JPH02229135A - Production of 2-hydroxy-4-phenylbutyric acid - Google Patents
Production of 2-hydroxy-4-phenylbutyric acidInfo
- Publication number
- JPH02229135A JPH02229135A JP1049611A JP4961189A JPH02229135A JP H02229135 A JPH02229135 A JP H02229135A JP 1049611 A JP1049611 A JP 1049611A JP 4961189 A JP4961189 A JP 4961189A JP H02229135 A JPH02229135 A JP H02229135A
- Authority
- JP
- Japan
- Prior art keywords
- hydrochloric acid
- hydroxy
- hydrolysis
- hpba
- reaction
- 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 7
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 17
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000007062 hydrolysis Effects 0.000 claims abstract description 11
- 239000006227 byproduct Substances 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 claims description 15
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 abstract 3
- 102000015427 Angiotensins Human genes 0.000 abstract 1
- 108010064733 Angiotensins Proteins 0.000 abstract 1
- 229940123468 Transferase inhibitor Drugs 0.000 abstract 1
- 239000003558 transferase inhibitor Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 15
- XFGMPZRFMGBTDI-POFDKVPJSA-N (2s)-n-[(2s)-1-[[(2s)-1-[(2s)-2-[[2-[[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidin-1-yl]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2s)-4-methyl-2-[[(2s)-5-oxopyrrolidine-2-carbonyl]amino]pe Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)C(=O)[C@@H]1CCC(=O)N1 XFGMPZRFMGBTDI-POFDKVPJSA-N 0.000 description 8
- 101800001365 Red pigment-concentrating hormone Proteins 0.000 description 8
- XFGMPZRFMGBTDI-UHFFFAOYSA-N p-Glu-Leu-Asn-Phe-Ser-Pro-Gly-Trp-NH2 Natural products C=1C=CC=CC=1CC(C(=O)NC(CO)C(=O)N1C(CCC1)C(=O)NCC(=O)NC(CC=1C2=CC=CC=C2NC=1)C(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CC(C)C)NC(=O)C1CCC(=O)N1 XFGMPZRFMGBTDI-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WGBNZXLJSLMFKX-UHFFFAOYSA-N 2-hydroxy-4-phenylbutanamide Chemical compound NC(=O)C(O)CCC1=CC=CC=C1 WGBNZXLJSLMFKX-UHFFFAOYSA-N 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000004064 recycling Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- -1 tolyl butyrate Chemical compound 0.000 description 2
- BHPFDLWDNJSMOS-UHFFFAOYSA-N 2-(9,10-diphenylanthracen-2-yl)-9,10-diphenylanthracene Chemical compound C1=CC=CC=C1C(C1=CC=C(C=C11)C=2C=C3C(C=4C=CC=CC=4)=C4C=CC=CC4=C(C=4C=CC=CC=4)C3=CC=2)=C(C=CC=C2)C2=C1C1=CC=CC=C1 BHPFDLWDNJSMOS-UHFFFAOYSA-N 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N 2-hydroxy-2-methylpropanenitrile Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000011938 amidation process Methods 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 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
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明はアンジオテンシン変換酵素阻害剤等の合成中間
体として有用である。２−ヒドロキシ４−フェニル酪酸
（以下、ＨＰ Ｂ Ａと略記する）の製造方法に関する
。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention is useful as a synthetic intermediate for angiotensin-converting enzyme inhibitors and the like. The present invention relates to a method for producing 2-hydroxy 4-phenylbutyric acid (hereinafter abbreviated as HP BA).
（従来の技術）
２−ヒドロキシカルボン酸類を製造する方法の一つとし
て、シアンヒドリン類を鉱酸で加水分解する方法か知ら
れている。（例えは、アセトンシアンヒドリンに関して
は特公昭６：３−６１９３２号に、ＶＬ酪酸トリルに関
しては特開昭５７−８２３４０号に、またマンデロニ）
〜リルについてはＯｒｇａｎｉｃ ５ｙｎｔｈｅｓｅｓ
、 Ｃｏ１１ｅｃｔｉｖｅ Ｖｏｌｕｎｅ Ｔ、 ３
３６頁に記載されている。）。しかし化合物のタイプに
よってその反応性が大ｒｉＪに異るため、使用する鉱酸
の種類および濃度、反応温度等を適切に選ばない限り目
的とする２−ヒドロキシカルボン酸類を満足すべき収率
で得ることは芦しい。また、２−ヒドロキシカルボン酸
類は酸性条件下で自己エステル化し、グリコリドやポリ
エステル等の縮合物を形成し易いことも収率を下げる大
きな原因となっている。(Prior Art) As one of the methods for producing 2-hydroxycarboxylic acids, a method of hydrolyzing cyanohydrins with mineral acids is known. (For example, regarding acetone cyanohydrin, see Japanese Patent Publication No. 6:3-61932, and regarding VL tolyl butyrate, see Japanese Patent Application Publication No. 57-82340, and Mandeloni)
~Organic 5yntheses for Lil
, Co11active Volume T, 3
It is described on page 36. ). However, since the reactivity varies greatly depending on the type of compound, unless the type and concentration of the mineral acid used, reaction temperature, etc. are appropriately selected, the desired 2-hydroxycarboxylic acids cannot be obtained in a satisfactory yield. It's refreshing. Furthermore, 2-hydroxycarboxylic acids tend to self-esterify under acidic conditions and form condensates such as glycolide and polyester, which is another major cause of lower yields.
一方Ｔ−ｉ Ｐ Ｂ Ａを３−フェニルプロピオンアル
デヒドシアンヒドリン（以下、Ｐ Ｐ ＣＨと略記する
。On the other hand, T-iPBA is 3-phenylpropionaldehyde cyanohydrin (hereinafter abbreviated as PPCH).
）から直接製造する方法は未だよく知られていないが、
特開昭６．２−１７８５５５号には、ｐｐｃＨを一部２
−ヒドロキシー４−フェニル酪酸アミドとしたのち、ア
ルカリで加水分解してＨＰ Ｂ Ａを得る方法が提案さ
れている。) is still not well known, but
In JP-A No. 6.2-178555, ppcH is partially
-Hydroxy-4-phenylbutyric acid amide is prepared and then hydrolyzed with an alkali to obtain HPBA.
（発明が解決しようとする課題）
しかしながらこの方法はアミド化工程において、過酸化
水素やアンモニアといった比較的高価な薬剤を多量に使
用すること、また反応後の混合物から過剰量の過酸化水
素やアンモニアを除去するために繁雑な操作を要するこ
と、さらに反応収率が６５％と低いことなどの欠点があ
る。(Problems to be Solved by the Invention) However, this method requires the use of large amounts of relatively expensive chemicals such as hydrogen peroxide and ammonia in the amidation process, and also requires the use of excessive amounts of hydrogen peroxide and ammonia from the mixture after the reaction. It has drawbacks such as requiring complicated operations to remove and furthermore, the reaction yield is as low as 65%.
本発明の目的はＰ Ｐ ＣＨを原料として、）（、Ｐ
ＢＡを簡便かつ高収率に製造することにある。The purpose of the present invention is to use P P CH as a raw material, )(, P
The object of the present invention is to produce BA simply and with high yield.
（課題を解決するための手段）
本発明者らは上記の如き問題点を有するＨ Ｐ ＢＡの
製造方法に関して検討を重ねた結果、ＰＰＣＨを塩酸で
加水分解することにより上記目的を達成することを見出
し本発明に至った。(Means for Solving the Problems) As a result of repeated studies on the production method of H P BA having the above-mentioned problems, the present inventors have found that the above object can be achieved by hydrolyzing PPCH with hydrochloric acid. Heading This invention has been achieved.
本発明において使用するＰ Ｐ ＣＨは、３−フェニル
プロピオンアルデヒドを塩基性触媒のもとて青酸と反応
させることによって容易に製造することができ、特に精
製することなくそのまま使用できる。P P CH used in the present invention can be easily produced by reacting 3-phenylpropionaldehyde with hydrocyanic acid in the presence of a basic catalyst, and can be used as it is without any particular purification.
ＲＰＣＨの加水分解反応に使用する鉱酸としては硫酸、
塩酸、硝酸等が考えられるが、塩酸を使用することが望
ましく硫酸等では満足すべき結果が得られない。塩酸の
濃度は２５％以上、好ましくは濃塩酸を使用する。塩酸
濃度が２５％以下では加水分解反応に長時間を要し反応
が十分に進行しない。またＲＰＣＨに対する塩酸の使用
量は等モル量以上、好ましくは１．３〜２倍モル量であ
る。塩酸の使用量が１．３倍モル量以下では反応混合物
（反応生成物であるＨＰＢＡは反応液に難溶性であり固
体として析出する）のスラリー濃度が高くなり取扱が困
難になる。Mineral acids used in the hydrolysis reaction of RPCH include sulfuric acid,
Hydrochloric acid, nitric acid, etc. are conceivable, but it is preferable to use hydrochloric acid; sulfuric acid etc. do not give satisfactory results. The concentration of hydrochloric acid is 25% or more, preferably concentrated hydrochloric acid. If the hydrochloric acid concentration is less than 25%, the hydrolysis reaction will take a long time and will not proceed sufficiently. The amount of hydrochloric acid used is equal to or more than the molar amount of RPCH, preferably 1.3 to 2 times the molar amount. If the amount of hydrochloric acid used is less than 1.3 times the molar amount, the slurry concentration of the reaction mixture (HPBA, which is a reaction product, is poorly soluble in the reaction solution and precipitates as a solid) becomes high, making it difficult to handle.
反応は発熱反応であり、反応温度は４０℃以上、好まし
くは６０〜９０℃に保つことが必要である。The reaction is exothermic and it is necessary to maintain the reaction temperature at 40°C or higher, preferably between 60 and 90°C.
４０℃以下では不完全加水分解物である２−ヒドロキシ
−４−フェニル酪酸アミドが残存し、ＨＰＢＡの単離精
製が繁雑になる。At temperatures below 40°C, 2-hydroxy-4-phenylbutyric acid amide, which is an incompletely hydrolyzed product, remains, making the isolation and purification of HPBA complicated.
反応時間は反応温度によって変化するが、上記温度範囲
では通常１〜１０時間必要である。The reaction time varies depending on the reaction temperature, but in the above temperature range, 1 to 10 hours is usually required.
ＰＰＣＨと塩酸との混合方法に特に制限はないが、一般
には塩酸中にＰＰＣＨを滴下する。Although there is no particular restriction on the method of mixing PPCH and hydrochloric acid, generally PPCH is added dropwise into hydrochloric acid.
次に反応混合物からＨＰＢＡを単離する方法の実施態様
の一例を述べるが、本発明は該方法に限定されるもので
はない。Next, an example of an embodiment of a method for isolating HPBA from a reaction mixture will be described, but the present invention is not limited to this method.
反応混合物は通常スラリー状態にあり、ＨＰＢＡの一部
が固体として析出している。これをそのまま冷却すると
全体がシャーベット状に固化し取扱いが困誼となるなめ
、熱時、よく撹拌された水中に抜出し、冷却してＨＰＢ
Ａを析出させる（反応混合物を水中に抜出す際、撹拌が
不充分な場合は塊状の固体が析出する）。このようにし
て析出したＨＰＢＡには油状物（後述）が付着、包含さ
れ、通常の濾過操作では完全に除去することが困難であ
る。したがって）（ＰＢＡを濾過する前に、芳香族炭化
水素、塩素化炭化水素等のＨＰＢＡの溶解度が小さい溶
剤を添加し、よく撹拌しなのち濾過することにより、油
状物をＴ（ＰＢＡの結晶から効率よく除くことができる
。炉別されたＨＰＢＡはさらに少量の溶剤で洗浄したの
ち水洗することにより、純度の高いＨＰ ｌ’３ Ａを
６０〜７０％の収率で得ることができる。The reaction mixture is usually in a slurry state, with some of the HPBA precipitated as a solid. If this is cooled as it is, the entire product will solidify into a sherbet-like shape, making it difficult to handle.
A is precipitated (if stirring is insufficient when the reaction mixture is taken out into water, a lumpy solid will precipitate). The HPBA thus precipitated contains oily substances (described later), which are difficult to completely remove by ordinary filtration operations. Therefore, by adding a solvent in which HPBA has a low solubility, such as an aromatic hydrocarbon or a chlorinated hydrocarbon, and stirring well before filtering PBA), the oily substance can be removed from the T(PBA crystals). It can be efficiently removed.By further washing the HPBA separated by a furnace with a small amount of solvent and then washing with water, highly pure HPl'3A can be obtained at a yield of 60 to 70%.
以上に述べたＲＰＣＨの塩酸による加水分解では、目的
物であるＨ Ｐ Ｂ Ａの他にがなりの量の油状物を副
生じ、収率を低下させる原因となる。この油状物はＨＰ
ＢＡが自己エステル化したグリコリドやポリエステル
等の縮合物であると考えられる。本発明はさらにこの油
状物からＨＰＢＡを回収する方法を提案するものである
。すなわち、本発明によれば上記油状物を塩酸で処理す
ることによりＨＰＢＡを回収することができる。In the above-described hydrolysis of RPCH with hydrochloric acid, in addition to the target product H P B A, a considerable amount of oily matter is produced as a by-product, which causes a decrease in the yield. This oily substance is available on HP
It is thought that BA is a self-esterified condensate of glycolide, polyester, etc. The present invention further proposes a method for recovering HPBA from this oily substance. That is, according to the present invention, HPBA can be recovered by treating the oily substance with hydrochloric acid.
塩酸処理にＨされる油状物とは、ＲＰ ＣＨの加水分解
生成物からＨＰ Ｂ Ａを沢別する際に分離してくる油
状物質であり、ＨＰ Ｂ Ａの濾過・精製を容易にする
ために沢過時に添加した溶剤（前述）によって８釈され
たものでもよい。油状物の塩酸処理には濃塩酸を使用す
ることが望ましく、またその使用量は多い程望ましいが
、一般には油状物またはその溶液に対して１０〜６０重
旦％の範囲である。処理温度は室温〜９０℃１好ましく
は、５０〜９０℃で、１〜５時間加熱することにより達
成される。塩酸処理された反応混合物から■ＴＰＢＡを
回収する方法としては、前述したＲ ＰＣＨの加水分解
反応混合物からＨＰ Ｂ Ａを単離する方法に準して行
うことかできる。The oily substance that is treated with hydrochloric acid is an oily substance that is separated when HPBA is separated from the hydrolysis product of RPCH, and in order to facilitate the filtration and purification of HPBA. It may also be diluted with the solvent (described above) added at the time of filtration. It is preferable to use concentrated hydrochloric acid for the hydrochloric acid treatment of oily substances, and the amount used is preferably as large as possible, but generally it is in the range of 10 to 60% by weight based on the oily substance or its solution. The treatment temperature is room temperature to 90°C, preferably 50 to 90°C, and is achieved by heating for 1 to 5 hours. The method for recovering TPBA from the hydrochloric acid-treated reaction mixture can be carried out in accordance with the method for isolating HPBA from the RPCH hydrolysis reaction mixture described above.
以上の如き油状物回収］二層をイ・１加することにより
、ＨＰ ｒ３ Ａの収率は６５〜８０％にまで向」二す
る。By adding the above-mentioned oil recovery] two layers, the yield of HP r3 A can be increased to 65-80%.
副生油状物からＨＰ Ｂ Ａを回収するさらに他の方法
として、油状物をＰＰＣｌ−■の加水分解工程にリサイ
クルする方法が有効である。すなわち、ＰＰ ＣＴ（を
塩酸で加水分解するにあたり、前回バッチで回収された
油状物を一緒にして、Ｐ Ｐ Ｃ）−ｒの加水分解反応
と、油状物からのＴ−ｒ Ｐ Ｂ Ａの回収とを同時に
行わせることができる。この際使用する塩酸の量はＲＰ
ＣＨの加水分解に必要とする量でよく、また反応条件
も特に変更する必要はない。As yet another method for recovering HPBA from the by-product oil, it is effective to recycle the oil to the PPCl-■ hydrolysis step. That is, when hydrolyzing PPCT(with hydrochloric acid), the oily substance recovered in the previous batch is combined, and the hydrolysis reaction of PPC-r and the recovery of T-rPBA from the oily substance are carried out. can be performed at the same time. The amount of hydrochloric acid used at this time is RP
The amount required for hydrolysis of CH may be sufficient, and there is no need to particularly change the reaction conditions.
」二層のような回収方法によって回収工程は簡略化され
、リサイクルを繰返ず度にＨＰ Ｂ Ａの収率は向上し
、５回目のリサイクルてほぼ定常値となり、以降は９５
％以上の高収率でＨＰＢＡを製造することができる。The recovery process was simplified by the two-layer recovery method, and the yield of HP B A improved with each recycling, reaching a nearly steady value at the 5th recycling, and from then on, the yield of HP B A increased to 95%.
HPBA can be produced with a high yield of % or more.
（実施例）
以下、実施例をあげて本発明をさらに具体的に説明する
。(Examples) Hereinafter, the present invention will be explained in more detail by giving examples.
実施例１
撹拌機、還流冷却器、薬剤供給口および温度計を備えた
２０ρ力ラス製反応器に濃塩酸８０７１ａＦｒを仕込み
、薬剤供給口よりＰ Ｐ ＣＩ（（純度９８％）６．３
２ｋｇを反応液温か５０℃を越えないように保ちながら
１時間にわたって徐々に添加した。Example 1 Concentrated hydrochloric acid 8071aFr was charged into a 20p glass reactor equipped with a stirrer, a reflux condenser, a drug supply port, and a thermometer, and P P CI ((purity 98%) 6.3
2 kg was gradually added over 1 hour while maintaining the temperature of the reaction solution not to exceed 50°C.
最初２０℃の反応液温はＲＰ ＣＨの添加にともない徐
々に上昇し、５０’Ｃになった時点でコントロールしな
。ＲＰＣＨの添加終了後液温を８０℃に高め１時間反応
を続けた。液体りｖ７マトグラフにより２−ヒドロキシ
−４−フェニル酪酸アミドの残存量が無くなったことを
確認し反応を終了しな。The temperature of the reaction solution, which was initially 20°C, gradually rose as RPCH was added, and was no longer controlled when it reached 50°C. After the addition of RPCH was completed, the liquid temperature was raised to 80°C and the reaction was continued for 1 hour. Confirm that there is no remaining amount of 2-hydroxy-4-phenylbutyric acid amide using a liquid chromatograph, and then terminate the reaction.
４０Ｊ２のポリエチレン製容器に水８．１２を入れ、は
けしく撹拌しながら上記反応液を加温状態のまま抜出し
、そのまま撹拌を続けて一夜放冷しな。Pour 8.12 g of water into a 40J2 polyethylene container, stir vigorously, and draw out the reaction solution while it is still warm. Continue stirring and leave to cool overnight.
その後生成したスラリー液にトルエン５ｐを加え、大型
のヌッチェを用いてＨＰ Ｂ Ａの結晶を濾取しな。結
晶をさらに２ρのトルエンで２回洗浄し、続いて水２！
！で３回洗浄したのち６０℃で減圧乾燥して白色のＨＰ
ＢＡ４．５４ｋｇを得なく収率６５、６％）。After that, add 5 parts of toluene to the slurry liquid produced, and filter out the HPBA crystals using a large Nutsche filter. The crystals were further washed twice with 2ρ of toluene, followed by 2! of water.
! After washing three times with
(Yield: 65, 6%) without obtaining 4.54 kg of BA.
次にＨＰＢＡの結晶を濾取した後の炉液を静置して二層
に分液させ、上層の油層（油状物含有証３３％）５．９
１に、、に製塩Ｄ ８００ ｆを加え、６０℃で４時間
処理しな。処理液を冷却し析出した固体を濾取し、３０
０ｍ１！のトルエンで２回、続いて３００ｍ１の水で３
回洗浄したのち同様に乾燥して、白色のＨＰ Ｂ Ａ
６２０ ｇを回収しなく収率９０％：全収率７４．６％
）。Next, the furnace liquid after filtering out the HPBA crystals was allowed to stand still to separate into two layers, and the upper oil layer (oil content: 33%) was 5.9
Add salt D 800 f to 1 and treat at 60°C for 4 hours. The treated solution was cooled, the precipitated solid was collected by filtration, and
0m1! of toluene twice, followed by 3 times with 300 ml of water.
After washing twice and drying in the same way, a white HPBA
90% yield without recovering 620 g: total yield 74.6%
).
実施例２
撹拌機、還流冷却器、滴下ｒ斗および温度計を備えた４
つロフラスコに濃塩酸２６．６ｋｇを仕込み、滴下枦斗
よりＰＰＣＨ（純度９８％）３０ｇを５０℃で３０分掛
って添加した。その後液温を８０℃に高め１時間保持し
て反応を完結させた。Example 2 4 liters equipped with stirrer, reflux condenser, addition funnel and thermometer
26.6 kg of concentrated hydrochloric acid was placed in a double-bottomed flask, and 30 g of PPCH (purity 98%) was added via a dropping funnel at 50° C. over 30 minutes. Thereafter, the liquid temperature was raised to 80° C. and maintained for 1 hour to complete the reaction.
反応液に水３０−を加え室温まで冷却したのち、さらに
トルエン３５−を加えよく撹ｔ’ｌ’ Ｌなのち濾過し
た。固体をトルエン２０−で２回、水２〇−で２回洗浄
し６０℃で減圧乾燥して白色のＩＴ Ｐ ＲＡを得た。After adding 30 mm of water to the reaction solution and cooling it to room temperature, 35 mm of toluene was further added, stirred thoroughly, and then filtered. The solid was washed twice with 20° of toluene and twice with 20° of water, and dried under reduced pressure at 60°C to obtain white IT PRA.
次にＨＰ Ｂ Ａを濾過しなＰ液および洗浄液を合わせ
て油層を分離し、トルエンを減圧下に泉発させ油状物を
得な。この油状物を次回のＲＰ ＣＨの加水分解におい
て濃塩酸と一緒にフラスコに仕込み、以降」−記と同様
にして加水分解・分解操作を繰返しな。結果をまとめて
第１表に示した。油状物を原料系にリサイクル使用する
ことにより収率は向上し、５回の繰返しで９５％の収率
に到達した。Next, filter the HPBA, combine the P liquid and the washing liquid, separate the oil layer, and evaporate toluene under reduced pressure to obtain an oily substance. In the next hydrolysis of RP CH, charge this oil into a flask together with concentrated hydrochloric acid, and repeat the hydrolysis and decomposition operations in the same manner as described in "-". The results are summarized in Table 1. The yield was improved by recycling the oil into the raw material system, and a yield of 95% was reached after 5 repetitions.
第１表 ＲＰＣＨの繰返し加水分解
（発明の効果）
本発明によれば、Ｐ Ｐ ＣＩ−ｒから簡便な操作で１
１ＰＢＡを製造することができ、従来の２−ヒドロキシ
−４−フェニル酪酸アミドを経由する方法に比べて大中
に収率が改良された。Table 1 Repeated hydrolysis of RPCH (effects of the invention) According to the present invention, 1
1PBA could be produced, and the yield was significantly improved compared to the conventional method via 2-hydroxy-4-phenylbutyric acid amide.
Claims (3)
ンを、２５％以上の塩酸の存在下に、４０〜９０℃で加
水分解することを特徴とする２−ヒドロキシ−４−フェ
ニル酪酸の製造方法。(1) A method for producing 2-hydroxy-4-phenylbutyric acid, which comprises hydrolyzing 3-phenylpropionaldehyde cyanohydrin at 40 to 90°C in the presence of 25% or more hydrochloric acid.
理し、２−ヒドロキシ−４−フェニル酪酸を回収する工
程を附加したことを特徴とする請求項１に記載の２−ヒ
ドロキシ−４−フェニル酪酸の製造方法。2-hydroxy-4-phenylbutyric acid according to claim 1, further comprising the step of: (2) treating an oily substance produced as a by-product in the hydrolysis reaction with hydrochloric acid to recover 2-hydroxy-4-phenylbutyric acid; Method for producing phenylbutyric acid.
ェニルプロピオンアルデヒドシアンヒドリンの加水分解
工程にリサイクルすることを特徴とする請求項１記載の
２−ヒドロキシ−４−フェニル酪酸の製造方法。(3) The method for producing 2-hydroxy-4-phenylbutyric acid according to claim 1, characterized in that the oily substance produced as a by-product in the hydrolysis reaction is recycled to the hydrolysis step of 3-phenylpropionaldehyde cyanohydrin. .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1049611A JPH02229135A (en) | 1989-02-28 | 1989-02-28 | Production of 2-hydroxy-4-phenylbutyric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1049611A JPH02229135A (en) | 1989-02-28 | 1989-02-28 | Production of 2-hydroxy-4-phenylbutyric acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02229135A true JPH02229135A (en) | 1990-09-11 |
Family
ID=12836028
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1049611A Pending JPH02229135A (en) | 1989-02-28 | 1989-02-28 | Production of 2-hydroxy-4-phenylbutyric acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02229135A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002042244A3 (en) * | 2000-11-23 | 2002-08-15 | Fermenta Biotech Ltd | Synthesis of chiral intermediates useful in preparing pharmacologically active compounds |
| US6864389B2 (en) | 2000-06-02 | 2005-03-08 | Nippon Shokubai Co., Ltd. | Method for producing α-hydroxycarboxylic acid |
| JP2006241066A (en) * | 2005-03-03 | 2006-09-14 | Mitsubishi Rayon Co Ltd | Method for producing optically active mandelic acids |
| JP2006282546A (en) * | 2005-03-31 | 2006-10-19 | Mitsubishi Rayon Co Ltd | Method for producing mandelic acid compounds |
| JP2007223993A (en) * | 2006-02-27 | 2007-09-06 | Mitsubishi Rayon Co Ltd | Method for producing optically active mandelic acid or its derivative |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5782340A (en) * | 1980-11-13 | 1982-05-22 | Asahi Chem Ind Co Ltd | Preparation of lactic acid |
| JPS57128653A (en) * | 1981-02-03 | 1982-08-10 | Mitsubishi Gas Chem Co Inc | Preparation of alpha-oxyisobutyric acid |
| JPS62106042A (en) * | 1985-10-31 | 1987-05-16 | Mitsui Toatsu Chem Inc | Production of carboxylic acid |
-
1989
- 1989-02-28 JP JP1049611A patent/JPH02229135A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5782340A (en) * | 1980-11-13 | 1982-05-22 | Asahi Chem Ind Co Ltd | Preparation of lactic acid |
| JPS57128653A (en) * | 1981-02-03 | 1982-08-10 | Mitsubishi Gas Chem Co Inc | Preparation of alpha-oxyisobutyric acid |
| JPS62106042A (en) * | 1985-10-31 | 1987-05-16 | Mitsui Toatsu Chem Inc | Production of carboxylic acid |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6864389B2 (en) | 2000-06-02 | 2005-03-08 | Nippon Shokubai Co., Ltd. | Method for producing α-hydroxycarboxylic acid |
| WO2002042244A3 (en) * | 2000-11-23 | 2002-08-15 | Fermenta Biotech Ltd | Synthesis of chiral intermediates useful in preparing pharmacologically active compounds |
| JP2006241066A (en) * | 2005-03-03 | 2006-09-14 | Mitsubishi Rayon Co Ltd | Method for producing optically active mandelic acids |
| JP2006282546A (en) * | 2005-03-31 | 2006-10-19 | Mitsubishi Rayon Co Ltd | Method for producing mandelic acid compounds |
| JP2007223993A (en) * | 2006-02-27 | 2007-09-06 | Mitsubishi Rayon Co Ltd | Method for producing optically active mandelic acid or its derivative |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2012512137A (en) | Purification method of adefovir dipivoxil | |
| DK1377544T4 (en) | Purification of 2-Nitro-4-Methylsulfonylbenzoic acid | |
| SK8997A3 (en) | Process for the preparation of 5-amino-2,4,6-triiodine-1,3- -benzenedicarboxylic acid | |
| AU2002249384A1 (en) | Purification of 2-nitro-4-methylsulphonylbenzoic acid | |
| JPH02229135A (en) | Production of 2-hydroxy-4-phenylbutyric acid | |
| JPS5941924B2 (en) | Purification method of thionyl chloride | |
| JPS6210510B2 (en) | ||
| JP2001247529A (en) | Method of producing alpha-amino acid amide | |
| JPH069683A (en) | Production of pharmaceutical grade highly pure iodeoxycholicacid | |
| US4876387A (en) | Process for preparing 2,4,5-trifluorobenzoic acid | |
| CA1135271A (en) | Process for the production of 3-thienylmalonic acid | |
| JP4209022B2 (en) | Process for producing isocyanoacetic acid alkyl esters | |
| JPH08225749A (en) | Production of high-purity 3-hydroxy-n-benzimidazolon-5-yl-2-naphthamide necessary for azo pigment | |
| JP4303685B2 (en) | Method for producing 2-cyclopenten-1-one | |
| JP2582889B2 (en) | Production method of high-purity aminosulfenyl chloride | |
| JPS62111942A (en) | Production of 3,4,5,6-tetrafluorophthalic acid | |
| JPH06192170A (en) | Production of 4-bromomethylbiphenyl compound | |
| JP2000211905A (en) | Production of aqueous solution of free hydroxylamine | |
| JPS63174963A (en) | Production of 2-hydroxynaphthalene-6-carbonitrile compound | |
| JPH09227490A (en) | Production of 3-(or 4-)cyanobenzaldehyde | |
| JP4143295B2 (en) | Method for producing 9,9-disubstituted-2,3,6,7-xanthenetetracarboxylic dianhydride | |
| JPS63303947A (en) | Production of o-formylbenzoic acid | |
| JPH0788336B2 (en) | Process for producing 5-amino-2,4,6-triiodoisophthalic acid | |
| JPH09328458A (en) | Production of dl-aspartic acid | |
| JPS589044B2 (en) | Production method of hydroxylamine↓-O↓-sulfonic acid |