンの中間体などとして有用である。 The present invention relates to a process for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid. This dicarboxylic acid is represented by the following formula and is useful as an intermediate of biotin.
１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を製造する方法としては、２，３−ビス（ベンジルアミノ）コハク酸をホスゲンと反応させる方法が知られている。例えば、米国特許第２４８９２３２号明細書（特許文献１）には、キシレンと水の二相系溶媒中で上記反応を行うことが開示されており、ジャーナル・オブ・ザ・アメリカン・ケミカル・ソサイエティ（Journal of the American Chemical Society）、（米国）、１９７８年、第１００巻、ｐ．１５５８−１５６３（非特許文献１）には、トルエンと水の二相系溶媒中で上記反応を行うことが開示されている。また、米国特許第４６５９８３７号明細書（特許文献２）には、水単独溶媒中で上記反応を行うことが開示されており、米国特許第５１５１５２５号明細書（特許文献３）には、ジクロロメタンと水又はアニソールと水の二相系溶媒中で上記反応を行うことが開示されている。 As a method for producing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, a method of reacting 2,3-bis (benzylamino) succinic acid with phosgene is known. For example, US Pat. No. 2,489,232 (Patent Document 1) discloses that the above reaction is carried out in a two-phase solvent of xylene and water, and Journal of the American Chemical Society ( Journal of the American Chemical Society), (USA), 1978, Vol. 100, p. 1558-1563 (Non-patent Document 1) discloses that the above reaction is carried out in a two-phase solvent of toluene and water. In addition, US Pat. No. 4,659,837 (Patent Document 2) discloses that the above reaction is carried out in a solvent of water alone, and US Pat. No. 5,151,525 (Patent Document 3) discloses dichloromethane and It is disclosed to perform the above reaction in water or a two-phase solvent of anisole and water.
反応溶媒として、非特許文献１や特許文献１のように、キシレンやトルエンの如き芳香族炭化水素と水の二相系溶媒を用いたり、特許文献２のように、水を単独で用いたりすると、反応後、酸性条件下に１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を析出させて取り出す際、この析出物がペースト状になり易いため、反応器に付着して取り出し難くなり、操作の負担増を招き、収率も必ずしも十分でない。また、特許文献３のように、ジクロロメタンの如き脂肪族ハロゲン系溶媒を用いると、環境面での配慮が特に必要となり、アニソールの如きエーテル系溶媒を用いると、防災面での配慮が特に必要となり、いずれも操作の負担増を招く。 As a reaction solvent, a non-patent document 1 or a patent document 1 uses a two-phase solvent of an aromatic hydrocarbon such as xylene or toluene and water, or a patent document 2 uses water alone. After the reaction, when 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid is precipitated under acidic conditions and taken out, the precipitate is likely to become a paste and is attached to the reactor. It becomes difficult to take out, increases the burden of operation, and the yield is not always sufficient. In addition, as in Patent Document 3, when an aliphatic halogen solvent such as dichloromethane is used, environmental considerations are particularly required, and when an ether solvent such as anisole is used, special considerations are required in terms of disaster prevention. , Both of which increase the burden of operation.
そこで、本発明の目的は、２，３−ビス（ベンジルアミノ）コハク酸とホスゲンから、操作性良く、良好な収率で１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を製造しうる方法を提供することにある。 Therefore, an object of the present invention is to prepare 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid from 2,3-bis (benzylamino) succinic acid and phosgene with good operability and good yield. It is in providing the method which can be manufactured.
本発明者は鋭意研究を行った結果、反応溶媒としてモノクロロベンゼンと水の二相系溶媒を採用することにより、上記目的を達成できることを見出し、本発明を完成するに至った。 As a result of diligent research, the present inventor has found that the above object can be achieved by adopting a two-phase solvent of monochlorobenzene and water as a reaction solvent, and has completed the present invention.
すなわち、本発明は、２，３−ビス（ベンジルアミノ）コハク酸を、モノクロロベンゼン及び水からなる二相系溶媒中で、ホスゲンと反応させることにより、１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を製造する方法を提供するものである。 That is, the present invention relates to 1,3-dibenzyl-2-oxoimidazolidine by reacting 2,3-bis (benzylamino) succinic acid with phosgene in a two-phase solvent composed of monochlorobenzene and water. A method for producing -4,5-dicarboxylic acid is provided.
本発明によれば、２，３−ビス（ベンジルアミノ）コハク酸とホスゲンから、操作性良く、良好な収率で１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸又はその塩を製造することができる。 According to the present invention, 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid or a mixture thereof can be obtained from 2,3-bis (benzylamino) succinic acid and phosgene with good operability and good yield. Salts can be produced.
本発明で原料に用いる２，３−ビス（ベンジルアミノ）コハク酸は、例えば特許文献１に記載されるように、２，３−ジブロモコハク酸をベンジルアミンと反応させることにより、調製することができ、通常、晶析や抽出などにより分離精製されて使用される。なお、この２，３−ビス（ベンジルアミノ）コハク酸は、２位と３位の不斉炭素の立体化学に関し、メソ体であってもよいし、（２Ｒ，３Ｒ）体であってもよいし、（２Ｓ，３Ｓ）体であってもよいし、これらのうちの２種又は３種の混合物であってもよい。 2,3-bis (benzylamino) succinic acid used as a raw material in the present invention can be prepared by reacting 2,3-dibromosuccinic acid with benzylamine, as described in Patent Document 1, for example. Usually, it is used after being separated and purified by crystallization or extraction. The 2,3-bis (benzylamino) succinic acid may be a meso form or a (2R, 3R) form with respect to the stereochemistry of the asymmetric carbons at the 2-position and 3-position. And (2S, 3S) body may be sufficient and the mixture of 2 types or 3 types of these may be sufficient.
本発明では、上記の２，３−ビス（ベンジルアミノ）コハク酸を、ホスゲンと反応させることにより、１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を製造するが、その際、反応溶媒として、モノクロロベンゼンと水の二相系溶媒を用いる。このように所定の溶媒を用いて反応を行うことにより、操作性良く、良好な収率で１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を製造することができる。 In the present invention, 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid is produced by reacting the above 2,3-bis (benzylamino) succinic acid with phosgene. At this time, a two-phase solvent of monochlorobenzene and water is used as a reaction solvent. By performing the reaction using a predetermined solvent in this manner, 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid can be produced with good operability and good yield.
ホスゲンは、液体であってもよいし、気体であってもよく、その使用量は、転化率などに応じて適宜調整されるが、通常、２，３−ビス（ベンジルアミノ）コハク酸の１〜１０モル倍程度である。 The phosgene may be a liquid or a gas, and the amount used is appropriately adjusted according to the conversion rate and the like, but is usually 1 of 2,3-bis (benzylamino) succinic acid. It is about 10 mol times.
モノクロロベンゼンの使用量は、通常、２，３−ビス（ベンジルアミノ）コハク酸の３〜１００重量倍程度である。水の使用量は、通常、２，３−ビス（ベンジルアミノ）コハク酸の３〜１００重量倍程度であり、またモノクロロベンゼンの０．１〜１０重量倍程度である。なお、必要により、モノクロロベンゼン以外の有機溶媒を併用することもできるが、その使用量は、通常、モノクロロベンゼンの０．１重量倍以下である。 The amount of monochlorobenzene used is usually about 3 to 100 times the weight of 2,3-bis (benzylamino) succinic acid. The amount of water used is usually about 3 to 100 times the weight of 2,3-bis (benzylamino) succinic acid and about 0.1 to 10 times the weight of monochlorobenzene. If necessary, an organic solvent other than monochlorobenzene can be used in combination, but the amount used is usually 0.1 times or less that of monochlorobenzene.
反応は、２，３−ビス（ベンジルアミノ）コハク酸、モノクロロベンゼン及び水の混合物を仕込液とし、この中に、ホスゲンを導入することにより行うのが有利である。反応温度は通常０〜７０℃程度である。また、反応は、中性ないし塩基性条件下に、具体的には反応液のｐＨを７〜１２に保って行うのが好ましい。なお、反応液中、原料の２，３−ビス（ベンジルアミノ）コハク酸が有する２つのアミノ基のプロトン化・非プロトン化の状態ないし２つのカルボキシル基の解離・非解離の状態は、反応液のｐＨによって異なり、また、目的物の１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸が有する２つのカルボキシル基の解離・非解離の状態も、反応液のｐＨによって異なる。 The reaction is advantageously carried out by using a mixture of 2,3-bis (benzylamino) succinic acid, monochlorobenzene and water as a feed liquid and introducing phosgene into the mixture. The reaction temperature is usually about 0 to 70 ° C. The reaction is preferably carried out under neutral or basic conditions, specifically, maintaining the pH of the reaction solution at 7-12. In the reaction solution, the two amino groups possessed by the raw material 2,3-bis (benzylamino) succinic acid are in a protonated / unprotonated state or in a dissociated / non-dissociated state of two carboxyl groups. The state of dissociation / non-dissociation of the two carboxyl groups of the target 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid also varies depending on the pH of the reaction solution.
上記のｐＨ調整は、反応液に無機塩基を添加しながら行うのがよく、かかる無機塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウムなどが挙げられ、中でも水酸化カリウムが好ましく用いられる。 The pH adjustment is preferably performed while adding an inorganic base to the reaction solution. Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like. Among them, potassium hydroxide is preferably used.
反応の進行は、ガスクロマトグラフィー、高速液体クロマトグラフィー、薄層クロマトグラフィー、核磁気共鳴スペクトルなどで追跡することができる。 The progress of the reaction can be followed by gas chromatography, high performance liquid chromatography, thin layer chromatography, nuclear magnetic resonance spectrum, or the like.
反応の後処理操作としては、反応混合物を、モノクロロベンゼン層と、１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を含む水層とに分離した後、該水層に例えば塩酸、硫酸、硝酸、リン酸などの鉱酸を加えて、酸性条件下に１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸を析出させる方法が有利に採用される。本発明によれば、この析出物がペースト状になるのを防止でき、操作性良く取り出すことができる。特に、前記のように２，３−ジブロモコハク酸とベンジルアミンから原料の２，３−ビス（ベンジルアミノ）コハク酸を調製すると、該原料中にベンジルアミンが含まれることがあり、かかる原料を用いて反応を行うと、上記析出物がペースト状になり易くなるが、本発明によればかかる不具合も効果的に解消しうる。かくして得られる１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸は、さらに洗浄や晶析などにより精製してもよい。 As a post-treatment operation of the reaction, the reaction mixture is separated into a monochlorobenzene layer and an aqueous layer containing 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid, A method in which a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like is added to precipitate 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid under acidic conditions is advantageously employed. According to the present invention, this precipitate can be prevented from becoming a paste and can be taken out with good operability. In particular, when 2,3-bis (benzylamino) succinic acid as a raw material is prepared from 2,3-dibromosuccinic acid and benzylamine as described above, benzylamine may be contained in the raw material. When the reaction is carried out, the precipitates are likely to become a paste, but according to the present invention, such problems can be effectively eliminated. The 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid thus obtained may be further purified by washing or crystallization.
以下、本発明の実施例を示すが、本発明はこれによって限定されるものではない。例中、濃度を表す％は特記ないかぎり重量基準である。 Examples of the present invention will be described below, but the present invention is not limited thereto. In the examples,% representing concentration is based on weight unless otherwise specified.
参考例１
２Ｌフラスコに、２，３−ジブロモコハク酸１９６ｇと４−メチル−２−ペンタノン４００ｇを入れて攪拌した。この中に、ベンジルアミン５１９ｇを４０℃にて１時間かけて滴下した後、８０℃で２時間、次いで１００℃で２時間、保持した。得られた反応混合物に４９重量％水酸化カリウム水溶液３６０ｇと水１５５ｇを加えて混合後、油層と水層とに分離した。水層を４−メチル−２−ペンタノン２００ｇで２回洗浄し、２，３−ビス（ベンジルアミノ）コハク酸を１７．５％、及びベンジルアミンを３．８％含む水溶液９６１ｇを得た。
Reference example 1
In a 2 L flask, 196 g of 2,3-dibromosuccinic acid and 400 g of 4-methyl-2-pentanone were added and stirred. Into this, 519 g of benzylamine was dropped at 40 ° C. over 1 hour, and then kept at 80 ° C. for 2 hours and then at 100 ° C. for 2 hours. To the obtained reaction mixture, 360 g of a 49 wt% potassium hydroxide aqueous solution and 155 g of water were added and mixed, and then separated into an oil layer and an aqueous layer. The aqueous layer was washed twice with 200 g of 4-methyl-2-pentanone to obtain 961 g of an aqueous solution containing 17.5% 2,3-bis (benzylamino) succinic acid and 3.8% benzylamine.
実施例１
参考例１で得られた２，３−ビス（ベンジルアミノ）コハク酸を含む水溶液１１８ｇ〔２，３−ビス（ベンジルアミノ）コハク酸０．０６３１モル〕とクロロベンゼン５８ｇを、５００ｍＬフラスコに入れて３２℃に保持した。この中にホスゲン３５ｇを６時間かけて吹き込んだ後、３２℃で０．５時間保持した。また、この吹き込みと保持の間、反応液のｐＨが１０．８に保たれるように、４９％水酸化カリウム水溶液９４ｇを加えた。得られた反応混合物を油層と水層とに分離し、該水層に、撹拌下、２５℃で２０％塩酸１１２ｇを滴下して、混合物のｐＨを１．０としたことろ、１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸が、フラスコの内壁や攪拌器に付着することなく、析出した。この析出物を濾取し、常温で減圧乾燥して、純度８８％の１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸２２．４ｇ（０．０５５６モル、収率８８％）を得た。
Example 1
118 g of an aqueous solution containing 2,3-bis (benzylamino) succinic acid obtained in Reference Example 1 [0.0631 mol of 2,3-bis (benzylamino) succinic acid] and 58 g of chlorobenzene were placed in a 500 mL flask and 32 Held at 0C. Into this, 35 g of phosgene was blown in over 6 hours, and then maintained at 32 ° C. for 0.5 hour. Further, 94 g of a 49% aqueous potassium hydroxide solution was added so that the pH of the reaction solution was maintained at 10.8 during the blowing and holding. The obtained reaction mixture was separated into an oil layer and an aqueous layer, and 112 g of 20% hydrochloric acid was added dropwise to the aqueous layer with stirring at 25 ° C. to adjust the pH of the mixture to 1.0. -Dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid precipitated without adhering to the inner wall of the flask or the stirrer. The precipitate was collected by filtration and dried at room temperature under reduced pressure to obtain 22.4 g (0.0556 mol, yield 88%) of 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid having a purity of 88%. )
比較例１
参考例１で得られた２，３−ビス（ベンジルアミノ）コハク酸を含む水溶液５７２ｇ〔２，３−ビス（ベンジルアミノ）コハク酸０．３０５モル〕とトルエン２５０ｇを、２Ｌフラスコに入れて３２℃に保持した。この中にホスゲン１７１ｇを６時間かけて吹き込んだ後、３２℃で０．５時間保持した。また、この吹き込みと保持の間、反応液のｐＨが１０．８に保たれるように、２９重量％水酸化カリウム水溶液１１００ｇを加えた。得られた反応混合物を油層と水層とに分離し、該水層に、攪拌下、２５℃で２０％塩酸５０６ｇを滴下して、混合物のｐＨを１．７としたところ、１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸が、ペースト状になって、フラスコの壁面や撹拌器に付着して、析出した。この析出物をかき取って濾取し、常温で減圧乾燥して、純度７６％の１，３−ジベンジル−２−オキソイミダゾリジン−４，５−ジカルボン酸１０４ｇ（０．２２４モル、収率７４％）を得た。
Comparative Example 1
Into a 2 L flask, 572 g of an aqueous solution containing 2,3-bis (benzylamino) succinic acid obtained in Reference Example 1 [0.305 mol of 2,3-bis (benzylamino) succinic acid] and 250 g of toluene were placed in a 2 L flask. Held at 0C. After 171 g of phosgene was blown into this over 6 hours, it was kept at 32 ° C. for 0.5 hours. Further, 1100 g of a 29 wt% potassium hydroxide aqueous solution was added so that the pH of the reaction solution was maintained at 10.8 during the blowing and holding. The obtained reaction mixture was separated into an oil layer and an aqueous layer, and 506 g of 20% hydrochloric acid was added dropwise to the aqueous layer with stirring at 25 ° C. to adjust the pH of the mixture to 1.7. Dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid became a paste and deposited on the wall of the flask and the stirrer. The precipitate was scraped off, collected by filtration, and dried under reduced pressure at room temperature to give 104 g (0.224 mol, yield 74) of 76% pure 1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid. %).
Claims (2)
The production method according to claim 1, wherein the pH of the reaction solution is maintained at 7-12.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109734669A (en) * | 2019-02-19 | 2019-05-10 | 安徽泰格维生素实业有限公司 | A kind of refining methd of double benzyl dicarboxylic acids |
| CN113121444A (en) * | 2019-12-30 | 2021-07-16 | 大丰海嘉诺药业有限公司 | Method for synthesizing vitamin H intermediate through pipelining |
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| JP2001213860A (en) * | 2000-02-01 | 2001-08-07 | Sumitomo Chem Co Ltd | Method for producing aryl allyl sulfone |
| JP2004137244A (en) * | 2001-11-19 | 2004-05-13 | Sumitomo Chem Co Ltd | Method for producing geranyl aryl sulfone |
| JP2004168774A (en) * | 2002-11-08 | 2004-06-17 | Sumitomo Chem Co Ltd | Method for producing 2-bromocyclopentanone |
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| US2489232A (en) * | 1949-11-22 | Synthesis of biotin | ||
| US5151525A (en) * | 1991-06-18 | 1992-09-29 | Ppg Industries, Inc. | Process for producing 2-oxo-1,3-dibenzyl-4,5-cis-imidazolidinedicarboxylic acid |
| JP2001213860A (en) * | 2000-02-01 | 2001-08-07 | Sumitomo Chem Co Ltd | Method for producing aryl allyl sulfone |
| JP2004137244A (en) * | 2001-11-19 | 2004-05-13 | Sumitomo Chem Co Ltd | Method for producing geranyl aryl sulfone |
| JP2004168774A (en) * | 2002-11-08 | 2004-06-17 | Sumitomo Chem Co Ltd | Method for producing 2-bromocyclopentanone |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109734669A (en) * | 2019-02-19 | 2019-05-10 | 安徽泰格维生素实业有限公司 | A kind of refining methd of double benzyl dicarboxylic acids |
| CN113121444A (en) * | 2019-12-30 | 2021-07-16 | 大丰海嘉诺药业有限公司 | Method for synthesizing vitamin H intermediate through pipelining |
| CN113121444B (en) * | 2019-12-30 | 2024-03-15 | 大丰海嘉诺药业有限公司 | Method for synthesizing vitamin H intermediate through pipeline |
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