JPH03215451A - Racemization of optically active 2-hydroxy-4-phenylbutyric acid - Google Patents
Racemization of optically active 2-hydroxy-4-phenylbutyric acidInfo
- Publication number
- JPH03215451A JPH03215451A JP2010154A JP1015490A JPH03215451A JP H03215451 A JPH03215451 A JP H03215451A JP 2010154 A JP2010154 A JP 2010154A JP 1015490 A JP1015490 A JP 1015490A JP H03215451 A JPH03215451 A JP H03215451A
- Authority
- JP
- Japan
- Prior art keywords
- optically active
- hydroxy
- racemization
- phenylbutyric acid
- 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.)
- Pending
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 23
- 230000006340 racemization Effects 0.000 title abstract description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 15
- 239000002585 base Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- -1 alkaline earth metal salt Chemical class 0.000 abstract description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 3
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 150000001412 amines Chemical class 0.000 abstract description 2
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- HHHKFGXWKKUNCY-FHWLQOOXSA-N cilazapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N2[C@@H](CCCN2CCC1)C(O)=O)=O)CC1=CC=CC=C1 HHHKFGXWKKUNCY-FHWLQOOXSA-N 0.000 abstract description 2
- 229960005025 cilazapril Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 6
- 108010058865 angiotensinase Proteins 0.000 abstract 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 230000004048 modification Effects 0.000 abstract 1
- 238000012986 modification Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229960003424 phenylacetic acid Drugs 0.000 description 3
- 239000003279 phenylacetic acid Substances 0.000 description 3
- JNJCEALGCZSIGB-VIFPVBQESA-N (2s)-2-hydroxy-4-phenylbutanoic acid Chemical compound OC(=O)[C@@H](O)CCC1=CC=CC=C1 JNJCEALGCZSIGB-VIFPVBQESA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000004280 Sodium formate Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 235000019254 sodium formate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- 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
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- JZPRXQSCMBDGKP-UHFFFAOYSA-N 1-isocyanato-3,5-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC(N=C=O)=CC([N+]([O-])=O)=C1 JZPRXQSCMBDGKP-UHFFFAOYSA-N 0.000 description 1
- MDFWXZBEVCOVIO-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[2.2.1]heptan-3-amine Chemical compound C1CC2(C)C(N)CC1C2(C)C MDFWXZBEVCOVIO-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000003916 acid precipitation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 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
- 238000000605 extraction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- PJJZFXPJNUVBMR-UHFFFAOYSA-L magnesium benzoate Chemical compound [Mg+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 PJJZFXPJNUVBMR-UHFFFAOYSA-L 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (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
のラセミ化法に関するものである。DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a method for racemizing optically active 2-hydroxy-4-phenylbutyric acid.
〈従来の技術〉
光学活性２−ヒドロキシ−４−フエニル醋酸は種々の医
薬品の原料として有用である。たとえば、（Ｒ）−２−
ヒドロキシ−４−フェニル酪酸エチルはアンジオテンシ
ン変換酵素の阻害刑として有効な血圧降下剤であるシラ
ザプリルの原料となる（Ｊ． Ｃｈｅｗ， Ｓｏｃ．
Ｐｅｒｋｉｎ ＴｒａＩｌｓ１．１０１１ （１９８
６））．この光学活性２ヒドロキシ−４−フェニル酪酸
の製法としては、化学的に合成したラセミ体の２−ヒド
ロキシ４−フエニル酪酸を１−メントールのエステルに
誘導し、光学分割する方法（Ａｎｎ． ｃｈｉｍ．，λ
旦、９７ （１９３３））および同じくラセミ体の２＝
ヒドロキシー４−フェニル酪酸を光学活性ボルニルアミ
ンで光学分割する方法（Ｃｈｅｗ． Ｂｅｒ．旦』一、
６７１（１９５６））などが知られている．しかし、副
生物となる一方の光学活性２−ヒドロキシ−４−フエニ
ル酪酸をラセミ化して再利用する方法は知られていない
。<Prior Art> Optically active 2-hydroxy-4-phenyl acetic acid is useful as a raw material for various pharmaceuticals. For example, (R)-2-
Ethyl hydroxy-4-phenylbutyrate is the raw material for cilazapril, an antihypertensive agent effective as an angiotensin-converting enzyme inhibitor (J. Chew, Soc.
Perkin TraIls1.1011 (198
6)). A method for producing optically active 2-hydroxy-4-phenylbutyric acid is a method in which chemically synthesized racemic 2-hydroxy-4-phenylbutyric acid is induced into an ester of 1-menthol and optically resolved (Ann. chim., λ
Dan, 97 (1933)) and racemic 2=
Method for optically resolving hydroxy-4-phenylbutyric acid with optically active bornylamine (Chew. Ber. Dan) 1.
671 (1956)) are known. However, there is no known method for racemizing and reusing optically active 2-hydroxy-4-phenylbutyric acid, one of the by-products.
く発明が解決しようとする課題〉
すなわち、光学分割で副生物となる一方の光学活性２−
ヒドロキシ−４−フェニル酪酸をラセミ化することがで
きれば、再び光学分割の原料として使用でき、光字活性
２−ヒドロキシ−４−フェニル酪酸の工業的に有利な製
法となる．く課題を解決するための手段および作用〉本
発明者らは、光学活性２−ヒドロキシ−４−フェニル酪
酸のラセミ化法について鋭意検討を行った結果、無水酢
酸および塩基の存在下、加熱することによって光学活性
２−ヒドロキシ−４−フェニル酪酸をラセミ化できるこ
とを見出した。Problems to be Solved by the Invention> In other words, one of the optically active 2-
If hydroxy-4-phenylbutyric acid can be racemized, it can be used again as a raw material for optical resolution, resulting in an industrially advantageous process for producing photoactive 2-hydroxy-4-phenylbutyric acid. Means and Effects for Solving the Problems As a result of extensive research into the racemization method of optically active 2-hydroxy-4-phenylbutyric acid, the present inventors found that heating in the presence of acetic anhydride and a base. It has been found that optically active 2-hydroxy-4-phenylbutyric acid can be racemized by the following method.
すなわち、本発明は、光学活性２−ヒドロキシ−４−フ
エニル酪酸をラセミ化するにあたり、無水酢酸および塩
基の存在下、加熱することを特徴とする光学活性２−ヒ
ドロキシ−４−フェニル酪酸のラセミ化法である。That is, the present invention provides a racemization process for optically active 2-hydroxy-4-phenylbutyric acid, which is characterized by heating in the presence of acetic anhydride and a base. It is the law.
本発明において原料として使用する光学活性２−ヒドロ
キシ−４−フェニル酪酸は、いかなる方法で製造された
ものでもよく、またＲ体であってもＳ体であってもよい
。原料としては実質的にラセミ体以外の任意の光学純度
のものが使用できる．
本発明においては、無水酢酸および塩基の共存下にラセ
ミ化反応を行うことが重要である．本発明で用いられる
無水酢酸の量は光字活性２−ヒドロキシ−４−フエニル
酪酸１モルに対し０．５〜１０モル、好ましくは１．０
〜３．０モル量である．
本発明で用いられる塩基としては、たとえば、低級脂肪
族カルボン酸のアルカリ金属またはアルカリ土類金属塩
、芳香族カルボン酸のアルカリ金属またはアルカリ．土
類金属塩、有機アミンなどを挙げることができる．具体
的には、ギ酸ナトリウム、ギ酸カリウム、酢酸ナトリウ
ム、酢酸カリウム、安息香酸ナトリウム、安息香酸マグ
ネシウム、ピリジン、トリエチルアミンなどを挙げるこ
とができる．
塩基の添加量としては、光学活性２−ヒドロキシ−４−
フエニル酪酸１モルに対し、０．０１〜５モル、好まし
くは０．０５〜２．０モル量である．反応を行うに際し
ては、本質的にラセミ化反応を阻害しない溶媒、たとえ
ば、酢酸、ベンゼン、トルエンなどを用いることができ
るが、特に必須の条件ではない．
本発明方法を実施するに際し、反応温度は１５〜２００
℃、好ましくは５０〜１５０℃である．また反応時間は
用いる無水酢酸および塩基の量、反応温度によって異な
るが１〜２４時間で十分である．
反応を終了した反応液からラセミ化した２−ヒドロキシ
ー４−フェニル酪酸を得るには、ラセミ化反応後、水酸
化ナトリウム、水酸化カリウムなどの強アルカリまたは
塩酸、硫酸などの強酸で加水分解し、酢酸エチル、クロ
ロホルム、ベンゼンなどの有機溶媒で抽出するか、また
は水溶液を強酸性にすることにより酸析させるなどの通
常の単離方法を用いることができる。The optically active 2-hydroxy-4-phenylbutyric acid used as a raw material in the present invention may be produced by any method, and may be in the R form or the S form. As raw materials, materials of virtually any optical purity other than the racemate can be used. In the present invention, it is important to perform the racemization reaction in the presence of acetic anhydride and a base. The amount of acetic anhydride used in the present invention is 0.5 to 10 mol, preferably 1.0 mol, per 1 mol of photoactive 2-hydroxy-4-phenylbutyric acid.
~3.0 mole amount. Examples of the base used in the present invention include alkali metal or alkaline earth metal salts of lower aliphatic carboxylic acids, alkali metal or alkali salts of aromatic carboxylic acids. Examples include earth metal salts and organic amines. Specific examples include sodium formate, potassium formate, sodium acetate, potassium acetate, sodium benzoate, magnesium benzoate, pyridine, and triethylamine. The amount of base added is optically active 2-hydroxy-4-
The amount is 0.01 to 5 mol, preferably 0.05 to 2.0 mol, per 1 mol of phenylbutyric acid. When carrying out the reaction, a solvent that does not essentially inhibit the racemization reaction, such as acetic acid, benzene, toluene, etc., can be used, but this is not an essential condition. When carrying out the method of the present invention, the reaction temperature is 15 to 200°C.
℃, preferably 50 to 150℃. The reaction time varies depending on the amounts of acetic anhydride and base used and the reaction temperature, but 1 to 24 hours is sufficient. To obtain racemized 2-hydroxy-4-phenylbutyric acid from the reaction solution that has completed the reaction, after the racemization reaction, hydrolyze it with a strong alkali such as sodium hydroxide or potassium hydroxide or a strong acid such as hydrochloric acid or sulfuric acid. Conventional isolation methods can be used, such as extraction with an organic solvent such as ethyl acetate, chloroform, or benzene, or acid precipitation by making an aqueous solution strongly acidic.
く実總例〉
以下、実施例により本発明をさらに詳細に説明するが、
本発明はこれらの実施例に限定されるものではない。Practical Examples> The present invention will be explained in more detail with reference to Examples below.
The present invention is not limited to these examples.
なお、実施例中、光学純度は次のように測定したものを
示す．
く光字純度の測定〉
２−ヒドロキシ−４−フェニル酪酸２５■を塩酸飽和エ
タノール溶液５ ｍｌに加え、６０℃で１時間エステル
化する、次いでエタノールを濃縮除去し、トルエン１０
ｍｌ中ピリジン２００４を触媒として３．５−ジニトロ
フエニルイソシアネート１００■と６５℃で１時間反応
させる．これを高速液体クロマトグラフイー（ＨＰＬＣ
）を用いて次の条件で分析し光学純度％を求めた。In addition, in the examples, optical purity is measured as follows. Measurement of purity> Add 25 μl of 2-hydroxy-4-phenylbutyric acid to 5 ml of hydrochloric acid saturated ethanol solution and esterify at 60°C for 1 hour. Then, concentrate and remove the ethanol and add 10 μl of toluene.
ml of pyridine 2004 as a catalyst and 100 μl of 3,5-dinitrophenyl isocyanate at 65°C for 1 hour. This is performed using high performance liquid chromatography (HPLC).
) under the following conditions to determine the optical purity %.
ＨＰＬＣ条件
カラム：ＳＵＭＩＰＡＸ ＯＡ−３０００（住友化学工
業製》５μ、４． ６ Ｘ ２５０ｍ
移動層：ｎ−ヘキサン／１．２−ジクロ口エタン／エタ
ノール＝８０／１ ９／１
１．０ｍｌ／ｍｉｎ
ＵＶ ：２５４ｎｍ
保持時間： （Ｒ）−２−ヒドロキシ−４−フエニル酪
酸エチル７、７ ｗｉｎ
（Ｓ）−２−ヒドロキシ−４−フェ
ニル醋酸エチル１６．５ｍｉｎ
実施例１
（Ｓ）−２−ヒドロキシ−４−フェニル醋酸（光学純度
７１％ｅ．ｅ．）５ｇ、無水酢酸３ｇおよび酢酸カリウ
ム２．５ｇを酢酸１０ｍｌ中に加え、１０５゜Ｃで６時
間加熱撹拌した．酢酸をエバボレートした後、５Ｎ水酸
化ナトリウム水溶液３０ ｍｌを加え３時間還流した。HPLC conditions Column: SUMIPAX OA-3000 (manufactured by Sumitomo Chemical) 5 μ, 4.6 x 250 m Mobile phase: n-hexane/1.2-dichloroethane/ethanol = 80/1 9/1 1.0 ml/min UV : 254 nm Retention time: (R)-2-hydroxy-4-phenylbutyrate ethyl 7,7 win (S)-2-hydroxy-4-phenyl ethyl acetate 16.5 min Example 1 (S)-2-hydroxy-4 - 5 g of phenyl acetic acid (optical purity 71% ee), 3 g of acetic anhydride, and 2.5 g of potassium acetate were added to 10 ml of acetic acid, and the mixture was heated and stirred at 105°C for 6 hours. After acetic acid was evaporated, 5N hydroxide was added. 30 ml of sodium aqueous solution was added and the mixture was refluxed for 3 hours.
冷却後、濃硫酸でｐＨ１、５に調整することにより析出
した結晶を枦過し、光学純度３％ｅ．ｅ．のラセミ化し
た２ヒドロキシー４−フェニル酪酸４．５ｇ（収率９０
％）を得た．
実施例２
（Ｓ）−２−ヒドロキシ−４−フェニル酪酸（光学純度
７１％ｅ．ｅ． ） １． ８ ｇに無水酢Ｗ１５．１
ｇおよび酢酸ナトリウム０．８ｇを加え、１３０゜Ｃで
１１時間加熱撹拌した。その後５Ｎ水酸化ナトリウム２
７ｍ１を加え、さらに４時間還流した．冷却後、濃硫酸
でｐＨ１．４に調整し、酢酸エチル３０ｍ１で３回抽出
した。有機層を水洗、乾燥した後、溶媒を留去すること
により光学純度１％ｅ．ｅ．のラセミ化した２−ヒドロ
キシー４ーフェニル酪酸１．６ｇ（収率９１％）を得な
．実施例３
（Ｓ）−２−ヒドロキシ−４−フェニル酪酸（光学純度
７１％ｅ．ｅ． ） １． ８ ｇに無水酢酸５．１ｇ
およびギ酸ナトリウム０．７ｒを加え、１３０℃で１１
時間加熱撹拌した。その後５Ｎ水酸化ナトリウム水溶液
２２ｍｌを加え、さらに３時間還流した．冷却後、実施
例２と同様に処理し、光学純度２％ｅ． ｅ．のラセミ
化した２−ヒドロキシー４−フェニル酪酸１．４６ｇ（
収率８１％》を得た。After cooling, the pH was adjusted to 1.5 with concentrated sulfuric acid, and the precipitated crystals were filtered to obtain an optical purity of 3%e. e. 4.5 g of racemized 2-hydroxy-4-phenylbutyric acid (yield 90
%) was obtained. Example 2 (S)-2-hydroxy-4-phenylbutyric acid (optical purity 71%ee) 1. 8g anhydrous vinegar W15.1
g and 0.8 g of sodium acetate were added thereto, and the mixture was heated and stirred at 130°C for 11 hours. Then 5N sodium hydroxide 2
7 ml was added and the mixture was refluxed for an additional 4 hours. After cooling, the pH was adjusted to 1.4 with concentrated sulfuric acid, and the mixture was extracted three times with 30 ml of ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off to obtain an optical purity of 1%e. e. Obtain 1.6 g (91% yield) of racemized 2-hydroxy-4-phenylbutyric acid. Example 3 (S)-2-hydroxy-4-phenylbutyric acid (optical purity 71%ee) 1. 8 g to 5.1 g of acetic anhydride
and 0.7r of sodium formate and heated to 130℃ for 11 hours.
The mixture was heated and stirred for hours. Thereafter, 22 ml of 5N aqueous sodium hydroxide solution was added, and the mixture was further refluxed for 3 hours. After cooling, it was treated in the same manner as in Example 2, and the optical purity was 2% e. e. 1.46 g of racemized 2-hydroxy-4-phenylbutyric acid (
A yield of 81% was obtained.
実施例４
（Ｓ）−２−しドロキシ−４−フェニル酪酸（光学純度
７１％ｅ．ｅ．）１、８ｇに無水酢酸５．１ｇおよびト
リエチルアミンｉ．ｏｒを加え、１３０℃で１０時間加
熱撹拌した。その後５Ｎ水酸化ナトリウム水溶液１２ｍ
ｌを加え、さらに４時間還流した。冷却後、実施例２と
同様に処理し、光学純度３％ｅ．ｅ．のラセミ化した２
−ヒドロキシー４−フェニル酪酸１．６６ｇ（収率９２
％）を得た。Example 4 To 1.8 g of (S)-2-droxy-4-phenylbutyric acid (optical purity 71% ee), 5.1 g of acetic anhydride and triethylamine i. or was added, and the mixture was heated and stirred at 130°C for 10 hours. Then 12ml of 5N sodium hydroxide aqueous solution
1 was added, and the mixture was further refluxed for 4 hours. After cooling, the same treatment as in Example 2 was carried out to obtain an optical purity of 3%e. e. racemized 2
-Hydroxy-4-phenylbutyric acid 1.66g (yield 92
%) was obtained.
比較例１
（Ｒ）−２−ヒドロキシ−４−フェニル醋酸（光学純度
７１％ｅ．ｅ． ） ３． ０ ｇと無水酢酸９．０ｇ
を加え、１１０℃で７時間加熱撹拌した。その後５Ｎ水
酸化ナトリウム水溶？１！ ５ ０ ［１１１を加え、
さらに４時間還流しな．冷却後、濃硫酸でｐＨ１．５に
調整することにより析出した結晶を枦過し、光字純度７
１％ｅ．ｅ．の（Ｒ）−２−ヒドロキシ−４−フェニル
酪酸２６ｇ（収率８７％）を得た。Comparative Example 1 (R)-2-hydroxy-4-phenyl acetic acid (optical purity 71%ee) 3. 0 g and acetic anhydride 9.0 g
was added, and the mixture was heated and stirred at 110°C for 7 hours. Then 5N sodium hydroxide solution? 1! 5 0 [add 111,
Reflux for another 4 hours. After cooling, the precipitated crystals were filtered by adjusting the pH to 1.5 with concentrated sulfuric acid, and the purity was 7.
1%e. e. 26 g (yield: 87%) of (R)-2-hydroxy-4-phenylbutyric acid was obtained.
く発明の効果〉
本発明によれば光学活性２−ヒドロキシ−４フェニル酪
酸を簡単に効率よくラセミ化することができ、ラセミ化
物を再び光学分割の原料として供給できるため工業的に
有利である。Effects of the Invention> According to the present invention, optically active 2-hydroxy-4 phenylbutyric acid can be easily and efficiently racemized, and the racemized product can be supplied again as a raw material for optical resolution, which is industrially advantageous.
Claims (1)
するにあたり、無水酢酸および塩基の存在下、加熱する
ことを特徴とする光学活性２−ヒドロキシ−４−フェニ
ル酪酸のラセミ化法。A method for racemizing optically active 2-hydroxy-4-phenylbutyric acid, which comprises heating in the presence of acetic anhydride and a base.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2010154A JPH03215451A (en) | 1990-01-18 | 1990-01-18 | Racemization of optically active 2-hydroxy-4-phenylbutyric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2010154A JPH03215451A (en) | 1990-01-18 | 1990-01-18 | Racemization of optically active 2-hydroxy-4-phenylbutyric acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH03215451A true JPH03215451A (en) | 1991-09-20 |
Family
ID=11742356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2010154A Pending JPH03215451A (en) | 1990-01-18 | 1990-01-18 | Racemization of optically active 2-hydroxy-4-phenylbutyric acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03215451A (en) |
-
1990
- 1990-01-18 JP JP2010154A patent/JPH03215451A/en active Pending
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