JPH03200739A - Optically active 2-hydroxy-4-phenyl butyric acid and production of ester of same butyric acid - Google Patents
Optically active 2-hydroxy-4-phenyl butyric acid and production of ester of same butyric acidInfo
- Publication number
- JPH03200739A JPH03200739A JP34238289A JP34238289A JPH03200739A JP H03200739 A JPH03200739 A JP H03200739A JP 34238289 A JP34238289 A JP 34238289A JP 34238289 A JP34238289 A JP 34238289A JP H03200739 A JPH03200739 A JP H03200739A
- Authority
- JP
- Japan
- Prior art keywords
- hydroxy
- optically active
- phenyl
- acid
- butyric 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.)
- Granted
Links
- JNJCEALGCZSIGB-UHFFFAOYSA-N 2-hydroxy-4-phenylbutanoic acid Chemical compound OC(=O)C(O)CCC1=CC=CC=C1 JNJCEALGCZSIGB-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title 2
- 150000002148 esters Chemical class 0.000 title 1
- 239000002904 solvent Substances 0.000 claims abstract description 14
- ZGGWKQRHPWUSNY-UHFFFAOYSA-N 2-hydroxy-4-phenylbut-3-enoic acid Chemical compound OC(=O)C(O)C=CC1=CC=CC=C1 ZGGWKQRHPWUSNY-UHFFFAOYSA-N 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 15
- 238000000034 method Methods 0.000 abstract description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 6
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 4
- 239000012046 mixed solvent Substances 0.000 abstract description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 2
- 239000002253 acid Substances 0.000 abstract 1
- 230000003287 optical effect Effects 0.000 description 12
- 125000005907 alkyl ester group Chemical group 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 238000005886 esterification reaction Methods 0.000 description 5
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- ZGGWKQRHPWUSNY-XCODYQFDSA-N (e,2r)-2-hydroxy-4-phenylbut-3-enoic acid Chemical compound OC(=O)[C@H](O)\C=C\C1=CC=CC=C1 ZGGWKQRHPWUSNY-XCODYQFDSA-N 0.000 description 3
- ZSQWQTABLXAFEZ-UHFFFAOYSA-N 2-phenylbut-3-enoic acid Chemical compound OC(=O)C(C=C)C1=CC=CC=C1 ZSQWQTABLXAFEZ-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229950009215 phenylbutanoic acid Drugs 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- JNJCEALGCZSIGB-SECBINFHSA-N (2r)-2-hydroxy-4-phenylbutanoic acid Chemical compound OC(=O)[C@H](O)CCC1=CC=CC=C1 JNJCEALGCZSIGB-SECBINFHSA-N 0.000 description 1
- ZGGWKQRHPWUSNY-VIFPVBQESA-N (2s)-2-hydroxy-4-phenylbut-3-enoic acid Chemical compound OC(=O)[C@@H](O)C=CC1=CC=CC=C1 ZGGWKQRHPWUSNY-VIFPVBQESA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PPKAIMDMNWBOKN-UHFFFAOYSA-N 2-Oxo-4-phenylbutyric acid Chemical compound OC(=O)C(=O)CCC1=CC=CC=C1 PPKAIMDMNWBOKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- GUDBSTJKAWCJQP-UHFFFAOYSA-N [Mg]CC1=CC=CC=C1 Chemical compound [Mg]CC1=CC=CC=C1 GUDBSTJKAWCJQP-UHFFFAOYSA-N 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZJYKSSGYDPNKQS-LLVKDONJSA-N ethyl (2r)-2-hydroxy-4-phenylbutanoate Chemical compound CCOC(=O)[C@H](O)CCC1=CC=CC=C1 ZJYKSSGYDPNKQS-LLVKDONJSA-N 0.000 description 1
- OTGHWLKHGCENJV-UHFFFAOYSA-N glycidic acid Chemical compound OC(=O)C1CO1 OTGHWLKHGCENJV-UHFFFAOYSA-N 0.000 description 1
- 238000009904 heterogeneous catalytic hydrogenation reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- LJFCDOMDEACIMM-UHFFFAOYSA-N zinc chromium(3+) oxygen(2-) Chemical compound [O-2].[Cr+3].[Zn+2] LJFCDOMDEACIMM-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は光学活性２−ヒドロキシ−４−フェニル酪酸及
びそのアルキルエステルの製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for producing optically active 2-hydroxy-4-phenylbutyric acid and its alkyl ester.
光学活性２−ヒドロキシ−４−フェニル酪酸及びそのア
ルキルエステルは種々の医薬品合成原料として有用であ
る。Optically active 2-hydroxy-4-phenylbutyric acid and its alkyl esters are useful as raw materials for the synthesis of various pharmaceuticals.
〔従来の技術及び発明が解決しようとする課題〕光学活
性な２−ヒドロキシ−４−フェニル酪酸及びそれらのア
ルキルエステルの製造方法としては、化学的不斉還元に
よる方法（ＥＰ ２０６９９３号）、ベンジルマグネシ
ウムクロリドと光学活性グリシド酸から化学合成する方
法（特開昭６２−２１２３２９号）、ラセミ体を光学分
割剤により分割する方法（口、Ｂｉｑｕａｒｄ、 Ａｎ
ｎ、ｄｅ、Ｃｈｉ＋ｎｉｅ、、 ｖｏｌ。[Prior art and problems to be solved by the invention] Methods for producing optically active 2-hydroxy-4-phenylbutyric acid and their alkyl esters include a method using chemical asymmetric reduction (EP 206993), a method using benzylmagnesium A method of chemical synthesis from chloride and optically active glycidic acid (Japanese Patent Application Laid-Open No. 62-212329), a method of resolving a racemate using an optical resolving agent (Kuchi, Biquard, An.
n, de, Chi+nie,, vol.
２０、１４６（１９３３））、微生物の持つ不斉還元能
を利用し、２−ケト−４−フェニル酪酸から製造する方
法（ＷＯ８９１０７１４７号、 ＮＯ８９１０７６４
８号）等が知られている。20, 146 (1933)), a method for producing from 2-keto-4-phenylbutyric acid using the asymmetric reduction ability of microorganisms (WO89107147, NO8910764)
No. 8) etc. are known.
しかしながら、化学的不斉還元による方法は目的物の光
学純度が十分には高いとは言えず、また化学合成による
方法は原料の光学活性なアミノ酸が高価であること、ラ
セミ体を光学分割剤で分割する方法は分割剤が高価であ
ること、微生物の不斉還元能を利用する方法は一般的に
高濃度での反応が困難であること等、種々の問題点が有
り、より優れた工業的製造方法の開発が望まれていた。However, the optical purity of the target product cannot be said to be sufficiently high in the chemical asymmetric reduction method, and the optically active amino acids used as raw materials are expensive, and the racemic form cannot be separated using an optical resolving agent. The splitting method has various problems, such as the splitting agent being expensive, and the method using the asymmetric reduction ability of microorganisms generally having difficulty in reacting at high concentrations. There was a desire to develop a manufacturing method.
このような状況に鑑み本発明者らは、さらに優れた光学
活性２−ヒドロキシ−４−フェニル酪酸及びそれらのア
ルキルエステルの製造方法を得るべく鋭意研究した結果
、光学活性な２−ヒドロキシ−４−フェニル−３−ブテ
ン酸を溶媒の存在下、水素添加し夫々対応する光学活性
な２〜ヒドロキシ−４−フェニル酪酸を製造しうること
、及びこのようにして製造した光学活性２−ヒドロキシ
−４−フェニル酪酸をエステル化することにより光学活
性な２−ヒドロキシ４−フェニル酪酸アルキルエステル
を製造しうることを見出だし本発明を完成した。In view of this situation, the present inventors conducted intensive research to obtain even more superior methods for producing optically active 2-hydroxy-4-phenylbutyric acid and their alkyl esters. It is possible to produce the corresponding optically active 2-hydroxy-4-phenylbutyric acid by hydrogenating phenyl-3-butenoic acid in the presence of a solvent, and the optically active 2-hydroxy-4-phenylbutyric acid produced in this way. The present invention was completed by discovering that optically active 2-hydroxy 4-phenylbutyric acid alkyl ester can be produced by esterifying phenylbutyric acid.
本発明で使用する光学活性な２−ヒドロキシ４−フェニ
ル−３−ブテン酸とは（Ｒ） −２ヒドロキシ−４−フ
ェニル−３−ブテン酸或いは（Ｓ） −２−ヒドロキシ
−４−フェニル−３−ブテン酸を意味し、これらの両エ
ナンチオマーの等量混合物であるクセ１体以外であれば
両者の組成比がいかなるものでも良いが、−船釣には限
りなく一方のエナンチオマーの比率が高いほうが有用で
ある。これらの光学活性な２−ヒドロキシ−４−フェニ
ル−３−ブテン酸はいかなる製造法によって作られたも
のでもかまわないが、本発明者らによる微生物の不斉還
元能を利用した方法（特開昭６３−１０５８９３号、特
開昭６３−１７３４６９号、特開昭６３−２５３０２０
号）により製造された光学活性な２−ヒドロキシ−４−
フェニル−３−ブテン酸は光学純度も高く本発明に用い
る原料として好適である。What is the optically active 2-hydroxy-4-phenyl-3-butenoic acid used in the present invention? (R)-2hydroxy-4-phenyl-3-butenoic acid or (S)-2-hydroxy-4-phenyl-3 - This refers to butenoic acid, and the composition ratio of both enantiomers can be any ratio as long as it is not a single substance that is a mixture of equal amounts of both enantiomers. - For boat fishing, it is infinitely better to have a higher ratio of one enantiomer. Useful. These optically active 2-hydroxy-4-phenyl-3-butenoic acids may be produced by any production method, but the present inventors have proposed a method using the asymmetric reduction ability of microorganisms (Japanese Patent Application Laid-Open No. 63-105893, JP 63-173469, JP 63-253020
Optically active 2-hydroxy-4- produced by
Phenyl-3-butenoic acid has high optical purity and is suitable as a raw material for use in the present invention.
本発明において、 （Ｒ）−２−ヒドロキシ−４フェニ
ル−３−ブテン酸、或いハ（Ｓ）−：２ヒドロキシ−４
−フェニル−３−ブテン酸の水素添加反応は、適当な溶
媒中で、適当な触媒存在下、温度は例えば０〜３００″
Ｃの範囲内、好ましくは１０〜７０″Ｃの範囲内で、圧
力は例えば常圧から２００ ｋｇ／ ｃｉの範囲内、好
ましくは常圧で通常の不均一系接触水素添加反応の定法
に準じて行えば良く、特に制限は無い。In the present invention, (R)-2-hydroxy-4phenyl-3-butenoic acid, or (S)-:2hydroxy-4
-The hydrogenation reaction of phenyl-3-butenoic acid is carried out in an appropriate solvent in the presence of an appropriate catalyst at a temperature of, for example, 0 to 300''.
within the range of C, preferably within the range of 10 to 70''C, and the pressure is, for example, within the range of normal pressure to 200 kg/ci, preferably normal pressure, according to the standard method for a normal heterogeneous catalytic hydrogenation reaction. You can do it; there are no particular restrictions.
ここで用いられる溶媒としてはエタノール、メタノール
、酢酸、ジオキサン、シクロヘキサン、水、テトラヒド
ロフラン、酢酸エチル、ジメチルホルムアミド、トルエ
ン等を例示することができる。これらの溶媒は単独で使
用しても良いし、混合して使用しても良いが、通常、光
学活性２−ヒドロキシ−４−フェニル−３−ブテン酸の
２〜１０重景倍使用される。また、この際、最終的に目
的とするアルキルエステルに対応したアルコールを含む
有機溶媒中で反応を行うことにより、生成物を単離する
ことなく次のエステル化工程に進むことができ収率の向
上が可能である。例えば、この例としては、トルエンと
エタノールの混合溶媒系が挙げられる。Examples of the solvent used here include ethanol, methanol, acetic acid, dioxane, cyclohexane, water, tetrahydrofuran, ethyl acetate, dimethylformamide, and toluene. These solvents may be used alone or in combination, but are usually used in an amount of 2 to 10 times the optically active 2-hydroxy-4-phenyl-3-butenoic acid. In addition, at this time, by conducting the reaction in an organic solvent containing an alcohol corresponding to the final target alkyl ester, it is possible to proceed to the next esterification step without isolating the product, which reduces the yield. Improvement is possible. For example, this may include a mixed solvent system of toluene and ethanol.
水素添加反応の触媒としてはコロイド白金、白金ブラン
ク、コロイドパラジウム、パラジウム−カーボン、還元
ニッケル、白金付きラネーニッケル、還元コバルト、還
元銅、亜鉛−クロム酸化物等が例示できる。この際の触
媒の添加量としては原料に対し０．１〜ｌＯ重量％の範
囲、より好ましくは１〜２重量％程度を使用する。Examples of catalysts for the hydrogenation reaction include colloidal platinum, platinum blank, colloidal palladium, palladium-carbon, reduced nickel, platinized Raney nickel, reduced cobalt, reduced copper, and zinc-chromium oxide. The amount of catalyst added at this time is in the range of 0.1 to 10% by weight, more preferably about 1 to 2% by weight based on the raw material.
水素の添加反応が終了したら反応終了液から濾過により
触媒を除き、濾液を得る。この濾液からは脱溶剤操作等
により生成した光学活性２−ヒドロキシ−４−フェニル
酪酸を単離することもできるが、そのまま次のエステル
化工程に移ることも可能である。When the hydrogen addition reaction is completed, the catalyst is removed from the reaction-completed liquid by filtration to obtain a filtrate. The optically active 2-hydroxy-4-phenylbutyric acid produced can be isolated from this filtrate by a solvent removal operation or the like, but it is also possible to proceed to the next esterification step as it is.
即ち、その濾液に必要に応じてアルコールを追加し、エ
ステル化のための触媒、例えば、硫酸、パラトルエンス
ルホン酸を基質に対し重量比で１〜１０％程度添加し常
法により、加熱、脱水することにより目的のアルキルエ
ステルが得られる。That is, alcohol is added to the filtrate as necessary, and a catalyst for esterification, such as sulfuric acid or para-toluenesulfonic acid, is added at a weight ratio of 1 to 10% based on the substrate, and the mixture is heated and dehydrated by a conventional method. By doing so, the desired alkyl ester can be obtained.
ここで使用されるアルコールとしては、エタノール、メ
タノール、ブタノール、プロパツール等が挙げられる。Examples of the alcohol used here include ethanol, methanol, butanol, propatool, and the like.
エステル化に際しては、通常、大過剰のアルコールが用
いられるが使用するアルコールが水と共沸しない場合に
はベンゼン、トルエンなどの水と共沸する溶媒との混合
系にまり共沸脱水させる事が好しい。During esterification, a large excess of alcohol is usually used, but if the alcohol used does not azeotrope with water, it can be mixed with a solvent such as benzene or toluene that is azeotropic with water, and azeotropic dehydration can be performed. I like it.
このようにしてエステル化反応が終了したら、続いて、
脱溶剤操作を行う。次いで、定法により減圧蒸留を行い
、目的物のアルキルエステルを得る。After the esterification reaction is completed in this way,
Perform solvent removal operation. Next, vacuum distillation is performed using a conventional method to obtain the target alkyl ester.
以下本発明を具体的に実施例にて説明するが、本分明は
これらの内容に限定されるものではない。The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these examples.
尚、光学活性２−ヒドロキシ−４−フェニル酪酸のアル
キルエステルの光学純度は、光学異性体分離カラムを用
いた高速液体クロマトグラフィー（カラム：ダイセル化
学工業製キラルセルＯＢ、 溶媒： ｎ−ヘキサン／
２−プロパツール＝１９：１）により求めた。The optical purity of the alkyl ester of optically active 2-hydroxy-4-phenylbutyric acid was determined by high performance liquid chromatography using an optical isomer separation column (column: Chiralcel OB manufactured by Daicel Chemical Industries, Ltd., solvent: n-hexane/
2-propatool=19:1).
実施例１
（Ｒ） −２−ヒドロキシ−４−フェニル−３−プテン
酸（光学純度９９．８％ｅ、ｅ）の酢酸エチル溶液３３
．５ｇ （純分２０．１６ ｇ 、０．１１５ａｏｌ）
をエタノール１１．６ ｇ、トルエン７３．８ｇの混合
溶媒へ加えた。Example 1 Ethyl acetate solution of (R)-2-hydroxy-4-phenyl-3-butenoic acid (optical purity 99.8% e,e) 33
．． 5g (Pure 20.16g, 0.115aol)
was added to a mixed solvent of 11.6 g of ethanol and 73.8 g of toluene.
そこへ５０湿％パラジウムーカーボン０．６ｇを入れ、
水素法により水素を供給し、常圧下、室温で接触水素添
加反応を行った。高速液体クロマトグラフィーにより反
応経過を追跡したところ２３時間で反応は完了した。次
にパラジウム−カーボンを濾過で除き、濾液１２２．５
ｇを得た。この濾液中には（Ｒ）−２−ヒドロキシ−
４−フェニル酪酸が１９．８ｇ （収率９８．２％、光
学純度９９．７％ｅ、ｅ）含まれていた。この濾液１１
９ ｇ （（Ｒ） −２−ヒドロキシ−４−フェニル酪
酸１９．２ｇヲ含ム）に濃硫酸０．２ｇを入れ共沸脱水
を行った。５時間後エタノール５０ｇを追加し、反応を
完結させた。この反応液から脱溶剤を行った後、減圧蒸
留し目的物の（Ｒ） −２−ヒドロキシ−４−フェニル
酪酸エチルエステルヲ２０．３ ｇ （収率９１．４％
。Add 0.6g of 50% humidity palladium-carbon to it,
Hydrogen was supplied by a hydrogen method, and a catalytic hydrogenation reaction was carried out at room temperature under normal pressure. The reaction progress was followed by high performance liquid chromatography, and the reaction was completed in 23 hours. Next, palladium-carbon was removed by filtration, and the filtrate 122.5
I got g. This filtrate contains (R)-2-hydroxy-
It contained 19.8 g of 4-phenylbutyric acid (yield 98.2%, optical purity 99.7% e, e). This filtrate 11
0.2 g of concentrated sulfuric acid was added to 9 g (containing 19.2 g of (R)-2-hydroxy-4-phenylbutyric acid) to perform azeotropic dehydration. After 5 hours, 50 g of ethanol was added to complete the reaction. After removing the solvent from this reaction solution, it was distilled under reduced pressure to obtain 20.3 g of (R)-2-hydroxy-4-phenylbutyric acid ethyl ester (yield 91.4%).
.
光学純度９９．７％ｅ、ｅ、 ）得た。An optical purity of 99.7% e, e, ) was obtained.
実施例２
（Ｓ） −２−ヒドロキシ−４−フェニル−３−ブテン
酸（光学純度９９．０％ｅ、ｅ） １０ ｇ （０，０
５７ａｏｌ）をメタノール５．８ ｇ、 ）ルエン３
６．９ ｇの混合溶媒へ加えた。そこへ５０湿％パラジ
ウムーカーボン０．３ｇを入れ、水素を供給し、常圧下
１．室温で接触水素添加反応を行った。高速液体クロマ
トグラフィーにより反応経過を追跡したところ１５時間
で反応は完了した。次にパラジウム−カーボンを濾過で
除き、濾液６２．５ ｇを得た。この濾液中には（Ｓ）
−２−ヒドロキシ−４−フェニル酪酸が９．８ｇ（収
率９６．９％、光学純度９８．８％ｅ、ｅ、）含まれて
いた。この濾液６０ｇ （（Ｓ）−２−ヒドロキシ−４
−フェニル酪酸９．４ｇを含む）にパラトルエンスルホ
ン酸０．２ｇを入れ共沸脱水を行った。２時間後メタノ
ール２０ｇを追加し、反応を完結させた。この反応液か
ら脱溶剤を行った後、減圧蒸留し目的物の（Ｓ） −２
−ヒドロキシ−４−フェニル酪酸メチルエステルを９．
３ｇ（収率９１．７％、光学純度９８．５％ｅ、ｅ、）
得た。Example 2 (S) -2-hydroxy-4-phenyl-3-butenoic acid (optical purity 99.0% e,e) 10 g (0,0
57 aol) methanol 5.8 g, ) toluene 3
Added to 6.9 g of mixed solvent. 0.3 g of 50% palladium-carbon was put there, hydrogen was supplied, and 1.0 g was added under normal pressure. Catalytic hydrogenation reaction was carried out at room temperature. The progress of the reaction was followed by high performance liquid chromatography, and the reaction was completed in 15 hours. Next, palladium-carbon was removed by filtration to obtain 62.5 g of filtrate. This filtrate contains (S)
It contained 9.8 g of -2-hydroxy-4-phenylbutyric acid (yield 96.9%, optical purity 98.8%e, e,). 60 g of this filtrate ((S)-2-hydroxy-4
- 0.2 g of p-toluenesulfonic acid was added to 9.4 g of phenylbutyric acid, and azeotropic dehydration was performed. After 2 hours, 20 g of methanol was added to complete the reaction. After removing the solvent from this reaction solution, the target product (S)-2 is distilled under reduced pressure.
-Hydroxy-4-phenylbutyric acid methyl ester9.
3g (yield 91.7%, optical purity 98.5%e, e,)
Obtained.
本発明により光学活性２−ヒドロキシ−４−フェニル酪
酸及びそのアルキルエステルの工業的製造が可能になっ
た。The present invention has made it possible to industrially produce optically active 2-hydroxy-4-phenylbutyric acid and its alkyl esters.
Claims (1)
ニル−３−ブテン酸を水素添加することを特徴とする光
学活性２−ヒドロキシ−４−フェニル酪酸の製造方法。 ２、溶媒の存在下、光学活性２−ヒドロキシ−４−フェ
ニル−３−ブテン酸を水素添加したのち、エステル化す
ることを特徴とする光学活性２−ヒドロキシ−４−フェ
ニル酪酸アルキルエステルの製造法。[Claims] 1. A method for producing optically active 2-hydroxy-4-phenylbutyric acid, which comprises hydrogenating optically active 2-hydroxy-4-phenyl-3-butenoic acid in the presence of a solvent. 2. A method for producing optically active 2-hydroxy-4-phenylbutyric acid alkyl ester, which comprises hydrogenating optically active 2-hydroxy-4-phenyl-3-butenoic acid and then esterifying it in the presence of a solvent. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1342382A JP2688528B2 (en) | 1989-12-28 | 1989-12-28 | Process for producing optically active 2-hydroxy-4-phenylbutyric acid alkyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1342382A JP2688528B2 (en) | 1989-12-28 | 1989-12-28 | Process for producing optically active 2-hydroxy-4-phenylbutyric acid alkyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03200739A true JPH03200739A (en) | 1991-09-02 |
| JP2688528B2 JP2688528B2 (en) | 1997-12-10 |
Family
ID=18353295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1342382A Expired - Fee Related JP2688528B2 (en) | 1989-12-28 | 1989-12-28 | Process for producing optically active 2-hydroxy-4-phenylbutyric acid alkyl ester |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2688528B2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0759424A1 (en) * | 1995-08-22 | 1997-02-26 | Ajinomoto Co., Inc. | Process for producing optically active 2-hydroxy-4-arylbutyric acid or its ester, and intermediate therefor |
| KR100363824B1 (en) * | 1999-12-31 | 2002-12-11 | 한국화인케미칼주식회사 | A method for preparing ethyl (r)-2-bromo-4-phenylbutyrate and its intermediates |
| US7094920B2 (en) | 2001-05-21 | 2006-08-22 | Fermenta Biotech Limited | Stereoselective synthesis of 2-hydroxy-4-phenylbutyric acid esters |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62212329A (en) * | 1986-03-14 | 1987-09-18 | Sankyo Co Ltd | Production of alpha-hydroxycarboxylic acid derivative |
| JPS6479134A (en) * | 1987-09-21 | 1989-03-24 | Kanegafuchi Chemical Ind | Production of optically active (r)-2-hydroxy-4-phenyllactic acid |
| JPH01225499A (en) * | 1988-03-04 | 1989-09-08 | Toray Ind Inc | Production of optically active 2-hydroxy-4-phenylbutyric acid ester |
| JPH01281098A (en) * | 1988-05-02 | 1989-11-13 | Daicel Chem Ind Ltd | Production of optically active carboxylic acid and optically active carboxylic acid ester |
-
1989
- 1989-12-28 JP JP1342382A patent/JP2688528B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62212329A (en) * | 1986-03-14 | 1987-09-18 | Sankyo Co Ltd | Production of alpha-hydroxycarboxylic acid derivative |
| JPS6479134A (en) * | 1987-09-21 | 1989-03-24 | Kanegafuchi Chemical Ind | Production of optically active (r)-2-hydroxy-4-phenyllactic acid |
| JPH01225499A (en) * | 1988-03-04 | 1989-09-08 | Toray Ind Inc | Production of optically active 2-hydroxy-4-phenylbutyric acid ester |
| JPH01281098A (en) * | 1988-05-02 | 1989-11-13 | Daicel Chem Ind Ltd | Production of optically active carboxylic acid and optically active carboxylic acid ester |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0759424A1 (en) * | 1995-08-22 | 1997-02-26 | Ajinomoto Co., Inc. | Process for producing optically active 2-hydroxy-4-arylbutyric acid or its ester, and intermediate therefor |
| KR100363824B1 (en) * | 1999-12-31 | 2002-12-11 | 한국화인케미칼주식회사 | A method for preparing ethyl (r)-2-bromo-4-phenylbutyrate and its intermediates |
| US7094920B2 (en) | 2001-05-21 | 2006-08-22 | Fermenta Biotech Limited | Stereoselective synthesis of 2-hydroxy-4-phenylbutyric acid esters |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2688528B2 (en) | 1997-12-10 |
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