JP2716243B2 - N-benzyl-3-hydroxysuccinamic acid and method for producing the same - Google Patents
N-benzyl-3-hydroxysuccinamic acid and method for producing the sameInfo
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- JP2716243B2 JP2716243B2 JP12461690A JP12461690A JP2716243B2 JP 2716243 B2 JP2716243 B2 JP 2716243B2 JP 12461690 A JP12461690 A JP 12461690A JP 12461690 A JP12461690 A JP 12461690A JP 2716243 B2 JP2716243 B2 JP 2716243B2
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- Japan
- Prior art keywords
- benzyl
- acid
- hydroxysuccinamic
- producing
- malic acid
- 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.)
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Description
【発明の詳細な説明】 [産業上の利用分野] 本発明は、N−ベンジル−3−ヒドロキシスクシンア
ミド酸またはその塩、およびそれらの製造法に関する。
本発明の化合物は医薬、農薬合成中間体、各種薬品合成
中間体として多様な用途が期待される有用な化合物であ
る。Description: TECHNICAL FIELD The present invention relates to N-benzyl-3-hydroxysuccinamic acid or a salt thereof, and a method for producing them.
The compound of the present invention is a useful compound that is expected to have various uses as intermediates for synthesizing drugs, agricultural chemicals and various chemicals.
[従来の技術・発明が解決しようとする課題] 本発明のN−ベンジル−3−ヒドロキシスクシンアミ
ド酸(I)は、たとえばトルエンなどの溶媒中で加熱、
脱水することにより、医薬品合成中間体として有用なN
−ベンジルリンゴ酸イミド(IV)へと導びくことができ
る。またN−ベンジルリンゴ酸イミド(IV)は、還元す
ることにより、1−ベンジル−3−ピロリジノール
(V)へ導びくことができる。[Problems to be solved by the prior art] The N-benzyl-3-hydroxysuccinamic acid (I) of the present invention is heated in a solvent such as toluene, for example.
By dehydration, N is useful as a pharmaceutical synthesis intermediate
-To benzylmalimide (IV). Also, N-benzylmalic imide (IV) can be led to 1-benzyl-3-pyrrolidinol (V) by reduction.
本発明のN−ベンジル−3−ヒドロキシスクシンアミ
ド酸は現在までに合成された例のない新規化合物であ
る。したがって、その製造法に関する従来の知見はな
い。 The N-benzyl-3-hydroxysuccinamic acid of the present invention is a novel compound which has not been synthesized so far. Therefore, there is no conventional knowledge about the production method.
本発明は、前記の有用性を有するN−ベンジル−3−
ヒドロキシスクシンアミド酸を提供することを目的とす
る。The present invention relates to N-benzyl-3- having the above-mentioned utility.
It is intended to provide hydroxysuccinamic acid.
[課題を解決するための手段] 本発明は、 (1)式(I): で表わされるN−ベンジル−3−ヒドロキシスクシンア
ミド酸またはその塩、 (2)式(II): で表わされるリンゴ酸クロラリドもしくはその塩または
それらの混合物にベンジルアミンを反応させることを特
徴とするN−ベンジル−3−ヒドロキシスクシンアミド
酸(I)またはその塩の製造法、および (3)式(III): で表わされる2−トリフルオロアセトキシコハク酸無水
物(III)にベンジルアミンを反応させることを特徴と
するN−ベンジル−3−ヒドロキシスクシンアミド酸
(I)またはその塩の製造法 に関する。[Means for Solving the Problems] The present invention provides: (1) Formula (I): N-benzyl-3-hydroxysuccinamic acid or a salt thereof represented by the following formula (2): A method for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof, which comprises reacting benzylamine with malic acid chloride or a salt thereof or a mixture thereof represented by the formula: (III): A process for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof, characterized by reacting benzylamine with 2-trifluoroacetoxysuccinic anhydride (III) represented by the formula:
[作用・実施例] 本発明の化合物は、つぎの2種の方法によって製造で
きる。[Action / Example] The compound of the present invention can be produced by the following two methods.
(1)リンゴ酸クロラリドを用いる方法 リンゴ酸クロラリドもしくはその塩またはそれらの混
合物を溶媒に加え、撹拌下に必要に応じて塩基たとえば
トリアルキルアミン、ピリジンなどの約1当量を加え、
ベンジルアミンを滴下後60〜140℃、好ましくは60〜100
℃に加熱し、その温度を保って1〜20時間撹拌する。(1) Method using malic acid chloralide Malic acid chloralide or a salt thereof or a mixture thereof is added to a solvent, and if necessary, about 1 equivalent of a base such as a trialkylamine or pyridine is added under stirring,
60-140 ° C. after the addition of benzylamine, preferably 60-100 ° C.
C. and stir at that temperature for 1-20 hours.
溶媒としては、芳香族系、有機ハロゲン系、エーテル
系の溶剤のいずれか、またはそれらの混合溶剤を用いる
ことができるが、ベンゼン、トルエン、キシレンなどの
芳香族系溶剤を用いるのが好ましい。As the solvent, any of aromatic, organic halogen, and ether solvents or a mixed solvent thereof can be used, but it is preferable to use an aromatic solvent such as benzene, toluene, and xylene.
ベンジルアミンはリンゴ酸クロラリドまたはその塩に
対して1〜2当量用いるのが好ましい。Benzylamine is preferably used in an amount of 1 to 2 equivalents to malic acid chloralide or a salt thereof.
反応終了後、反応生成物をアルカリ水溶液を用いて反
応液から水層に抽出後、水層を酸性にして、有機溶剤で
抽出することにより目的生成物の粗結晶をうることがで
きる。精製はシリカゲルカラムクロマトグラフィー、溶
剤からの結晶化などの一般的な手段により行なえばよ
い。After completion of the reaction, the reaction product is extracted from the reaction solution with an aqueous alkali solution into an aqueous layer, and then the aqueous layer is acidified and extracted with an organic solvent to obtain crude crystals of the target product. Purification may be performed by a general means such as silica gel column chromatography and crystallization from a solvent.
(2)2−トリフルオロアセトキシコハク酸無水物を用
いる方法 2−トリフルオロアセトキシコハク酸無水物を溶媒に
加え撹拌下に0〜20℃でベンジルアミンを滴下後、0〜
50℃で3〜24時間撹拌を続ける。(2) Method using 2-trifluoroacetoxysuccinic anhydride 2-trifluoroacetoxysuccinic anhydride was added to the solvent, and benzylamine was added dropwise at 0 to 20 ° C with stirring.
Continue stirring at 50 ° C. for 3-24 hours.
溶媒としては、芳香族系、有機ハロゲン系、エーテル
系の溶剤のいずれか1種、またはそれらの2種以上の混
合溶剤を用いることができるが、ジエチルエーテル、テ
トラヒドロフラン(THF)などのエーテル系溶剤を用い
るのが好ましい。As the solvent, any one of aromatic solvents, organic halogen solvents, and ether solvents, or a mixed solvent of two or more thereof can be used, and ether solvents such as diethyl ether and tetrahydrofuran (THF) can be used. It is preferable to use
ベンジルアミンは2−トリフルオロアセトキシコハク
酸無水物に対し2〜4当量用いるのがよい。Benzylamine is preferably used in an amount of 2 to 4 equivalents based on 2-trifluoroacetoxysuccinic anhydride.
反応終了後の後処理は、前記のリンゴ酸クロラリドを
用いる方法のばあいと同様に行なえばよい。Post-treatment after completion of the reaction may be performed in the same manner as in the above-mentioned method using malic acid chloralide.
本発明の化合物の合成原料として用いる式(II)のリ
ンゴ酸クロラリドの合成は、たとえばリービッヒス・ア
ンナーレン・デア・ヘミー(Liebigs Ann.Chem.)、677
巻、200頁(1964年)に記載されているように、安価な
リンゴ酸と抱水クロラールを硫酸を触媒として反応させ
ることにより容易に実施できる。Synthesis of malic acid chloralide of the formula (II) used as a raw material for the synthesis of the compound of the present invention can be carried out, for example, by the method of Liebigs Ann. Der Chemie, 677.
As described in Vol. 200, 1964, it can be easily carried out by reacting inexpensive malic acid with chloral hydrate using sulfuric acid as a catalyst.
また、式(III)の2−トリフルオロアセトキシコハ
ク酸無水物の合成は、たとえばジャーナル・オブ・オー
ガニック・ケミストリー(Journal of Organic Chemist
ry)、47巻、4928頁(1982年)に記載されているよう
に、リンゴ酸と、トリフルオロ酢酸無水物を反応させる
ことにより、容易に実施できる。Further, the synthesis of 2-trifluoroacetoxysuccinic anhydride of the formula (III) is carried out, for example, by using the Journal of Organic Chemistry.
ry), Vol. 47, p. 4928 (1982), and can be easily carried out by reacting malic acid with trifluoroacetic anhydride.
つぎに実施例をあげて本発明をさらに具体的に説明す
るが、本発明はこれらの実施例のみに限定されるもので
はない。Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to only these examples.
参考例1 [リンゴ酸クロラリドの合成] DL−リンゴ酸26.4gおよび抱水クロラール37.6gの混合
物に、濃硫酸50mlを加え、室温で4.5時間攪拌後、室温
で20時間放置した。反応混合物を氷水にあけ、攪拌した
のち、過した。えられた結晶を水洗後、酢酸エチル80
0mlに溶解し、溶液を無水硫酸ナトリウムで乾燥したの
ち過、濃縮して、m.p.173〜175℃のリンゴ酸クロラリ
ド48.4gをえた。収率は94%であった。Reference Example 1 [Synthesis of malic acid chloralide] To a mixture of 26.4 g of DL-malic acid and 37.6 g of chloral hydrate was added 50 ml of concentrated sulfuric acid, and the mixture was stirred at room temperature for 4.5 hours and then left at room temperature for 20 hours. The reaction mixture was poured into ice water, stirred, and then passed. After washing the obtained crystals with water, ethyl acetate 80
After dissolving in 0 ml, the solution was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 48.4 g of malic acid chloralide having an mp of 173 to 175 ° C. The yield was 94%.
実施例1 [N−ベンジル−3−ヒドロキシスクシンアミド酸の合
成] リンゴ酸クロラリド25.0gをトルエン1に溶解し、
攪拌しながらトリエチルアミン9.6gを加え、つづいてベ
ンジルアミン11.2gを加えたのち、95〜105℃で2時間攪
拌を続けた。反応液を室温まで冷却し、炭酸水素ナトリ
ウムの飽和水溶液で2回抽出後、水層を6N HCl水溶液で
pH2に調節し、酢酸エチルで3回抽出した。有機層を、
硫酸マグネシウムで乾燥後過、濃縮した。えられた粗
結晶を酢酸エチル−ヘキサンから再結晶して、N−ベン
ジル−3−ヒドロキシスクシンアミド酸10.7g(収率51
%)をえた。Example 1 [Synthesis of N-benzyl-3-hydroxysuccinamic acid] 25.0 g of malic acid chloralide was dissolved in toluene 1,
After stirring, 9.6 g of triethylamine was added, followed by 11.2 g of benzylamine, followed by stirring at 95 to 105 ° C for 2 hours. The reaction solution was cooled to room temperature, extracted twice with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was extracted with a 6N aqueous HCl solution.
It was adjusted to pH 2 and extracted three times with ethyl acetate. The organic layer
After drying over magnesium sulfate, the mixture was concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 10.7 g of N-benzyl-3-hydroxysuccinamic acid (yield 51
%).
m.p.:103〜104.5℃ 1H−NMR(90MHz、アセトン−d6、内部標準テトラメチル
シラン)δ(ppm):2.52(dd,J=16,8Hz,1H)、2.89(d
d,J=18.5,3.5Hz,1H)、4.41(d,J=6Hz,2H)、4.32〜
4.60(m,1H)、7.02〜7.43(m,5H)、7.85(br.s,1H) シリカゲル薄層クロマトグラフィー Rf:0.52 (酢酸エチル:メタノール=1:1) 元素分析値:(C11H13NO4として) 計算値(%):C59.19 H5.87 N6.27 測定値(%):C59.50 H5.72 N6.19 実施例2 [N−ベンジル−3−ヒドロキシスクシンアミド酸の合
成] DL−リンゴ酸6.7gに、氷冷下攪拌しながらトリフルオ
ロ酢酸無水物25gを加え、徐々に室温まで昇温した。5
時間後反応液を氷冷しながら真空ポンプで減圧にして、
過剰のトリフルオロ酢酸無水物およびトリフルオロ酢酸
を留去した。えられた2−トリフルオロアセトキシコハ
ク酸無水物の粗生成物に乾燥テトラヒドロフラン80mlを
加え、氷冷下攪拌しながらベンジルアミン17.7gを0.5時
間かけて滴下した。滴下後室温にまで昇温し16時間攪拌
後、反応液を炭酸水素ナトリウム水溶液中に注ぎアルカ
ル性にしたのち酢酸エチルで抽出した。つぎに水層を6N
HCl水溶液でpH3〜4にして酢酸エチルで抽出後、えら
れた有機層を硫酸マグネシウムで乾燥したのち過、濃
縮して、5.5gの粗生成物をえた。これをシリカゲルカラ
ムクロマトグラフィー(ヘキサン:酢酸エチル=1:50)
で精製後、えられた結晶を酢酸エチル−ヘキサンから再
結晶して、N−ベンジル−3−ヒドロキシスクシンアミ
ド酸4.1gをえた。通算収率は37%であった。mp: 103-104.5 ℃ 1 H-NMR (90 MHz, acetone-d 6 , internal standard tetramethylsilane) δ (ppm): 2.52 (dd, J = 16.8 Hz, 1H), 2.89 (d
d, J = 18.5, 3.5Hz, 1H), 4.41 (d, J = 6Hz, 2H), 4.32-
4.60 (m, 1H), 7.02~7.43 (m, 5H), 7.85 (br.s, 1H) silica gel thin layer chromatography Rf: 0.52 (ethyl acetate: methanol = 1: 1) Elemental analysis: (C 11 H (As 13 NO 4 ) Calculated value (%): C59.19 H5.87 N6.27 Measured value (%): C59.50 H5.72 N6.19 Example 2 [N-benzyl-3-hydroxysuccinamic acid Synthesis of DL-malic acid] To 6.7 g of DL-malic acid, 25 g of trifluoroacetic anhydride was added with stirring under ice cooling, and the temperature was gradually raised to room temperature. 5
After a period of time, the pressure of the reaction solution was reduced with a vacuum pump while cooling with ice,
Excess trifluoroacetic anhydride and trifluoroacetic acid were distilled off. 80 ml of dry tetrahydrofuran was added to the obtained crude product of 2-trifluoroacetoxysuccinic anhydride, and 17.7 g of benzylamine was added dropwise over 0.5 hour while stirring under ice cooling. After the dropwise addition, the temperature was raised to room temperature, and the mixture was stirred for 16 hours. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution to make it alkaline, and then extracted with ethyl acetate. Next, the water layer is 6N
After adjusting the pH to 3 to 4 with an aqueous HCl solution and extracting with ethyl acetate, the obtained organic layer was dried over magnesium sulfate, and then concentrated to obtain 5.5 g of a crude product. This was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 50).
After the purification, the obtained crystals were recrystallized from ethyl acetate-hexane to obtain 4.1 g of N-benzyl-3-hydroxysuccinamic acid. The overall yield was 37%.
[発明の効果] 本発明によるN−ベンジル−3−ヒドロキシスクシン
アミド酸はたとえばN−ベンジルリンゴ酸イミドや1−
ベンジル−3−ピロリジノールなどの合成中間体として
有用であり、該化合物は安価なリンゴ酸からえられるリ
ンゴ酸クロラリドまたは2−トリフルオロアセトキシコ
ハク酸無水物とベンジルアミンとから容易に製造するこ
とができる。[Effect of the Invention] N-benzyl-3-hydroxysuccinamic acid according to the present invention is, for example, N-benzylmalic imide or 1-benzylmalinimide.
It is useful as a synthetic intermediate such as benzyl-3-pyrrolidinol, and the compound can be easily produced from malic acid chloralide or 2-trifluoroacetoxysuccinic anhydride obtained from inexpensive malic acid and benzylamine. .
Claims (3)
ミド酸またはその塩。(1) Formula (I): And N-benzyl-3-hydroxysuccinamic acid or a salt thereof.
それらの混合物にベンジルアミンを反応させることを特
徴とする請求項1記載のN−ベンジル−3−ヒドロキシ
スクシンアミド酸(I)またはその塩の製造法。2. Formula (II): 2. The method for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof according to claim 1, wherein benzylamine is reacted with malic acid chloralide represented by the formula or a salt thereof or a mixture thereof.
物(III)にベンジルアミンを反応させることを特徴と
する請求項1記載のN−ベンジル−3−ヒドロキシスク
シンアミド酸(I)またはその塩の製造法。(3) Formula (III): 2. A method for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof according to claim 1, wherein benzylamine is reacted with 2-trifluoroacetoxysuccinic anhydride (III) represented by the formula: Law.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12461690A JP2716243B2 (en) | 1990-05-15 | 1990-05-15 | N-benzyl-3-hydroxysuccinamic acid and method for producing the same |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12461690A JP2716243B2 (en) | 1990-05-15 | 1990-05-15 | N-benzyl-3-hydroxysuccinamic acid and method for producing the same |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0421663A JPH0421663A (en) | 1992-01-24 |
JP2716243B2 true JP2716243B2 (en) | 1998-02-18 |
Family
ID=14889832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12461690A Expired - Lifetime JP2716243B2 (en) | 1990-05-15 | 1990-05-15 | N-benzyl-3-hydroxysuccinamic acid and method for producing the same |
Country Status (1)
Country | Link |
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JP (1) | JP2716243B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021019555A1 (en) * | 2019-07-26 | 2021-02-04 | Indian Council Of Medical Research | A process for the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid and product prepared therefrom |
-
1990
- 1990-05-15 JP JP12461690A patent/JP2716243B2/en not_active Expired - Lifetime
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021019555A1 (en) * | 2019-07-26 | 2021-02-04 | Indian Council Of Medical Research | A process for the preparation of 4-amino-2-hydroxy-4-oxobutanoic acid and product prepared therefrom |
Also Published As
Publication number | Publication date |
---|---|
JPH0421663A (en) | 1992-01-24 |
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