JPS5913489B2 - Method for producing α-alkyl-α-phenylacetic acid - Google Patents
Method for producing α-alkyl-α-phenylacetic acidInfo
- Publication number
- JPS5913489B2 JPS5913489B2 JP50060960A JP6096075A JPS5913489B2 JP S5913489 B2 JPS5913489 B2 JP S5913489B2 JP 50060960 A JP50060960 A JP 50060960A JP 6096075 A JP6096075 A JP 6096075A JP S5913489 B2 JPS5913489 B2 JP S5913489B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- formula
- benzene
- general formula
- phenylacetic 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.)
- Expired
Links
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)
Description
【発明の詳細な説明】 この発明(本発明という。[Detailed description of the invention] This invention (referred to as the present invention).
以下同じ)はα−アルキルーα−フェニル酢酸の新規な
製造法に関するものである。α−アルキルーα−フェニ
ル酢酸は優れた抗炎10症剤としてひろく用いられてお
り、その製造法としても特公昭40−7491号、特公
昭47一18105号等数種のものが提供されている。The same applies hereinafter) relates to a new method for producing α-alkyl-α-phenylacetic acid. α-Alkyl-α-phenylacetic acid is widely used as an excellent anti-inflammatory drug, and several methods for its production have been provided, including Japanese Patent Publication No. 7491/1983 and Japanese Patent Publication No. 471-18105. .
しかるにこれらの方法はいずれも多くの工程を必要とし
ている。即ちたとえば特公昭40−749115号はP
−イソブチルフェニル酢酸をいつたんマロン酸誘導体と
したのちメチル化、脱炭酸し、特公昭47−18105
号はP−イソブチルアセトフェノンをヒダントインに転
換したのちアミノ酸に換え、脱アミンにより目的物を得
ている。したが20つてこれらの方法はイソブチルベン
ゼンからの工程がながく、収率的にも問題がある。これ
らの課題を解決するためにいろいろと研究した結果、比
較的温和な条件で収率よくα−アルキルーα−フェニル
酢酸を得る方法を見出し、ここに本発明を25完成する
にいたつたのである。即ち本発明は、一般式〔I〕
R−CH=CH−NR1〔I〕
(式中Rは(1)□基で、ROはアルキ
ル(C2〜C6)、シクロアルキル(C3〜C7)、R
□35(2)□基で、R゜およびR゜は
同一でも異つてもよく水素、ハロゲン、アルキル基であ
る。However, all of these methods require many steps. For example, Special Publication No. 40-749115 is P
- Isobutylphenyl acetic acid is converted into a malonic acid derivative, then methylated and decarboxylated.
In No. 1, P-isobutylacetophenone is converted to hydantoin, then converted to amino acid, and the desired product is obtained by deamination. However, these methods require a long process from isobutylbenzene and have problems in terms of yield. As a result of various studies to solve these problems, they discovered a method for obtaining α-alkyl-α-phenylacetic acid in good yield under relatively mild conditions, and thus completed the present invention. That is, the present invention provides general formula [I] R-CH=CH-NR1[I] (wherein R is (1)□ group, and RO is alkyl (C2-C6), cycloalkyl (C3-C7), R
In the □35(2)□ group, R° and R° may be the same or different and are hydrogen, halogen, or an alkyl group.
wぱn−ブチル基、イソブチル基を示す。)で表わされ
るエナミン類と、一般式〔〕
R′X
〔〕
(式中R7は低級アルキルを示し、Xはヨード、ブロム
を示す。w indicates a n-butyl group or an isobutyl group. ) and the enamines represented by the general formula [] R'X [] (wherein R7 represents lower alkyl, and X represents iodo or bromine.
)で表わされるハロゲン化アルキルを反応させ、得られ
る一般式〔〕(式中R.R/、KU前記と同じ)
で表わされる生成物を加水分解し、しかる後これを酸化
することを特徴とするα−アルキル−α−フエニル酢酸
の製造法に係るものである。) is reacted with an alkyl halide, the resulting product represented by the general formula [] (in the formula R.R/, KU is the same as above) is hydrolyzed, and then this is oxidized. The present invention relates to a method for producing α-alkyl-α-phenylacetic acid.
本発明に使用する前記一般式〔1〕で表わされるエナミ
ン類は窒素気流中で、無溶媒あるいはベンゼン、トルエ
ン、キシレン、アセトニトリル、エーテル等の不活性溶
媒中、塩基たとえばアルカリ金属類またはアルカリ土類
金属類の炭酸塩または水酸化物あるいはアミンの存在下
にWNH(式中および以下の記載に係る式中R.R″、
KUすべて前記と同じである。The enamines represented by the general formula [1] used in the present invention are prepared in a nitrogen stream without a solvent or in an inert solvent such as benzene, toluene, xylene, acetonitrile, ether, etc. with a base such as an alkali metal or alkaline earth. In the presence of metal carbonates or hydroxides or amines, WNH (R.R'' in the formula and in the formulas described below,
All KUs are the same as above.
)とR−CH2CHOを反応させることにより収率よく
得ることができる。即ち塩基を含むR″′l!NHアミ
ン溶液を冷却、攪拌しながらR−CH2CHOを滴下し
、10数時間冷却しながら攪拌を行う。反応後反応液を
沢過し、沢液を分溜して一般式〔1〕のエナミンを高収
率で得ることができる。引続き得られた一般式〔1〕の
エナミン類とその2倍モルのアルキルハライドを不活性
ガス気流中無水のアセトニトリル、ベンゼンのような不
活性溶媒中で還流下に10〜20時間加熱する。反応後
酢酸一酢酸ナトリウム緩衝溶液を加えて4時間窒素気流
中で還流する。その後反応液を冷却しH2Oを加えてベ
ンゼンで抽出する。ベンゼン抽出層を採出し、塩酸水溶
液、飽和重曹水溶液、飽和食塩水で洗滌し、硫酸マグネ
シウムで脱水後ベンゼンを溜去して一般式〔〕の粗品を
得る。必要に応じ分溜することにより純品を得ることが
できる。得られた一般式〔〕のエナミンは酸性水溶液で
5時間還流し、冷却後反応液をベンゼンで抽出し、ベン
ゼン層を稀塩酸、飽和重曹水、飽和食塩水で洗滌した後
硫酸マグネCHOを得る。必要により分溜することによ
り精品をえることができるが、本発明の目的物を得るた
めには特に精製する必要はない。このアルデヒドはアル
デヒドを酸化する際に用いられる常法による酸化たとえ
ば過マンガン酸塩、過酸化物、硝酸、クロム酸、金属酸
化物などによる酸化によつて行われる。好適には酸化銀
、過マンガン酸カリで酸化することが望ましい。酸化銀
もしくは過マンガン酸カリを水またはアルコール水に加
え、このアルデヒドを数時間にわたつて滴下し、後反応
液を還流下に加熱する。反応後H2Oを加えて▲過し、
沢液を酸性にしたのちベンゼン、酢酸エチル、エーテル
等の溶媒で抽出し、常法により精製してα−アルキル−
α−フエニル酢酸を得る。なお本発明で使用するR−C
H2CHOはこれに対応するアルコールの酸化により、
またはR−CHOをハロ酢酸エステルと縮合を行わせグ
リシト蓋エステルとしこれを脱炭酸することにより、あ
るいはR−CH2COOHの還元により、その他、それ
ぞれ収率よく得ることができる。参考例
HN(CH2CH2CH2CH3)225.8f7(0
.2m01)のアミンとエーテル50m1(エーテルの
代りにベンゼン、トルエン、キシレン、無溶媒で実施可
)と無水K2CO328yを窒素気流中で攪拌、氷??
―醪U35.27(0.2m01)のアルデヒドを滴下
、1晩48.8yを得(収率85%)実施例 1
N(C4H9)2のエナミン5.74y(0.02m0
1)とCH3l5.687(0.04m01)をCH3
CN2Oml中、窒素気流中で還流しながら加熱し、反
応完結後CH3COONal7、酢酸2m1および10
m1f)H2Oを含む緩衝溶液を加え4時間窒素気流下
に還流する。) and R-CH2CHO in a good yield. That is, the R'''l!NH amine solution containing the base is cooled and R-CH2CHO is added dropwise while stirring, and the mixture is stirred while cooling for 10 hours. After the reaction, the reaction liquid is filtered and the liquid is fractionated. The enamines of the general formula [1] can be obtained in high yield.Subsequently, the obtained enamines of the general formula [1] and twice the mole of the alkyl halide are mixed in anhydrous acetonitrile and benzene in a stream of inert gas. Heat under reflux for 10 to 20 hours in an inert solvent such as acetic acid.After the reaction, add sodium acetic acid monoacetate buffer solution and reflux for 4 hours in a nitrogen stream.Then, the reaction solution is cooled, added with H2O, and extracted with benzene. The benzene extract layer is collected, washed with an aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution, dehydrated with magnesium sulfate, and then distilled off the benzene to obtain a crude product of the general formula [ ].If necessary, perform fractional distillation. The enamine of the general formula [] obtained was refluxed in an acidic aqueous solution for 5 hours, and after cooling, the reaction solution was extracted with benzene, and the benzene layer was extracted with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. After washing with water, obtain sulfuric acid magne CHO.If necessary, a refined product can be obtained by fractional distillation, but there is no particular need for purification in order to obtain the object of the present invention.This aldehyde is For example, oxidation with permanganate, peroxide, nitric acid, chromic acid, metal oxide, etc. is carried out by a conventional method used for oxidation. Oxidation with silver oxide or potassium permanganate is preferable Add silver oxide or potassium permanganate to water or alcoholic water, add the aldehyde dropwise over several hours, and then heat the reaction solution under reflux.After the reaction, add H2O and filter.
After making the solution acidic, it is extracted with a solvent such as benzene, ethyl acetate, or ether, and purified by a conventional method to obtain α-alkyl-
α-phenylacetic acid is obtained. Note that R-C used in the present invention
By oxidation of the corresponding alcohol, H2CHO is
Alternatively, R-CHO can be condensed with a haloacetate ester to form a glycite cap ester, which is then decarboxylated, or by reduction of R-CH2COOH, each of which can be obtained in good yield. Reference example HN (CH2CH2CH2CH3) 225.8f7 (0
.. 2 m01) of amine, 50 m1 of ether (benzene, toluene, xylene, no solvent can be used instead of ether) and anhydrous K2CO328y are stirred in a nitrogen stream, and iced? ?
- 35.27 (0.2 m01) of aldehyde was added dropwise overnight to obtain 48.8 y (yield 85%) Example 1 5.74 y (0.02 m0) of N(C4H9)2 enamine
1) and CH3l5.687 (0.04m01) to CH3
Heating under reflux in a nitrogen stream in Oml of CN2, and after completion of the reaction, CH3COONal7, acetic acid 2ml and 10
m1f) Add a buffer solution containing H2O and reflux under a nitrogen stream for 4 hours.
反応後H2Oでうすめベンゼン25m1で抽出する。ベ
ンゼン層はHcl、H2Ol飽和NaHCO3aq、飽
和Naclaqで洗滌し、NgSO4で乾燥しベンゼン
を溜去して、4.827を得る(収率80%)
次に
INHclaq45mlで5時間還流下に加熱する。After the reaction, extract with H2O and 25 ml of diluted benzene. The benzene layer is washed with HCl, H2Ol saturated NaHCO3aq, saturated Naclaq, dried over NgSO4 and the benzene is distilled off to give 4.827 (80% yield), which is then heated under reflux with 45 ml of INHclaq for 5 hours.
冷却した反応液をベンゼンで抽出しベンゼン層をDll
−Hcl.H2Ol飽和NaHCO3水溶液、飽和Na
cl水で洗滌し、NgSO4で脱水後ベンゼンを溜去し
て8yをエタノール100m1に溶解したものを、Ag
NO3l3.57をH2Ol5Omlに溶解しNaOH
6.57を加えて得た酸化銀に攪拌加入し、これを4時
間加熱還流後エタノールを溜去し11の熱水を加え反応
液を沢過しf液を冷却してCOnc−Hcl(′PH3
としベンゼンで抽出、抽出液を稀アルカリ水溶液で抽出
し、Dil−Hclで酸性にしエーテルで抽出のちエー
テルを除き残渣77を得た(収率80%)
M.P75〜77℃、元素分析、理論値C75.7%
H8.7%、測定値C75.5% H8.9%、標準品
と混融しても融点降下を示さない。The cooled reaction solution was extracted with benzene, and the benzene layer was extracted with Dll.
-Hcl. H2Ol saturated NaHCO3 aqueous solution, saturated Na
After washing with Cl water and dehydrating with NgSO4, benzene was distilled off, and 8y was dissolved in 100 ml of ethanol.
Dissolve 3.57 ml of NO3 in 50 ml of H2Ol and add NaOH
The silver oxide obtained by adding 6.57 was stirred and heated under reflux for 4 hours, the ethanol was distilled off, the hot water of step 11 was added, the reaction solution was filtered, the f solution was cooled, and COnc-Hcl (' PH3
The extract was extracted with benzene, the extract was extracted with a dilute aqueous alkaline solution, acidified with Dil-Hcl, extracted with ether, and the ether was removed to obtain residue 77 (yield 80%). P75-77℃, elemental analysis, theoretical value C75.7%
H8.7%, measured value C75.5% H8.9%, shows no drop in melting point even when mixed with standard product.
実施例 2(1)原料の調製
HN(C4H9)225.8t(0.2モル)、エーテ
ル50m1および無水のK2CO328tをN2CH2
CHO4Of7(0.2モル)のアルデヒドをベンゼン
に溶解して滴下一晩攪拌後、沢過、沢N(C4H,)2
のエナミン粗成品を得る。Example 2 (1) Preparation of raw materials 225.8 t (0.2 mol) of HN (C4H9), 50 ml of ether and 328 t of anhydrous K2CO were mixed with N2CH2
CHO4Of7 (0.2 mol) aldehyde was dissolved in benzene and added dropwise. After stirring overnight, Sawafila, SawaN(C4H,)2
A crude enamine product is obtained.
53.17
(2)メチル化
のエナミン5.74t(0.02モル)とCH3l5.
68t(0.04モル)をCH3CN2Oml中、N2
気流中で還流加熱する。53.17 (2) Methylated enamine 5.74t (0.02 mol) and CH3l5.
68t (0.04 mol) in CH3CN2Oml, N2
Heat to reflux in a stream of air.
これをCH3COONalyl醋酸2m1およびH2O
lOmlを含む緩衝溶液を加え、4時間N2気流下に還
流する。Add this to 2 ml of CH3COONalyl acetic acid and H2O
Add 10 ml of buffer solution and reflux under N2 for 4 hours.
反応後は実施例1同様に処理して《 ゝX4?=CH−
N(C4H,)2の粗成品5.27tを得る。After the reaction, the same procedure as in Example 1 was carried out and the reaction was carried out in the same manner as in Example 1. =CH-
5.27 tons of crude product of N(C4H,)2 is obtained.
(3)加水分解
6.427(0.02モル)をINHClaq45ml
で5時間還流下に加熱する。(3) Hydrolyze 6.427 (0.02 mol) with 45 ml of INHClaq
Heat under reflux for 5 hours.
冷却以下実施例1同様に処理して〈CHOの粗成品4.
077を得る。After cooling, the same treatment as in Example 1 was carried out to obtain CHO crude product 4.
Get 077.
(4)酸化
《 》一さH−CHO8.47をエ
タノール100m1に溶解したものをAgNO3l3.
57をH2Ol5Omlに溶解し、NaOH6.5tを
加えて得た酸化銀に攪拌加入し、これを4時間80℃に
加熱還流後エタノールを溜去し、11の熱水を加えて反
応液をf過し(銀の結晶を沢過)、沢液を冷却してCO
ncHClでPH3としベンゼンで抽出、抽出液を稀ア
ルカリ水溶液(10%NaOH)で抽出しDil.HC
lで酸性にし、エーテルで抽出後、エーテルを除き、n
−ヘキサンから再結晶して目的物“(収率
83%)の成品を得た。(4) Oxidation 8.47 H-CHO dissolved in 100 ml of ethanol was mixed with 3 liters of AgNO.
57 was dissolved in 50ml of H2Ol and 6.5t of NaOH was added to the obtained silver oxide, which was then stirred and heated to 80°C for 4 hours under reflux, the ethanol was distilled off, hot water from 11 was added, and the reaction solution was filtered through f-filtration. (pass through the silver crystals), cool the slurry and remove CO.
The pH was adjusted to 3 with ncHCl, extracted with benzene, and the extract was extracted with a dilute alkaline aqueous solution (10% NaOH). H.C.
After acidifying with l and extracting with ether, remove the ether and add n
- The desired product was obtained by recrystallization from hexane (yield: 83%).
その理化学的性質は次のとおりである。Its physical and chemical properties are as follows.
元素分析:計算値 C79.64% H6.l9%実測
値 C8O.l7% H6.73%赤外部吸収スペクト
ル:3100〜2850、3000〜2500、170
011380、(Crn−1)M.P:121〜123
℃
性状:白色の微結晶粉末、わずかに刺戟臭および刺戟昧
がある。Elemental analysis: Calculated value C79.64% H6. l9% actual value C8O. l7% H6.73% infrared absorption spectrum: 3100-2850, 3000-2500, 170
011380, (Crn-1)M. P:121-123
°C Properties: White microcrystalline powder, with a slight pungent odor and pungent odor.
Claims (1)
R^[3]はアルキル(C_2〜C_6)、▲数式、化
学式、表等があります▼基で、R^[4]およびR^[
5]は同一でも異つてもよく、水素、ハロゲン、アルキ
ル基である。 R″はn−ブチル基、イソブチル基を示す。)で表わさ
れるエナミン類と、一般式〔II〕R′X〔II〕 (式中R′は低級アルキル基を示す。 Xはヨード、ブロムを示す。)で表わされるハロゲン化
アルキルを反応させ、得られる一般式〔III〕▲数式、
化学式、表等があります▼〔III〕(式中R、R′、R
″は前記と同じ) で表わされる生成物を加水分解し、しかるのちこれを酸
化することを特徴とするα−アルキル−α−フェニル酢
酸の製造法。[Claims] 1 General formula [I] R-CH=CH-NR″_2 [I] (In the formula, R is (1)▲A mathematical formula, a chemical formula, a table, etc.▼,
R^[3] is alkyl (C_2 to C_6), ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ group, and R^[4] and R^[
5] may be the same or different, and are hydrogen, halogen, or an alkyl group. R'' represents n-butyl group or isobutyl group) and general formula [II] R'X [II] (where R' represents a lower alkyl group. The general formula [III] ▲ formula obtained by reacting the alkyl halide represented by
There are chemical formulas, tables, etc. ▼ [III] (In the formula, R, R', R
A method for producing α-alkyl-α-phenylacetic acid, the method comprising: hydrolyzing a product represented by the formula (“ is the same as above) and then oxidizing it.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50060960A JPS5913489B2 (en) | 1975-05-23 | 1975-05-23 | Method for producing α-alkyl-α-phenylacetic acid |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP50060960A JPS5913489B2 (en) | 1975-05-23 | 1975-05-23 | Method for producing α-alkyl-α-phenylacetic acid |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS51136645A JPS51136645A (en) | 1976-11-26 |
JPS5913489B2 true JPS5913489B2 (en) | 1984-03-30 |
Family
ID=13157469
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP50060960A Expired JPS5913489B2 (en) | 1975-05-23 | 1975-05-23 | Method for producing α-alkyl-α-phenylacetic acid |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS5913489B2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62179984U (en) * | 1986-05-02 | 1987-11-14 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1431278A4 (en) * | 2001-09-28 | 2006-01-25 | Ihara Chemical Ind Co | Process for producing (2-nitrophenyl)acetonitrile derivative and intermediate therefor |
-
1975
- 1975-05-23 JP JP50060960A patent/JPS5913489B2/en not_active Expired
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62179984U (en) * | 1986-05-02 | 1987-11-14 |
Also Published As
Publication number | Publication date |
---|---|
JPS51136645A (en) | 1976-11-26 |
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