JPH066539B2 - Process for producing α-hydroxycarboxylic acid derivative - Google Patents
Process for producing α-hydroxycarboxylic acid derivativeInfo
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- JPH066539B2 JPH066539B2 JP61056471A JP5647186A JPH066539B2 JP H066539 B2 JPH066539 B2 JP H066539B2 JP 61056471 A JP61056471 A JP 61056471A JP 5647186 A JP5647186 A JP 5647186A JP H066539 B2 JPH066539 B2 JP H066539B2
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Description
【発明の詳細な説明】 発明の目的 α−ハイドロキシカルボン酸誘導体は有用な医薬品、た
とえばエナラブリルおよびその誘導体の合成における重
要中間体であることおよびα−ハイドロキシカルボン酸
は植物ホルモンの生理活性を有することが知られてい
る。従つてα−ハイドロキシカルボン酸の実用的な合成
法の開発が望まれている。発明者等はセリン誘導体を出
発物質として好収率でα−ハイドロキシカルボン酸が得
られる方法を見い出し、本発明を完成した。DETAILED DESCRIPTION OF THE INVENTION α-Hydroxycarboxylic acid derivatives are important intermediates in the synthesis of useful pharmaceuticals such as enabulril and its derivatives, and α-hydroxycarboxylic acids have physiological activity of plant hormones. It has been known. Therefore, development of a practical synthetic method of α-hydroxycarboxylic acid is desired. The present inventors have found a method for obtaining α-hydroxycarboxylic acid in good yield using a serine derivative as a starting material, and completed the present invention.
発明の構成 本発明は、式 〔式中、R1およびR2は、水素原子を示し、R3は水酸基、
NR6R7基（R6およびR7は、同一または異なつて、水素原
子、置換基を有してもよいフエニル基を示す。）を示
し、Ｙは、ハロゲン原子を示す。〕を有する化合物を塩
基で処理して 式 〔式中、R1，R2及びR3は、前述したものと同意義を示
す。〕を有する化合物に導き、ついでこの化合物に 式 RM (3) 〔式中、Ｒは、アルキル基、フエニル基、置換基を有し
てもよいベンジル基を示し、Ｍは、MgX（Ｍｇはマグネ
シウムを示し、Ｘは、塩素、臭素または沃素を示す。）
またはアルカリ金属を示す。〕を有する化合物を反応さ
せることを特徴とする 式 〔式中、Ｒ，R1，R2およびR3は、前述したものと同意義
を示す。〕を有する化合物の製法である。The invention comprises the formula [In the formula, R 1 and R 2 represent a hydrogen atom, R 3 is a hydroxyl group,
NR 6 R 7 group (R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group which may have a substituent), and Y represents a halogen atom. A compound having the formula [In the formula, R 1 , R 2 and R 3 have the same meanings as described above. ] To a compound having the formula RM (3) [wherein R represents an alkyl group, a phenyl group, or a benzyl group which may have a substituent, and M is MgX (Mg is magnesium). And X represents chlorine, bromine or iodine.)
Or an alkali metal is shown. ] The compound having the formula [In the formula, R, R 1 , R 2 and R 3 have the same meanings as described above. ] The manufacturing method of the compound which has.
上記説明中、Ｒにおけるアルキル基は、たとえばメチ
ル、エチル、プロピル、イソプロピル、ブチル、イソブ
チル、Ｓ−ブチルまたはｔ−ブチルがあげられる。In the above description, the alkyl group for R is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl or t-butyl.
R6およびR7における置換基を有するフエニル基の置換基
は、たとえばアルキル、アルコキシ基、ハロゲン原子、
トリフルオロメチル基、またはニトロ基があげられ、そ
のアルキル基は、たとえばメチル、エチル、プロピルま
たはイソプロピル基があげられ、アルコキシ基は、たと
えばトキシ、エトキシまたはプロポキシがあげられ、ハ
ロゲン原子は、弗素、塩素または臭素原子があげられ
る。The substituent of the phenyl group having a substituent in R 6 and R 7 is, for example, an alkyl group, an alkoxy group, a halogen atom,
Examples thereof include a trifluoromethyl group, or a nitro group, examples of the alkyl group include a methyl, ethyl, propyl or isopropyl group, examples of the alkoxy group include a toxy, ethoxy or propoxy group, and a halogen atom such as fluorine, Examples include chlorine or bromine atoms.
Ｒの置換基を有するベンジル基の置換基は、たとえばア
ルキル、アルコキシ基、ハロゲン原子、トリフルオロメ
チル基、またはニトロ基があげられ、そのアルキル基
は、たとえばメチル、エチル、プロピルまたはイソプロ
ピル基があげられ、アルコキシ基は、たとえばメトキ
シ、エトキシまたはプロポキシがあげられ、ハロゲン原
子は、弗素、塩素、または臭素があげられる。Examples of the substituent of the benzyl group having a substituent of R include an alkyl group, an alkoxy group, a halogen atom, a trifluoromethyl group, and a nitro group, and the alkyl group includes, for example, a methyl group, an ethyl group, a propyl group, and an isopropyl group. The alkoxy group is, for example, methoxy, ethoxy or propoxy, and the halogen atom is fluorine, chlorine or bromine.
Ｍのアルカリ金属は、たとえばリチウム、ナトリウムま
たはカリウムがあげられる。Examples of the alkali metal of M include lithium, sodium or potassium.
Ｙのハロゲン原子は、たとえば塩素、臭素または沃素原
子があげられる。The halogen atom of Y is, for example, chlorine, bromine or iodine atom.
本発明の製法を反応式で示すと次のとおりである。The reaction method of the production method of the present invention is as follows.
〔式中、R1，R2，Ｙ，ＲおよびＭは、前述したものと同
意義を示す。〕 セリン誘導体のアミノ基を常法に従つてハロゲン原子に
変換して得られる化合物(1)を塩基で処理しグリシド酸
誘導体(2)へ導き（第１工程）、この化合物に求核試薬
(3)を反応（第２工程）させるとα−ハイドロキシカル
ボン酸誘導体(4)が得られる。 [In the formula, R 1 , R 2 , Y, R and M have the same meanings as described above. The compound (1) obtained by converting the amino group of a serine derivative into a halogen atom by a conventional method is treated with a base to give a glycidic acid derivative (2) (first step), and this compound is a nucleophile
By reacting (3) (second step), an α-hydroxycarboxylic acid derivative (4) is obtained.
第１工程：本反応は、水、メタノール、エタノール、ア
セトン、アセトニトリル、テトラヒドロフラン、ジオキ
サン、ベンゼン、トルエン、酢酸エチル、塩化メチレン
または1,2−ジクロルエタン中、２当量以上、好ましく
は2.1〜３当量に塩基（たとえば水酸化カリウム、水酸
化ナトリウム、水酸化リチウム、水酸化カルシウム、炭
酸ナトリウム、炭酸水素ナトリウム、トリエチルアミ
ン、Ｎ−メチルモルホリンまたは1,8−ジアザビシクロ
〔5.4.0〕ウンデカ−７−エンがあげられる。）の存在
下、０゜〜室温で0.5〜２時間行う。反応液に酸（たと
えば硫酸水素カリウム、硫酸水素ナトリウム、硫酸、塩
酸、臭化水素酸、硝酸、トリフルオロ酢酸、トリクロロ
酢酸、モノクロロ酢酸、メタンスルホン酸、ベンゼンス
ルホン酸またはトルエンスルホン酸があげられる。）の
水溶液を加え中和後溶媒（たとえば第１工程の反応に使
用する溶媒のうち水と混合しない溶媒があげられる。）
で抽出するとグリシド酸誘導体(2)が得られる。こゝに
得られた化合物(2)は必要に応じて再結晶またはクロマ
トグラフイーにより精製できるが、精製せず次の反応に
用いることもできる。Step 1: This reaction is carried out in water, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, dioxane, benzene, toluene, ethyl acetate, methylene chloride or 1,2-dichloroethane in 2 equivalents or more, preferably 2.1 to 3 equivalents. Bases such as potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine or 1,8-diazabicyclo [5.4.0] undec-7-ene. Is carried out at 0 ° to room temperature for 0.5 to 2 hours. Examples of the reaction solution include acids (eg, potassium hydrogen sulfate, sodium hydrogen sulfate, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid). After the addition of the aqueous solution of 1) and neutralization, a solvent (for example, a solvent that is immiscible with water among the solvents used in the reaction of the first step can be mentioned)
The glycidic acid derivative (2) is obtained by extraction with. The compound (2) thus obtained can be purified by recrystallization or chromatography if necessary, but can also be used in the next reaction without purification.
第２工程：本反応はエールまたはテトラヒドロフラン
中、−78゜〜50℃好ましくは−20℃〜室温で１０分間〜
５時間好ましくは0.5〜２時間行う。化合物(3)は化合物
(2)に対して１〜５当量、好ましく１〜３当量であり、
化合物(3)がグリニヤ試薬である場合には本反応にハロ
ゲン化銅（たとえば塩化第一銅、臭化第一銅または沃化
第一銅があげられる）をグリニヤ試薬に対して0.1〜0.3
当量加えると目的物の収率が向上する。本反応終了後常
法に従って処理すると目的物(4)が得られ、必要ならば
再結晶またはクロマトグラフイーにより精製することが
できる。Second step: This reaction is carried out in ale or tetrahydrofuran at -78 ° C to 50 ° C, preferably -20 ° C to room temperature for 10 minutes to
It is carried out for 5 hours, preferably 0.5 to 2 hours. Compound (3) is a compound
1 to 5 equivalents relative to (2), preferably 1 to 3 equivalents,
When the compound (3) is a Grignard reagent, a copper halide (such as cuprous chloride, cuprous bromide or cuprous iodide) can be used in this reaction in an amount of 0.1 to 0.3 with respect to the Grignard reagent.
Addition of an equivalent amount improves the yield of the desired product. After the completion of this reaction, the desired product (4) is obtained by treating it according to a conventional method, and can be purified by recrystallization or chromatography if necessary.
発明の効果 グリシド酸誘導体(2)に対し求核試薬(3)は位置選択的反
応してα−ハイドロキシカルボン酸誘導体(4)を与え、
光学活性なセリン誘導体から導かれるグリシド酸誘導体
を用いて本反応を行うと立体選択的に光学活性なα−ハ
イドロキシカルボン酸(4)が好収率で得られる。Effect of the Invention The nucleophile (3) reacts regioselectively with respect to the glycidic acid derivative (2) to give the α-hydroxycarboxylic acid derivative (4),
By carrying out this reaction using a glycidic acid derivative derived from an optically active serine derivative, a stereoselectively optically active α-hydroxycarboxylic acid (4) can be obtained in a good yield.
以下に実施例をあげ本発明を具体的に説明する。The present invention will be specifically described below with reference to examples.
実施例１ (R)−グリシド酸 Ｌ−セリン165.0gに濃硫酸210mlと水2350mlの混合液を
加え−５℃に冷却した。これに臭化カリウム654.01gを
添加後、亜硝酸ソーダ1763.3ｇを水560mlに溶かした溶
液を滴加し、次いで室温で１時間撹拌後、窒素を通して
溶液中の一酸化窒素ガスを除いた。生成物を酢酸エチル
１ｌで抽出し、さらに酢酸エチル500mlで４回抽出後、
有機層を合わせ減圧下、濃縮すると(S)−α−ブロモ−
β−ハイドロキシプロピオン酸205.4gが得られた。これ
を水600mlに溶かし、０〜５℃に冷却し、苛性ソーダ102
gを水800mlに溶かした溶液を注加後、室温で１時間撹拌
した。反応液を０〜５℃に冷却し、30%硫酸水素カリウ
ム水溶液860mlを加えた後、酢酸エチル８ｌで抽出、さ
らに水層を酢酸エチル５ｌで２回抽出後、有機層を減圧
下濃縮すると無色油状物105.9g（収率97.8%）が得られ
た。Example 1 (R) -Glycidic acid To 165.0 g of L-serine, a mixed solution of 210 ml of concentrated sulfuric acid and 2350 ml of water was added and cooled to -5 ° C. After adding 654.01 g of potassium bromide thereto, a solution of 1763.3 g of sodium nitrite dissolved in 560 ml of water was added dropwise, and after stirring at room temperature for 1 hour, nitrogen monoxide gas in the solution was removed by passing nitrogen through the solution. The product was extracted with 1 liter of ethyl acetate and 4 times with 500 ml of ethyl acetate,
The organic layers are combined and concentrated under reduced pressure to give (S) -α-bromo-
205.4 g of β-hydroxypropionic acid was obtained. Dissolve this in 600 ml of water, cool to 0-5 ° C, and add caustic soda 102
After adding a solution of g in 800 ml of water, the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0 to 5 ° C., 860 ml of 30% potassium hydrogensulfate aqueous solution was added, and then extracted with 8 l of ethyl acetate, the aqueous layer was extracted twice with 5 l of ethyl acetate, and the organic layer was concentrated under reduced pressure to give colorless. An oily product (105.9 g, yield 97.8%) was obtained.
NMR(CDCl3)δppm: 3.00(2H,d,J＝3Hz),3.50(1H,t,J＝3Hz),11.15(S,1H) mp. 43℃（ベンゼン−ヘキサンより再結晶） 実施例２ (S)−グリシド酸 Ｄ−セリン１０ｇを出発原料とし、実施例１と同様の操
作を行い目的物6.5gが油状物として得られた。NMR (CDCl 3 ) δppm: 3.00 (2H, d, J = 3Hz), 3.50 (1H, t, J = 3Hz), 11.15 (S, 1H) mp. 43 ℃ (Recrystallized from benzene-hexane) Example 2 (S) -glycidic acid D-serine (10 g) was used as a starting material, and the same procedure as in Example 1 was repeated to obtain 6.5 g of the desired product as an oil.
NMR(CDCl3)δppm:3.05(2H,d,J＝3Hz),3.57(1H,t,J＝3H
z),11.10(1H,s) 実施例３ (R)−２−ハイドロキシ−４−フエニル酪酸 窒素気流下、ベンジルマグネシウムクロリド（1M/l−テ
トラヒドロフラン以下THFと略す。）78.1mlを−10℃に
冷却した。これにヨウ化第一銅1.49gを加え、そのまま
の温度で10分間撹拌した。これに(R)−グリシド酸2.29g
をTHF20mlに溶かした液を−10℃を保つように冷却しな
がら滴下した。滴下終了後室温で１時間撹拌した。反応
液を氷冷下、30%硫酸水素カリウム水溶液100ml中へゆつ
くりとそそぎ、酢酸エチル100mlで２回抽出した。その
酢酸エチル層を飽和重そう水100mlで３回抽出し、次に
この水層を塩酸でpH≒1.5に調整し、酢酸エチル(100ml)
で３回抽出した。無水硫酸マグネシウムで乾燥、過後
溶媒を減圧下留去し、トルエンで再結晶すると、目的の
(R)−２−ハイドロキシ−４−フエニル酪酸の結晶4.0g
（収率85%）を得た。NMR (CDCl 3 ) δppm: 3.05 (2H, d, J = 3Hz), 3.57 (1H, t, J = 3H
z), 11.10 (1H, s) Example 3 (R) -2-hydroxy-4-phenylbutyric acid 78.1 ml of benzylmagnesium chloride (1M / l-tetrahydrofuran abbreviated as THF hereinafter) was cooled to -10 ° C under a nitrogen stream. To this, 1.49 g of cuprous iodide was added, and the mixture was stirred at the same temperature for 10 minutes. (R) -glycidic acid 2.29 g
Was dissolved in 20 ml of THF and added dropwise while cooling so as to keep -10 ° C. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The reaction mixture was slowly poured into 100 ml of a 30% aqueous potassium hydrogensulfate solution under ice cooling, and extracted twice with 100 ml of ethyl acetate. The ethyl acetate layer was extracted 3 times with 100 ml of saturated sodium bicarbonate water, then the aqueous layer was adjusted to pH≈1.5 with hydrochloric acid, and ethyl acetate (100 ml) was added.
It was extracted 3 times with. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from toluene.
Crystals of (R) -2-hydroxy-4-phenylbutyric acid 4.0 g
(Yield 85%) was obtained.
mp 115〜116℃ NMR(CDCl3)δppm:1.83〜2.35(2H,m),2.79(2H,t,J＝7H
z),4.23(1H,dd,J＝7,5Hz),7.00(2H,br.S),7.20(5H,S) 実施例４ (S)−２−ハイドロキシ−４−フエニル酪酸 (S)−グリシド酸とベンジルマグネシウムクロリドを用
い、実施例３と同様に操作すると(S)−２−ハイドロキ
シ−４−フエニル酪酸が88%の収率が得られた。mp 115-116 ° C NMR (CDCl 3 ) δppm: 1.83 to 2.35 (2H, m), 2.79 (2H, t, J = 7H
z), 4.23 (1H, dd, J = 7,5Hz), 7.00 (2H, br.S), 7.20 (5H, S) Example 4 (S) -2-hydroxy-4-phenylbutyric acid (S)- When glycidic acid and benzylmagnesium chloride were used and operated in the same manner as in Example 3, a yield of (S) -2-hydroxy-4-phenylbutyric acid of 88% was obtained.
実施例５ (RS)−２−ハイドロキシ−４−フエニル酪酸 (RS)−グリシド酸とベンジルマグネシウムクロリドを用
い、実施例３と同様に操作して(RS)−２−ハイドロキシ
−４−フエニル酪酸が90%の収率で得られた。 Example 5 (RS) -2-Hydroxy-4-phenylbutyric acid Using (RS) -glycidic acid and benzylmagnesium chloride, the procedure of Example 3 was repeated to obtain (RS) -2-hydroxy-4-phenylbutyric acid. Obtained in 90% yield.
実施例６ (R)-β-フエニル乳酸 ヨウ化第一銅600mgを−10℃でフエニルマグネシウムブ
ロミド(2M/-THF)溶液17mlに加え、窒素雰囲気下30分
撹拌した。これに(R)−グリシド酸１ｇのTHF10mlの溶液
を内温−10〜−5℃保ちながら滴加し、同温度で１時間
撹拌後、室温でさらに１時間撹拌を続けた。反応液を氷
冷下３０％硫酸水素カリ水溶液50ml中へ注ぎ、次いで酢
酸エチル50mlで２回抽出し、抽出液を重そう水溶液50ml
で３回抽出し、水層を濃塩酸でpH１にした後、酢酸エチ
ル(50ml)で３回抽出した。硫酸マグネシウムで乾燥、
過後、溶媒を減圧下留去すると白色結晶の目的物1.71g
（収率90%）が得られた。Example 6 (R) -β-phenyllactic acid 600 mg of cuprous iodide was added to 17 ml of a phenylmagnesium bromide (2M / -THF) solution at −10 ° C., and the mixture was stirred under a nitrogen atmosphere for 30 minutes. A solution of 1 g of (R) -glycidic acid in 10 ml of THF was added dropwise while keeping the internal temperature at -10 to -5 ° C, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 1 hour. The reaction solution was poured into 50 ml of a 30% aqueous potassium hydrogen sulfate solution under ice cooling, and then extracted twice with 50 ml of ethyl acetate, and the extract solution was added with 50 ml of a sodium bicarbonate solution.
The mixture was extracted 3 times with, the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, and then extracted with ethyl acetate (50 ml) 3 times. Dried over magnesium sulfate,
After that, the solvent was distilled off under reduced pressure to give 1.71 g of the desired product as white crystals.
(Yield 90%) was obtained.
NMR(CDCl3+d6-DMSO)δppm:2.83〜3.17(2H,m),4.33(1H,d
d,J＝7.5Hz),7.23(5H,s),7.50(2H,br.S) 実施例７ (S)−β−フエニル乳酸 (S)−グリシド酸とフエニルマグネシウムブロミドを用
い、実施例６と同様に操作して(S)−β−フエニル乳酸
が91%の収率で得られた。 NMR (CDCl 3 + d 6 -DMSO) δppm: 2.83 to 3.17 (2H, m), 4.33 (1H, d
d, J = 7.5 Hz), 7.23 (5H, s), 7.50 (2H, br.S) Example 7 Using (S) -β-phenyl lactic acid (S) -glycidic acid and phenyl magnesium bromide, By the same procedure as in (6), (S) -β-phenyllactic acid was obtained with a yield of 91%.
実施例８ (R)−３−ｔ−ブチル乳酸 ｔ−ブチルマグネシユウムクロリド17.3ml（25%エーテ
ル溶液）を−10℃に冷却し、塩化第一銅300mgを加え、
窒素気流下同温度で30分撹拌した後、(R)−グリシド酸
１ｇのTHF10ml溶液を内温−10〜−５℃に保ちながら滴
加し、次いで室温で１時間30分撹拌をつづけた。実施例
３と同様に後処理を行い目的物1.49g（収率88%）が白色
結晶として得られた。 Example 8 (R) -3-t-butyl lactate 17.3 ml of t-butylmagnesium chloride (25% ether solution) was cooled to -10 ° C, and 300 mg of cuprous chloride was added,
After stirring for 30 minutes at the same temperature under a nitrogen stream, a solution of 1 g of (R) -glycidic acid in 10 ml of THF was added dropwise while keeping the internal temperature at -10 to -5 ° C, and then stirring was continued at room temperature for 1 hour and 30 minutes. Post-treatment was carried out in the same manner as in Example 3 to obtain 1.49 g of the desired product (yield 88%) as white crystals.
NMR(CDCl3+d6-DMSO)δppm;1.03(9H,s),1.30〜1.69(2H,
m),4.10(1H,dd,J＝7,5Hz),8.30(1H,br.S) 実施例９ (S)−３−ｔ−ブチル乳酸 (S)−グリシド酸とｔ−ブチルマグネシウムクロリドを
用い実施例８と同様に操作して(S)−３−ｔ−ブチル乳
酸が85%の収率で得られた。 NMR (CDCl 3 + d 6 -DMSO) δppm; 1.03 (9H, s), 1.30 to 1.69 (2H,
m), 4.10 (1H, dd, J = 7,5Hz), 8.30 (1H, br.S) Example 9 (S) -3-t-Butyllactic acid (S) -glycidic acid and t-butylmagnesium chloride Using the same procedure as in Example 8, (S) -3-t-butyllactic acid was obtained in a yield of 85%.
実施例10 (R)−４−（４−フルオロフエニル）−２−ハイドロキ
シ酪酸 ４−フルオロベンジルブロミド6.63gとマグネシユウム
1.14gとより調整した４−フルオロベンジルマグネシウ
ムブロミドのTHF溶液を−10℃に冷却し、これにヨウ化
第一銅600mgを加えて同温度で30分間撹拌した。(R)−グ
リシド酸1.03gのTHF10ml、溶液液を−10〜−５℃に保ち
ながら滴加し、次いで室温に戻して１時間撹拌後実施例
８と同様に後処理を行い目的物2.14g（収率92%）を得
た。 Example 10 (R) -4- (4-Fluorophenyl) -2-hydroxybutyric acid 4-fluorobenzyl bromide 6.63 g and magnesium
A THF solution of 4-fluorobenzylmagnesium bromide adjusted to 1.14 g was cooled to -10 ° C, 600 mg of cuprous iodide was added thereto, and the mixture was stirred at the same temperature for 30 minutes. (R) -glycidic acid (1.03 g) in THF (10 ml) was added dropwise while the solution was kept at -10 to -5 ° C., then the mixture was returned to room temperature and stirred for 1 hour, after which post-treatment was carried out in the same manner as in Example 2. (Yield 92%) was obtained.
NMR(CD3CDCD3)δppm;1.66〜2.50(2H,m),2.80(2H,t,J＝7
Hz),4.19(1H,dd,J＝7,5Hz),6.80〜7.46(4H,m),7.70(2H,
br.S) 実施例11 (R)−４−（３−トリル）−２−ハイドロキシ酪酸 ３−メチルベンジルマグネシウムクロリドと(R)−グリ
シド酸を塩化第一銅の共存下実施例３と同様に操作して
目的物が87%の収率で得られた。NMR (CD 3 CDCD 3 ) δppm; 1.66 to 2.50 (2H, m), 2.80 (2H, t, J = 7
Hz), 4.19 (1H, dd, J = 7.5Hz), 6.80 ~ 7.46 (4H, m), 7.70 (2H,
br.S) Example 11 (R) -4- (3-tolyl) -2-hydroxybutyric acid 3-methylbenzylmagnesium chloride and (R) -glycidic acid were coexisted with cuprous chloride in the same manner as in Example 3. The target product was obtained by the operation in a yield of 87%.
NMR(d6-DMSO+CDCl3)δppm;1.81〜2.40(2H,m),2.30(3H,
S),2.65〜3.05(2H,m),4.20(1H,dd,J＝7.5Hz)6.85〜7.35
(4H,m),8.90(2H,br.S) 実施例12 (S)−４−（３−トリル）−２−ハイドロキシ酪酸 (S)−グリシド酸と３−メチルベンジルマグネシウムク
ロリドを用い、実施例11と同様に操作して(S)−４−
（３−トリル）−２−ハイドロキシ酪酸が85%の収率で
得られた。NMR (d 6 -DMSO + CDCl 3 ) δppm; 1.81 to 2.40 (2H, m), 2.30 (3H,
S), 2.65-3.05 (2H, m), 4.20 (1H, dd, J = 7.5Hz) 6.85-7.35
(4H, m), 8.90 (2H, br.S) Example 12 Using (S) -4- (3-tolyl) -2-hydroxybutyric acid (S) -glycidic acid and 3-methylbenzylmagnesium chloride Operate as in Example 11 (S) -4-
(3-Tolyl) -2-hydroxybutyric acid was obtained with a yield of 85%.
実施例１３ (R)−４−（２−トリフルオロメチルフエニル）−２−
ハイドロキシ酪酸 ２−トリフルオロメチルベンジルマグネシウムブロミド
と(R)−グリシド酸を臭化第一銅の共存下実施例３と同
様に操作して目的物が93%の収率で得られた。Example 13 (R) -4- (2-trifluoromethylphenyl) -2-
Hydroxybutyric acid 2-trifluoromethylbenzylmagnesium bromide and (R) -glycidic acid were operated in the same manner as in Example 3 in the presence of cuprous bromide to obtain the desired product in a yield of 93%.
NMR(CDCl3+d6-DMSO)δppm;1.80〜2.50(2H,m),2.70〜3.2
1(2H,m),4.31(1H,dd,J＝7,5Hz),7.10〜7.82(4H,m),8.10
(2H,br.S). 実施例１４ (S)−４−（２−トリフルオロメチルフエニル）−２−
ハイドロキシ酪酸 (S)−グリシド酸と２−トリフルオロメチルベンジルマ
グネシウムブロミドを用い、実施例13と同様に操作して
(S)−４−（２−トリフルオロメチルフエニル）−２−
ハイドロキシ酪酸が86%収率で得られた。NMR (CDCl 3 + d 6 -DMSO) δppm; 1.80-2.50 (2H, m), 2.70-3.2
1 (2H, m), 4.31 (1H, dd, J = 7.5Hz), 7.10 ~ 7.82 (4H, m), 8.10
(2H, br.S). Example 14 (S) -4- (2-trifluoromethylphenyl) -2-
Hydroxybutyric acid (S) -glycidic acid and 2-trifluoromethylbenzylmagnesium bromide were used and operated in the same manner as in Example 13.
(S) -4- (2-trifluoromethylphenyl) -2-
Hydroxybutyric acid was obtained in 86% yield.
実施例15 (R)−４−（２−メトキシフエニル）−２−ハイドロキ
シ酪酸 ２−メトキシベンジルマグネシウムブロミドと(R)−グ
リシド酸とを臭化第一銅の共存下実施例６と同様に操作
して目的物が86%の収率で得られた。Example 15 (R) -4- (2-Methoxyphenyl) -2-hydroxybutyric acid 2-methoxybenzylmagnesium bromide and (R) -glycidic acid were coexisted with cuprous bromide in the same manner as in Example 6. By operation, the target product was obtained in a yield of 86%.
NMR(CDCl3+d6-DMSO)δppm;1.77〜2.40(2H,m),2.71〜3.0
4(2H,m),3.76(3H,s),4.25(1H,dd,J＝7,5Hz),6.51〜7.52
(4H,m),7.95(2H,br.S) 実施例16 (R)−４−（２−トリル）−２−ハイドロキシ酸酸 ２−メチルベンジルマグネシウムクロリドと(R)−グリ
シド酸を塩化第一銅の共存下実施例３と同様に操作して
目的物が90%の収率で得られた。NMR (CDCl 3 + d 6 -DMSO) δppm; 1.77 to 2.40 (2H, m), 2.71 to 3.0
4 (2H, m), 3.76 (3H, s), 4.25 (1H, dd, J = 7.5Hz), 6.51 ~ 7.52
(4H, m), 7.95 (2H, br.S) Example 16 (R) -4- (2-tolyl) -2-hydroxy acid acid 2-methylbenzylmagnesium chloride and (R) -glycidic acid The target product was obtained in a yield of 90% by the same procedure as in Example 3 in the presence of monocopper.
NMR(d6-DMSO)δppm;1.75〜2.38(2H,m),2.21(3H,s),2.65
〜3.01(2H,m),4.22(1H,dd,J＝7,5Hz),7.21(4H,s),7.91
(2H,br.s) 実施例17 (S)−４−（２−トリル）−２−ハイドロキシ酪酸 (S)−グリシド酸と２−メチルベンジルマグネシウムク
ロリドを用いて実施例16と同様に操作し、(S)−４−
（２−トリル）−２−ハイドロキシ酪酸が収率85%で得
られた。NMR (d 6 -DMSO) δppm; 1.75 to 2.38 (2H, m), 2.21 (3H, s), 2.65
~ 3.01 (2H, m), 4.22 (1H, dd, J = 7.5Hz), 7.21 (4H, s), 7.91
(2H, br.s) Example 17 (S) -4- (2-Tolyl) -2-hydroxybutyric acid (S) -Glycidic acid and 2-methylbenzylmagnesium chloride were used and operated in the same manner as in Example 16. , (S) -4-
(2-Tolyl) -2-hydroxybutyric acid was obtained with a yield of 85%.
実施例18 (R)−４−（２−クロロフエニル）−２−ハイドロキシ
酪酸 ２−クロロベンジルマグネシウムクロリドと(R)−グリ
シド酸酸を塩化第一銅の共存下実施例３と同様に操作し
て目的物が93%の収率で得られた。Example 18 (R) -4- (2-chlorophenyl) -2-hydroxybutyric acid 2-Chlorobenzylmagnesium chloride and (R) -glycidic acid were treated in the same manner as in Example 3 in the presence of cuprous chloride. The target product was obtained with a yield of 93%.
NMR(CDCl3+d6-DMSO)δppm;1.85〜2.51(2H,m),2.75〜3.1
6(2H,m),4.30(1H,dd,J＝7,5Hz),6.91〜7.52(4H,m),7.65
(2H,br.s) 実施例19 (S)−４−（２−クロロフエニル）−２−ハイドロキシ
酪酸 (S)−グリシド酸と２−クロロベンジルマグネシウムク
ロリドを用い実施例18と同様に操作して(S)−４−（２
−クロロフエニル）−２−ハイドロキシ酪酸が85%の収
率で得られた。NMR (CDCl 3 + d 6 -DMSO) δppm; 1.85 to 2.51 (2H, m), 2.75 to 3.1
6 (2H, m), 4.30 (1H, dd, J = 7.5Hz), 6.91-7.52 (4H, m), 7.65
(2H, br.s) Example 19 Using (S) -4- (2-chlorophenyl) -2-hydroxybutyric acid (S) -glycidic acid and 2-chlorobenzylmagnesium chloride, the procedure of Example 18 was repeated. (S) -4- (2
-Chlorophenyl) -2-hydroxybutyric acid was obtained in a yield of 85%.
実施例20 (R)−４−（３−メトキシフエニル）−２−ハイドロキ
シ酪酸 ３−メトキシベンジルマグネシウムブロミドと(R)−グ
リシド酸を臭化第一銅の共存下実施例３と同様に操作し
て目的物が86%の収率で得られた。Example 20 (R) -4- (3-Methoxyphenyl) -2-hydroxybutyric acid 3-methoxybenzylmagnesium bromide and (R) -glycidic acid were operated in the same manner as in Example 3 in the presence of cuprous bromide. Then, the target product was obtained in a yield of 86%.
NMR(CDCl3+d6-DMSO)δppm;1.82〜2.42(2H,m),2.70〜3.0
7(2H,m),3.74(3H,s),4.15(1H,dd,7,5Hz),6.62〜7.46(4
H,m),9.20(2H,br.r) 実施例21 (R)−４−（４−トキシフエニル）−２−ハイドロキシ
酪酸 ４−メトキシベンジルマグネシウムクロリドと(R)−グ
リシド酸をヨウ化第一銅の共存下実施例３と同様に操作
して目的物が88%の収率で得られた。NMR (CDCl 3 + d 6 -DMSO) δppm; 1.82 to 2.42 (2H, m), 2.70 to 3.0
7 (2H, m), 3.74 (3H, s), 4.15 (1H, dd, 7,5Hz), 6.62-7.46 (4
H, m), 9.20 (2H, br.r) Example 21 (R) -4- (4-Toxyphenyl) -2-hydroxybutyric acid 4-methoxybenzyl magnesium chloride and (R) -glycidic acid The target product was obtained in a yield of 88% by the same operation as in Example 3 in the presence of copper.
NMR(CDCl3+d6-DMSO)δppm;1.76〜2.38(2H,m),2.66〜3.0
2(2H,m),3.50(3H,s),4.11(1H,dd,J=7,5Hz),6.75(2H,d,J
＝8Hz),7.15(2H,d,J＝8Hz),9.20(2H,br.s) 実施例22 (R)−４−（４−ブロモフエニル）−２−ハイドロキシ
酪酸 ４−ブロモベンジルマグネシウムブロミドと(R)−グリ
シド酸を臭化第一銅の共存下実施例３と同様に操作して
目的物が87%の収率で得られた。NMR (CDCl 3 + d 6 -DMSO) δppm; 1.76 to 2.38 (2H, m), 2.66 to 3.0
2 (2H, m), 3.50 (3H, s), 4.11 (1H, dd, J = 7,5Hz), 6.75 (2H, d, J
= 8Hz), 7.15 (2H, d, J = 8Hz), 9.20 (2H, br.s) Example 22 (R) -4- (4-bromophenyl) -2-hydroxybutyric acid 4-bromobenzylmagnesium bromide and ( R) -glycidic acid was operated in the same manner as in Example 3 in the presence of cuprous bromide to obtain the target product in a yield of 87%.
NMR(CDCl3+d6-DMSO)δppm;1.65〜2.33(2H,m),2.55〜3.0
2(2H,m),4.17(1H,dd,J＝7,5Hz),7.03(2H,d,J＝8Hz),7.3
5(2H,d,J＝8Hz),8.96(1H,br.s) 実施例23 (R)−４−（４−ニトロフエニル）−２−ハイドロキシ
酪酸 ４−ニトロベンゼンマグネシウムクロリドと(R)−グリ
シド酸を臭化第一銅の共存下実施例３と同様に操作して
目的物が93%の収率が得られた。NMR (CDCl 3 + d 6 -DMSO) δppm; 1.65 to 2.33 (2H, m), 2.55 to 3.0
2 (2H, m), 4.17 (1H, dd, J = 7.5Hz), 7.03 (2H, d, J = 8Hz), 7.3
5 (2H, d, J = 8Hz), 8.96 (1H, br.s) Example 23 (R) -4- (4-nitrophenyl) -2-hydroxybutyric acid 4-nitrobenzene magnesium chloride and (R) -glycidic acid Was operated in the same manner as in Example 3 in the presence of cuprous bromide to obtain a target product in a yield of 93%.
NMR(d6-DMSO)δppm;1.85〜2.52(2H,m),2.71〜3.22(2H,
m),4.28(1H,dd,J＝7,5Hz),7.40(2H,d,J＝9Hz),8.11(2H,
d,J＝9Hz),9.70(2H,br.s) 実施例24 (R)−４−（２−ハイドロキシフエニル）−２−ハイド
ロキシ酪酸 ２−ｔ−ブチルジメチルシリルオキシベンジルマグネシ
ウムクロリドと(R)−グリシド酸を臭化第一銅の共存下
実施例３と同様の操作を行い目的物の２−ｔ−ブチルジ
メチルシリル体が90%の収率で得られた。これを弗化テ
トラブチルアンモニウム又は弗化カリと常法に従つて処
理する事により目的物が得られた。NMR (d 6 -DMSO) δppm; 1.85 to 2.52 (2H, m), 2.71 to 3.22 (2H,
m), 4.28 (1H, dd, J = 7,5Hz), 7.40 (2H, d, J = 9Hz), 8.11 (2H,
d, J = 9 Hz), 9.70 (2H, br.s) Example 24 (R) -4- (2-hydroxyphenyl) -2-hydroxybutyric acid 2-t-butyldimethylsilyloxybenzylmagnesium chloride and (R ) -Glycidic acid was carried out in the coexistence of cuprous bromide in the same manner as in Example 3 to obtain the target 2-t-butyldimethylsilyl compound in a yield of 90%. The desired product was obtained by treating this with tetrabutylammonium fluoride or potassium fluoride according to a conventional method.
NMR(d6-DMSO+CDCl3)δppm;1.55〜2.04(2H,m),2.72〜3.0
5(2H,m),4.22(1H,dd,J＝7,5Hz),6.45〜7.40(4H,m),9.66
(3H,br.s) 実施例25 (R)−β−フエニル乳酸 (R)−グリシド酸１ｇをTHF10ml溶かし−30℃に冷却し
た。これにフエニルリチウムの溶液12.6ml（２Ｍ／−
シクロヘキサン−ジエチルエーテル）を滴加し、−５〜
５℃で２時間撹拌後１Ｎ塩酸20mlを加え、次いで酢酸エ
チル50mlで抽出した。飽和重曹水30mlで抽出し、水層に
酢酸エチル50mlと濃塩酸50mlを加えて抽出を行い、有機
層を硫酸マグネシウムで乾燥後、過、濃縮すると目的
物が85%の収率で得られた。このものゝ物理データは実
施例６のそれらと一致した。NMR (d 6 -DMSO + CDCl 3 ) δppm; 1.55 to 2.04 (2H, m), 2.72 to 3.0
5 (2H, m), 4.22 (1H, dd, J = 7.5Hz), 6.45-7.40 (4H, m), 9.66
(3H, br.s) Example 25 1R of (R) -β-phenyllactic acid (R) -glycidic acid was dissolved in 10 ml of THF and cooled to -30 ° C. To this, 12.6 ml of a phenyllithium solution (2M /-
Cyclohexane-diethyl ether) was added dropwise, and -5
After stirring at 5 ° C for 2 hours, 20 ml of 1N hydrochloric acid was added, and then the mixture was extracted with 50 ml of ethyl acetate. The mixture was extracted with 30 ml of saturated aqueous sodium hydrogen carbonate, 50 ml of ethyl acetate and 50 ml of concentrated hydrochloric acid were added to the aqueous layer for extraction, the organic layer was dried over magnesium sulfate, and then concentrated to give the target product in a yield of 85%. . This physical data was in agreement with those of Example 6.
実施例26 Ｎ−（(R)−２−ハイドロキシバレリル〕−４−アニシ
ジン (R)グリシド（４−メトキシ）アニリド１ｇをTHF10mlに
溶かし、これをエチルマグネシウムブロミド10ml（３Ｍ
／−エーテル）、THF10mlおよびヨウ化第一銅0.6gの
混合液に−20℃〜−10℃で添加した。０℃で１時間撹拌
後、反応液を氷冷した30%硫酸水素カリウム水溶液30ml
に注ぎ、酢酸エチル50mlで３回抽出し、硫酸マグネシウ
ムで乾燥、過後、減圧下溶媒を留去して目的物0.92g
（収率80%）が白色粉末として得られた。Example 26 N-((R) -2-hydroxyvaleryl] -4-anisidine 1 g of (R) glycid (4-methoxy) anilide was dissolved in 10 ml of THF and 10 ml of ethyl magnesium bromide (3M
(/ -Ether), 10 ml of THF and 0.6 g of cuprous iodide were added at -20 ° C to -10 ° C. After stirring at 0 ° C for 1 hour, the reaction solution was ice-cooled and 30 ml of a 30% potassium hydrogen sulfate aqueous solution was added.
The product was extracted with 50 ml of ethyl acetate three times, dried over magnesium sulfate, and after drying, the solvent was distilled off under reduced pressure to obtain 0.92 g of the desired product.
(Yield 80%) was obtained as a white powder.
NMR(CDCl3)δppm;0.70〜2.30(7H,m),3.75(3H,s),3.90(1
H,br.s),4.00〜4.40(1H,m),6.78(2H,d,J＝9Hz),7.40(2
H,d,J＝9Hz),8.50(1H,br.s) 実施例27 Ｎ−〔(R)−２−ヒドロキシブチリル〕−４−アニシジ
ン (R)−グリシド（４−メトキシ）アニリド１ｇをTHF10ml
に溶かし、これをベンジルマグネシウムクロリド1.9g/T
HF20mlとヨウ化第一銅0.3gの混合液中に内温−20〜−10
℃に保ちながら滴加した。滴加後室温で２時間撹拌した
後、30%硫酸水素カリ水溶液30ml中に注加し、酢酸エチ
ル60mlで２回抽出後、硫酸マグネシウムで乾燥し、減圧
濃縮すると目的物1.19g（収率81%）が得られた。NMR (CDCl 3 ) δppm; 0.70 to 2.30 (7H, m), 3.75 (3H, s), 3.90 (1
H, br.s), 4.00 to 4.40 (1H, m), 6.78 (2H, d, J = 9Hz), 7.40 (2
H, d, J = 9 Hz), 8.50 (1H, br.s) Example 27 N-[(R) -2-hydroxybutyryl] -4-anisidine (R) -Glycid (4-methoxy) anilide 1 g THF 10 ml
Dissolved in benzyl magnesium chloride 1.9g / T
Inside temperature of -20 to -10 in a mixed solution of 20 ml of HF and 0.3 g of cuprous iodide.
The solution was added dropwise while keeping it at ℃. After dropwise addition, the mixture was stirred at room temperature for 2 hours, poured into 30 ml of 30% aqueous potassium hydrogen sulfate solution, extracted twice with 60 ml of ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.19 g of the desired product (yield 81 %)was gotten.
NMR(CDCl3+d6-DMSO)δppm;1.70〜2.30(2H,m),2.50〜3.0
0(2H,m),3.72(3H,s),4.30〜4.55(1H,m),5.20(1H,br.s),
6.82(2H,d,J＝9Hz),7.20(5H,s),7.56(2H,d,J＝9Hz),9.2
0(1H,br.s)NMR (CDCl 3 + d 6 -DMSO) δppm; 1.70-2.30 (2H, m), 2.50-3.0
0 (2H, m), 3.72 (3H, s), 4.30 ~ 4.55 (1H, m), 5.20 (1H, br.s),
6.82 (2H, d, J = 9Hz), 7.20 (5H, s), 7.56 (2H, d, J = 9Hz), 9.2
0 (1H, br.s)
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.5 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ｃ０７Ｃ 59/52 8827−4Ｈ 59/56 8827−4Ｈ 59/64 8827−4Ｈ 205/56 6917−4Ｈ 235/06 7106−4Ｈ // Ｃ０７Ｂ 53/00 Ｃ 7419−4Ｈ Ｃ０７Ｄ 303/48 ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 5 Identification code Internal reference number FI Technical display area C07C 59/52 8827-4H 59/56 8827-4H 59/64 8827-4H 205/56 6917-4H 235/06 7106-4H // C07B 53/00 C 7419-4H C07D 303/48
Claims (2)
NR6R7基（R6およびR7は、同一または異なつて水素原
子、置換基を有してもよいフェニル基を示す。）を示
す。〕を有する化合物に 式ＲＭ 〔式中、Ｒは、アルキル基、フェニル基、置換基を有し
てもよいベンジル基を示し、Ｍは、ＭｇＸ（Ｍｇはマグ
ネシウムを示し、Ｘは、塩素、臭素、または沃素を示
す。）またはアルカリ金属を示す。〕を有する化合物を
反応させることを特徴とする 式 〔式中、R1，R2及びR3は前述したものと同意義を示
す。〕を有するα−ハイドロキシカルボン酸誘導体の製
法。1. A formula [In the formula, R 1 and R 2 represent a hydrogen atom, R 3 represents a hydroxyl group,
NR 6 R 7 group (R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group which may have a substituent). [Wherein R represents an alkyl group, a phenyl group, or a benzyl group which may have a substituent, M represents MgX (Mg represents magnesium, X represents chlorine or bromine)] , Or iodine)) or an alkali metal. ] The compound having the formula [In the formula, R 1 , R 2 and R 3 have the same meanings as described above. ] The manufacturing method of the (alpha)-hydroxy carboxylic acid derivative which has.
NR6R7基（R6およびR7は、同一または異なって水素原
子、置換基を有してもよいフェニル基を示す。）を示
し、Ｙは、ハロゲン原子を示す。〕を有する化合物を塩
基で処理して 式 〔式中、R1，R2及びR3は前述したものと同意義を示
す。〕を有する化合物に導き、ついでこの化合物に 式ＲＭ 〔式中、Ｒは、アルキル基、フェニル基、置換基を有し
てもよいベンジル基を示し、Ｍは、ＭｇＸ（Ｍｇはマグ
ネシウムを示し、Ｘは、塩素、臭素、または沃素を示
す。）またはアルカリ金属を示す。〕を有する化合物を
反応させることを特徴とする 式 〔式中、R1，R2及びR3は前述したものと同意義を示
す。〕を有する化合物の製法。2. A formula [In the formula, R 1 and R 2 represent a hydrogen atom, R 3 represents a hydroxyl group,
NR 6 R 7 group (R 6 and R 7 are the same or different and each represents a hydrogen atom or a phenyl group which may have a substituent), and Y represents a halogen atom. A compound having the formula [In the formula, R 1 , R 2 and R 3 have the same meanings as described above. ] To a compound having the formula RM [wherein R represents an alkyl group, a phenyl group, or a benzyl group which may have a substituent, M represents MgX (Mg represents magnesium, X represents chlorine, bromine, or iodine) or an alkali metal. ] The compound having the formula [In the formula, R 1 , R 2 and R 3 have the same meanings as described above. ] The manufacturing method of the compound which has.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61056471A JPH066539B2 (en) | 1986-03-14 | 1986-03-14 | Process for producing α-hydroxycarboxylic acid derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61056471A JPH066539B2 (en) | 1986-03-14 | 1986-03-14 | Process for producing α-hydroxycarboxylic acid derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62212329A JPS62212329A (en) | 1987-09-18 |
| JPH066539B2 true JPH066539B2 (en) | 1994-01-26 |
Family
ID=13028017
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61056471A Expired - Lifetime JPH066539B2 (en) | 1986-03-14 | 1986-03-14 | Process for producing α-hydroxycarboxylic acid derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH066539B2 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5256552A (en) * | 1988-02-08 | 1993-10-26 | Daicel Chemical Industries, Ltd. | Process for the production of optically active 2-hydroxy-4-phenylbutyric acid |
| US4904822A (en) * | 1988-02-19 | 1990-02-27 | Kuraray Co., Ltd. | Process for the optical resolution of (+)-2-hydroxy-4-phenylbutanoic acid |
| JP2688528B2 (en) * | 1989-12-28 | 1997-12-10 | ダイセル化学工業株式会社 | Process for producing optically active 2-hydroxy-4-phenylbutyric acid alkyl ester |
| FI93833C (en) * | 1992-05-14 | 1995-06-12 | Orion Yhtymae Oy | Process for the preparation of propionic acid derivatives |
| CN1157391C (en) * | 1999-08-24 | 2004-07-14 | 阿古龙制药有限公司 | Method and intermediate for preparing is-a-oxazole formylamine and its analogue |
| US6774243B2 (en) | 1999-08-24 | 2004-08-10 | Agouron Pharmaceuticals, Inc. | Efficient synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates |
| US6355807B1 (en) | 1999-08-24 | 2002-03-12 | Agouron Pharmaceuticals, Inc. | Efficient synthetic routes for the preparation of rhinovirus protease inhibitors and key intermediates |
| EP1908747B1 (en) * | 2005-07-28 | 2012-01-04 | Kowa Company, Ltd. | Process for producing optically active 2-hydroxybutyric ester |
| CN102675088A (en) * | 2012-05-28 | 2012-09-19 | 温州市工业科学研究院 | Preparation method of alpha-hydroxy-cyclohexanecarboxylic acid |
| JP2018138519A (en) * | 2015-07-17 | 2018-09-06 | 株式会社カネカ | Method for producing 2-hydroxyester |
| CN105669423B (en) * | 2016-01-08 | 2018-06-29 | 江西科技师范大学 | The novel synthesis of two kinds of enantiomters of 4- (4- (benzyloxy) phenyl) -2- hydroxybutyric acids |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6156471A (en) * | 1984-07-28 | 1986-03-22 | Fujitsu Ltd | Semiconductor device |
-
1986
- 1986-03-14 JP JP61056471A patent/JPH066539B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62212329A (en) | 1987-09-18 |
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