JPH0118063B2 - - Google Patents
Info
- Publication number
- JPH0118063B2 JPH0118063B2 JP58207840A JP20784083A JPH0118063B2 JP H0118063 B2 JPH0118063 B2 JP H0118063B2 JP 58207840 A JP58207840 A JP 58207840A JP 20784083 A JP20784083 A JP 20784083A JP H0118063 B2 JPH0118063 B2 JP H0118063B2
- Authority
- JP
- Japan
- Prior art keywords
- isobutylphenyl
- reaction
- acid
- patent publication
- japanese patent
- 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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 16
- KEAGRYYGYWZVPC-UHFFFAOYSA-N 1-[4-(2-methylpropyl)phenyl]ethanone Chemical compound CC(C)CC1=CC=C(C(C)=O)C=C1 KEAGRYYGYWZVPC-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000001569 carbon dioxide Substances 0.000 claims description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 8
- APEODKDQAWQDLW-UHFFFAOYSA-N 2-hydroxy-2-[4-(2-methylpropyl)phenyl]propanoic acid Chemical compound CC(C)CC1=CC=C(C(C)(O)C(O)=O)C=C1 APEODKDQAWQDLW-UHFFFAOYSA-N 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000007789 gas Substances 0.000 description 8
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 4
- 229910052753 mercury Inorganic materials 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 2
- -1 isobutylphenyl Chemical group 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000003115 supporting electrolyte Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 150000003549 thiazolines Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- OBJMWYAZGBFFNS-UHFFFAOYSA-N 2-anilinopropanenitrile Chemical compound N#CC(C)NC1=CC=CC=C1 OBJMWYAZGBFFNS-UHFFFAOYSA-N 0.000 description 1
- HUQRIMBWHODUKL-UHFFFAOYSA-N 2-methyl-2-[4-(2-methylpropyl)phenyl]oxirane Chemical compound C1=CC(CC(C)C)=CC=C1C1(C)OC1 HUQRIMBWHODUKL-UHFFFAOYSA-N 0.000 description 1
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006477 desulfuration reaction Methods 0.000 description 1
- 230000023556 desulfurization Effects 0.000 description 1
- GZRYBYIBLHMWCD-UHFFFAOYSA-N dimethyl(methylidene)-$l^{4}-sulfane Chemical compound CS(C)=C GZRYBYIBLHMWCD-UHFFFAOYSA-N 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000007772 electrode material Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000005911 haloform reaction Methods 0.000 description 1
- 150000001469 hydantoins Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005895 oxidative decarboxylation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009283 thermal hydrolysis Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-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
- Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)
- 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】
本発明はＰ―イソブチルアセトフエノンを出発
物質とする２―（Ｐ―イソブチルフエニル）プロ
ピオン酸の改良された製造方法に関するものであ
る。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an improved process for producing 2-(P-isobutylphenyl)propionic acid starting from P-isobutylacetophenone.
下記式で表わせる２―（Ｐ―イソブチルフエニ
ル）プロピオン酸は抗炎症、鎮痛、解熱特性を有
し、有用な医薬品として用いられることは既に知
られている。 It is already known that 2-(P-isobutylphenyl)propionic acid represented by the following formula has anti-inflammatory, analgesic, and antipyretic properties and is used as a useful pharmaceutical.
従来かかる化合物は出発原料としてイソブチル
ベンゼン、Ｐ―イソブチルアセトフエノン、Ｐ―
イソブチルハロベンゼン、Ｐ―イソブチルフエニ
ル酢酸などを用い、縮合反応、酸化反応、還元反
応、グリニヤール反応、水素化反応、加水分解反
応、異性化反応、アルキル化反応、脱水反応、シ
アノ化反応などの組合わせによつて合成されてき
た。 Conventionally, such compounds have been prepared using isobutylbenzene, P-isobutylacetophenone, P-
Condensation reactions, oxidation reactions, reduction reactions, Grignard reactions, hydrogenation reactions, hydrolysis reactions, isomerization reactions, alkylation reactions, dehydration reactions, cyanation reactions, etc. using isobutylhalobenzene, P-isobutylphenylacetic acid, etc. They have been synthesized through combinations.
代表的出発原料であるＰ―イソブチルアセトフ
エノンを用いる場合、よく知られた合成法として
は(1)チアゾリン誘導体と脱水縮合させ、生成する
５―〔１―（Ｐ―イソブチルフエニル）エチリデ
ン〕チアゾリン誘導体を加水分解、次に脱硫、酸
化的脱炭酸を経由して合成する方法（特公昭54−
22338）。(2)ホルムアルデヒドメルカプタール―Ｓ
―オキシドのリチオ塩を添加し、生成したリチオ
化合物のアセチル化、脱酢酸、加水分解による方
法（特公昭53−50137）。(3)第二級アミンを反応さ
せ生成したエナミンをトリクロロ酢酸と反応させ
た後、水素還元、加熱加水分解による方法（特公
昭52−111535）。(4)シアノ酢酸エステルを反応さ
せ生成する２―シアノ―３―メチル―３―（Ｐ―
イソブチルフエニル）アクリル酸エステルを酸
化、次いで加水分解、脱炭酸、加水分解、酸化を
行なう方法（特公昭52−118444）。 When using P-isobutylacetophenone, a typical starting material, a well-known synthesis method is (1) dehydration condensation with a thiazoline derivative to produce 5-[1-(P-isobutylphenyl)ethylidene] Method for synthesizing thiazoline derivatives via hydrolysis, desulfurization, and oxidative decarboxylation (Japanese Patent Publication No. 1983-
22338). (2) Formaldehyde mercaptal-S
- A method in which a lithio salt of an oxide is added and the resulting lithio compound is acetylated, deaceticated, and hydrolyzed (Japanese Patent Publication No. 53-50137). (3) A method in which an enamine produced by reacting a secondary amine is reacted with trichloroacetic acid, followed by hydrogen reduction and thermal hydrolysis (Japanese Patent Publication No. 52-111535). (4) 2-cyano-3-methyl-3-(P-
A method in which acrylic acid ester (isobutylphenyl) is oxidized, followed by hydrolysis, decarboxylation, hydrolysis, and oxidation (Japanese Patent Publication No. 118444/1983).
(5)アルミニウムイソプロピレートを反応させた
後、１―Ｐ―イソブチルフエニルエタノールを臭
素化、グリニヤール反応を経た後、アルデヒドを
オキシムとし脱アンモニアを経由する方法（特公
昭52−131553）。(6)ダルツエン縮合反応後、加水
分解、加熱脱炭酸を行ない、生成するアルデヒド
の酸化ないしはハロホルム反応を行なう方法（特
公昭49−108040，51−65730）。(7)ジアルキルメチ
ルスルホニウム塩を塩基のもとに反応させ、生成
する２―（Ｐ―イソブチルフエニル）―２―メチ
ルオキシランを酸処理した後、酸化を行なう方法
（特公昭53−18535）。(8)ジメチルスルホニウムメ
チリドを塩基存在下に反応させ、生成する２―
（Ｐ―イソブチルフエニル）―１，２―エポキシ
プロパンを転位、酸化する方法（特公昭51−
100040）。(9)アニリンとシアン化カリを反応させ
生成する２―（Ｐ―イソブチルフエニル）―２―
アニリノプロピオニトリルを酸化、加水分解、還
元する方法（特公昭52−139037，52−139038）。
(10)シアン化ナトリウムと塩酸を作用させ、生成物
を加水分解して２―（Ｐ―イソブチルフエニル）
―２―ヒドロキシプロピオン酸となし、これに水
素を作用させて加水素分解を行なう方法（特公昭
51−95035）。(11)シアン化カリウムと炭酸アンモン
を作用させヒダントイン誘導体とした後、加水分
解、還元的脱アミノ化を行なう方法（特公昭51−
65731）。(12)クロロホルムを相間移動触媒条件下に
反応させ、生成する２―（Ｐ―イソブチルフエニ
ル）アクリル酸を接触還元する方法（特公昭52−
111534，53−90237）。（13）(12)と同様な条件下に
２―（Ｐ―イソブチルフエニル）―２―ヒドロキ
シプロピオン酸を生成させ、これを水素化分解す
る方法（特公昭53−34744）。などが知られてい
る。しかしながらこれらの従来法で、方法(1)〜(6)
は反応工程が４〜６段と長く、これらを含めると
出発原料からの総収率は低く、またグリニヤール
試薬を始めとする特殊な試薬を用いたり、反応時
間が長かつたり、中間体の不安定性、特殊な装置
を必要とするなど工業的製法としては不利であ
る。方法(7)，(8)は塩基としてナトリウムハイドラ
イドやリチウムハイドライドなど高価であり取り
扱い上危険性のある薬品を必要とする欠点を有す
る。方法(9)〜(11)は青酸ソーダもしくは青酸カリと
塩酸を用いるため反応中に有毒な青酸ガスの副性
を伴い危険である。方法(12)，（13）は反応工程数
も２段と短く最も有用性のある方法であるが中間
体合成における反応条件ならびに収率の点で難点
がある。 (5) A method in which aluminum isopropylate is reacted, 1-P-isobutylphenylethanol is brominated, Grignard reaction is performed, and aldehyde is converted into oxime and deammonia is removed (Japanese Patent Publication No. 52-131553). (6) A method in which after the Dalzen condensation reaction, hydrolysis and thermal decarboxylation are performed, and the resulting aldehyde is subjected to oxidation or haloform reaction (Japanese Patent Publication No. 49-108040, 51-65730). (7) A method in which a dialkylmethylsulfonium salt is reacted in the presence of a base, the resulting 2-(P-isobutylphenyl)-2-methyloxirane is treated with an acid, and then oxidized (Japanese Patent Publication No. 53-18535). (8) 2- produced by reacting dimethylsulfonium methylide in the presence of a base
Method for rearranging and oxidizing (P-isobutylphenyl)-1,2-epoxypropane (Japanese Patent Publication No. 1983-
100040). (9) 2-(P-isobutylphenyl)-2- produced by reacting aniline with potassium cyanide
Method for oxidizing, hydrolyzing, and reducing anilinopropionitrile (Japanese Patent Publication No. 52-139037, 52-139038).
(10) Hydrolyze the product by reacting sodium cyanide with hydrochloric acid to produce 2-(P-isobutylphenyl)
-2-Hydroxypropionic acid and hydrogen decomposition method (Tokuko Sho)
51−95035). (11) A method in which potassium cyanide and ammonium carbonate are reacted to form a hydantoin derivative, followed by hydrolysis and reductive deamination (Japanese Patent Publication No. 1973-
65731). (12) A method of reacting chloroform under phase transfer catalytic conditions and catalytically reducing the produced 2-(P-isobutylphenyl)acrylic acid (Japanese Patent Publication No. 1983-
111534, 53-90237). (13) A method of producing 2-(P-isobutylphenyl)-2-hydroxypropionic acid under the same conditions as in (12) and hydrogenolyzing it (Japanese Patent Publication No. 53-34744). etc. are known. However, with these conventional methods, methods (1) to (6)
The reaction process is as long as 4 to 6 steps, and when these steps are included, the total yield from the starting material is low, and special reagents such as Grignard reagents are used, reaction times are long, and intermediates are unstable. It is disadvantageous as an industrial production method because it requires qualitative and special equipment. Methods (7) and (8) have the disadvantage that they require chemicals such as sodium hydride or lithium hydride, which are expensive and dangerous to handle, as bases. Methods (9) to (11) are dangerous because they use sodium cyanide or potassium cyanide and hydrochloric acid and produce toxic cyanide gas as a by-product during the reaction. Methods (12) and (13) have the shortest number of reaction steps (two steps) and are the most useful methods, but they have drawbacks in terms of reaction conditions and yield in intermediate synthesis.
本発明者らは上述の各種問題点を排除し操作の
簡便性、工程の簡略化、好収率をもつて工業的に
実施の容易な方法で２―（Ｐ―イソブチルフエニ
ル）プロピオン酸を製造するべく鋭意研究した結
果、本発明を確立した。 The present inventors have solved the above-mentioned problems and produced 2-(P-isobutylphenyl)propionic acid in an industrially easy-to-implement method with ease of operation, simplification of process, and high yield. As a result of intensive research into manufacturing, the present invention was established.
すなわち、本発明の方法は次の反応式で総括的
に表わすことができる。 That is, the method of the present invention can be comprehensively expressed by the following reaction formula.
化合物（）のＰ―イソブチルアセトフエノン
を炭酸ガス気流下または加圧下に電解還元し、得
られる生成物を酸処理した後、化合物（）の２
―（Ｐ―イソブチルフエニル）―２―ヒドロキシ
プロピオン酸を生成させ、次いでこれを水素化分
解して化合物（）の２―（Ｐ―イソブチルフエ
ニル）プロピオン酸を製造する方法に関するもの
である。 P-isobutylacetophenone of compound () is electrolytically reduced under a carbon dioxide gas stream or under pressure, and the resulting product is treated with acid.
The present invention relates to a method for producing 2-(P-isobutylphenyl)propionic acid of the compound () by producing -(P-isobutylphenyl)-2-hydroxypropionic acid and then hydrogenolyzing the same.
また、本発明の一部は上述工業的製法として欠
点を有する既知製造方法(3)，(10)に記載されるとこ
ろの化合物（）の２―Ｐ―イソブチルフエニ
ル）―２―ヒドロキシプロピオン酸の水素化分解
という反応工程を包含しているが、本願方法の特
徴は前段の反応、即ち化合物（）の２―（Ｐ―
イソブチルフエニル）―２―ヒドロキシプロピオ
ン酸の合成方法を提供するものである。 In addition, a part of the present invention relates to the production of 2-P-isobutylphenyl)-2-hydroxypropionic acid of the compound () described in the known production methods (3) and (10) which have drawbacks as the above-mentioned industrial production methods. However, the feature of the method of the present invention is that the reaction in the first stage is the reaction step of hydrogenolysis of compound ().
The present invention provides a method for synthesizing isobutylphenyl)-2-hydroxypropionic acid.
本発明の実施にあたつては、まず出発物質であ
るＰ―イソブチルアセトフエノンを電解還元しこ
れを炭酸ガスと反応させる。この反応は非プロト
ン性溶媒に支持電解質を溶解した溶液を正負電極
をそなえた隔膜付電解反応槽に等分し、さらに反
応槽のカソード側にＰ―イソブチルアセトフエノ
ンを溶解した後、これを炭酸ガスで飽和させ、室
温下に撹拌しながら炭酸ガス気流下または加圧下
に規定量の通電を行なう。 In carrying out the present invention, first, the starting material, P-isobutylacetophenone, is electrolytically reduced and reacted with carbon dioxide gas. In this reaction, a solution of a supporting electrolyte dissolved in an aprotic solvent is divided equally into an electrolytic reaction tank equipped with a diaphragm equipped with positive and negative electrodes, and then P-isobutylacetophenone is dissolved in the cathode side of the reaction tank. The mixture is saturated with carbon dioxide gas, and a specified amount of electricity is applied under a stream of carbon dioxide gas or under pressure while stirring at room temperature.
本発明の方法において使用される非プロトン溶
媒の例としてはジメチルホルムアミド、アセトニ
トリル、ジオキサンなどがあげられる。なかでも
ジメチルホルムアミドが好適である。 Examples of aprotic solvents used in the method of the invention include dimethylformamide, acetonitrile, dioxane, and the like. Among them, dimethylformamide is preferred.
支持電解質としてはアルカリ金属ないしは炭化
水素を四つ持つたR4N型の第四アンモニウムの
塩であれば任意のものを用いることができるが、
なかでも支持塩の対還元電位の強さならびに有機
溶媒に対する溶解性の点からテトラブチルアンモ
ニウムのヨウド塩が好ましい。この時支持塩の使
用量は槽電圧ならびに反応中間体の泳動能を低め
るため高濃度が好ましい。望ましくは化合物
（）に対して５〜10倍モルの量が好適である。 As the supporting electrolyte, any salt of R 4 N type quaternary ammonium having four alkali metals or hydrocarbons can be used.
Among these, tetrabutylammonium iodide salt is preferred from the viewpoint of the strength of the reduction potential of the supporting salt and its solubility in organic solvents. At this time, the amount of supporting salt used is preferably high in concentration since it lowers the cell voltage and the migration ability of the reaction intermediate. Desirably, the amount is 5 to 10 times the molar amount of compound (2).
電極材料としては導電性物質であればその種類
を問わないが、カソード側電極としては水銀ない
しは炭素電極を用いることができる。なかでも水
銀電極が反応収率を向上させる点から好適に用い
られる。 Any type of electrode material may be used as long as it is conductive, but mercury or carbon electrodes can be used as the cathode electrode. Among these, a mercury electrode is preferably used because it improves the reaction yield.
電解方法としては定電位法、定電流法が共に用
いられるが、反応時間を短縮できる点から定電流
法が好適である。 Both a constant potential method and a constant current method are used as the electrolytic method, and the constant current method is preferable because it can shorten the reaction time.
最適電流密度は用いる電極、溶媒の種類によつ
て影響をうけるが、通常電解反応は400mA／cm2
〜500mA／cm2の範囲の電流密度で実施される。
水銀電極を用いジメチルホルムアミド溶媒中での
電流密度は463mA／cm2が好適である。 The optimum current density is affected by the type of electrode and solvent used, but the usual electrolytic reaction is 400mA/cm 2
Performed at current densities in the range ~500 mA/ cm2 .
The current density in dimethylformamide solvent using a mercury electrode is preferably 463 mA/cm 2 .
通電量は上記反応式で示されるように理論量の
通電、2F／molで十分であり、それ以上の通電量
はむしろ反応収率を低下させる。 As shown in the above reaction formula, a stoichiometric amount of current, 2F/mol, is sufficient, and a larger amount of current will rather reduce the reaction yield.
反応温度は−10℃〜室温で行なわれるが好まし
くは０℃〜10℃である。 The reaction temperature is -10°C to room temperature, preferably 0°C to 10°C.
本発明で原料として用いられるＰ―イソブチル
アセトフエノンはイソブチルベンゼンのフリーデ
ルクラフツのアセチル化によつて容易に合成する
ことができ、工業的に入手容易な薬品であり、ま
た炭酸ガスは未利用資源であり安価なものであ
る。 P-isobutylacetophenone used as a raw material in the present invention can be easily synthesized by Friedel-Crafts acetylation of isobutylbenzene, and is an industrially easily available chemical, and carbon dioxide gas is unused. It is a resource and is cheap.
かくしてこの反応により、２―（Ｐ―イソブチ
ルフエニル）―２―ヒドロキシプロピオン酸が合
成される。 Through this reaction, 2-(P-isobutylphenyl)-2-hydroxypropionic acid is synthesized.
次に、この２―（Ｐ―イソブチルフエニル）―
２―ヒドロキシプロピオン酸は触媒の存在下に常
圧水素気流中あるいは水素加圧下に還元され２―
（Ｐ―イソブチルフエニル）プロピオン酸を生成
する。 Next, this 2-(P-isobutylphenyl)-
2-Hydroxypropionic acid is reduced to 2-hydroxypropionic acid in the presence of a catalyst in a hydrogen stream at normal pressure or under hydrogen pressure.
(P-isobutylphenyl)propionic acid is produced.
この反応は無溶媒下でも実施可能であるが、通
常溶媒として脂肪族第一アルコールを用い、触媒
としてはラネーニツケルないしはパラジウムカー
ボンを用い、反応温度は室温ないし200℃の範囲
で行なわれる。 Although this reaction can be carried out without a solvent, it is usually carried out using an aliphatic primary alcohol as the solvent, using Raney nickel or palladium carbon as the catalyst, and at a reaction temperature in the range of room temperature to 200°C.
以上述べたとおり、本発明の方法を採用するこ
とにより従来知られている２―（Ｐ―イソブチル
フエニル）プロピオン酸の製造方法に比較し反応
操作が極めて容易であり、工程数が少なく、安価
な原料を用い穏やかな反応条件下に高収率で製造
でき、工業的に有利な製造方法である。 As described above, by adopting the method of the present invention, the reaction operation is extremely easy, the number of steps is small, and the cost is low compared to the conventionally known method for producing 2-(P-isobutylphenyl)propionic acid. It is an industrially advantageous production method, as it can be produced in high yield using suitable raw materials and under mild reaction conditions.
以下に実施例を載げ、本発明をさらに詳細に説
明する。 EXAMPLES The present invention will be explained in further detail with reference to Examples below.
実施例 １
２―（Ｐ―イソブチルフエニル）―２―ヒドロ
キシプロピオン酸の製造。Example 1 Production of 2-(P-isobutylphenyl)-2-hydroxypropionic acid.
ヨウ化テトラブチルアンモニウム18.4ｇをジメ
チルホルムアミド100mlに溶解した溶液をガラス
フイルター隔膜を有する内容積200mlの内径3.3cm
のガラス製Ｈ型電解反応槽の白金板（２cm×２
cm）を付したアノード室と水銀５mlを満たしたカ
ソード室にそれぞれ等量ずつ入れ、カソード室側
溶液にＰ―イソブチルアセトフエノン0.9ｇを溶
解する。カソード室の溶液を炭酸ガスで飽和させ
た後、反応温度が０〜５℃で強力磁気撹拌機でカ
ソード室を撹拌しながら炭酸ガス気流下、
463mA／cm2の定電流で965クーロンの通電を行な
つて反応させた。反応後、カソード室側溶液の溶
媒を100℃で減圧留去し、得られた白色固体を水
30mlに溶かした後、酸性にすると油状物が析出す
るので、これをエーテルで抽出、水洗の後、硫酸
性マグネシウムで乾燥し、エーテルを留去すると
２―（Ｐ―イソブチルフエニル）―２―ヒドロキ
シプロピオン酸が0.94ｇが得られた。収率85％、
ｎ―ヘキサンから再結晶すると融点110〜111℃の
白色結晶が得られる。 A solution of 18.4 g of tetrabutylammonium iodide dissolved in 100 ml of dimethylformamide was prepared using a glass filter with an internal volume of 200 ml and an inner diameter of 3.3 cm.
Platinum plate (2 cm x 2
Pour equal amounts into the anode chamber marked with cm) and the cathode chamber filled with 5 ml of mercury, and dissolve 0.9 g of P-isobutylacetophenone in the cathode chamber solution. After the solution in the cathode chamber was saturated with carbon dioxide gas, the reaction temperature was 0 to 5°C, and the cathode chamber was stirred with a strong magnetic stirrer under a stream of carbon dioxide gas.
The reaction was carried out by applying a current of 965 coulombs at a constant current of 463 mA/cm 2 . After the reaction, the solvent in the cathode chamber solution was distilled off under reduced pressure at 100°C, and the resulting white solid was poured into water.
After dissolving it in 30 ml and making it acidic, an oily substance will precipitate, so this is extracted with ether, washed with water, dried over magnesium sulfate, and the ether is distilled off to give 2-(P-isobutylphenyl)-2- 0.94 g of hydroxypropionic acid was obtained. Yield 85%,
Recrystallization from n-hexane gives white crystals with a melting point of 110-111°C.
元素分析（C13H18O3として）
実測値：Ｃ 70.37；H8.14
理論値：Ｃ 70.24；H8.16
IR値（KBr）
3445cm-1（OH），1745cm-1（COOH）
NMR値（δ／ppm）
7.47（ｄ，2H，Ｊ＝８Hz），7.13（ｄ，2H，Ｊ
＝８Hz），6.7〜5.8（bs，2H），2.46（ｄ，2H，
Ｊ＝7.5Hz），1.8（Ｓ，3H），2.2〜1.5（ｍ，
1H），0.9（ｄ，6H，Ｊ＝６Hz）
実施例 ２
実施例１と同様にして溶媒をアセトニトリルに
変え20〜25℃の反応温度で電流密度469mA／cm2
定電流で965クーロンの通電を行なつた場合、２
―（Ｐ―イソブチルフエニル）―２―ヒドロキシ
プロピオン酸が0.76ｇ得られた。収率68％。 Elemental analysis (as C 13 H 18 O 3 ) Actual value: C 70.37; H8.14 Theoretical value: C 70.24; H8.16 IR value (KBr) 3445 cm -1 (OH), 1745 cm -1 (COOH) NMR value ( δ/ppm) 7.47 (d, 2H, J = 8Hz), 7.13 (d, 2H, J
=8Hz), 6.7-5.8 (bs, 2H), 2.46 (d, 2H,
J = 7.5Hz), 1.8 (S, 3H), 2.2~1.5 (m,
1H), 0.9 (d, 6H, J = 6Hz) Example 2 Same as Example 1, but changing the solvent to acetonitrile, the current density was 469 mA/cm 2 at a reaction temperature of 20 to 25°C.
When energizing 965 coulombs with constant current, 2
0.76 g of -(P-isobutylphenyl)-2-hydroxypropionic acid was obtained. Yield 68%.
実施例 ３
２―（Ｐ―イソブチルフエニル）プロピオン酸
の製造。Example 3 Production of 2-(P-isobutylphenyl)propionic acid.
実施例１および２で得た２―（Ｐ―イソブチル
フエニル）―２―ヒドロキシプロピオン酸2.2ｇ
をエタノール25mlに溶かした濃塩酸少量を含む溶
液と５％パラジウムカーボン0.2ｇを100ml容量の
ステンレス製オートクレーブに入れ、水素初圧30
Kg、50℃で５時間接触還元を行なつた。反応終了
後触媒を別して除き、残査をｎ―ヘキサン30ml
で再結晶すると無色針状晶の２―（Ｐ―イソブチ
ルフエニル）プロピオン酸が1.8ｇ得られる。収
率88％、融点74〜76℃。 2.2 g of 2-(P-isobutylphenyl)-2-hydroxypropionic acid obtained in Examples 1 and 2
A solution containing a small amount of concentrated hydrochloric acid dissolved in 25 ml of ethanol and 0.2 g of 5% palladium carbon were placed in a 100 ml stainless steel autoclave, and the initial pressure of hydrogen was 30.
Catalytic reduction was carried out at 50°C for 5 hours. After the reaction is complete, remove the catalyst separately and add 30ml of n-hexane to the residue.
Recrystallization from the solution yields 1.8 g of 2-(P-isobutylphenyl)propionic acid in the form of colorless needles. Yield 88%, melting point 74-76℃.
Claims (1)
し、炭酸ガスと反応させて２―（Ｐ―イソブチル
フエニル）―２―ヒドロキシプロピオン酸を生成
させ、これを水素化分解することを特徴とする２
―（Ｐ―イソブチルフエニル）プロピオン酸の製
造方法。1. P-isobutylacetophenone is electrolytically reduced and reacted with carbon dioxide gas to produce 2-(P-isobutylphenyl)-2-hydroxypropionic acid, which is then hydrogenolyzed 2
- A method for producing (P-isobutylphenyl)propionic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58207840A JPS60100536A (en) | 1983-11-04 | 1983-11-04 | Preparation of 2-(p-isobutylphenyl)propionic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58207840A JPS60100536A (en) | 1983-11-04 | 1983-11-04 | Preparation of 2-(p-isobutylphenyl)propionic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60100536A JPS60100536A (en) | 1985-06-04 |
| JPH0118063B2 true JPH0118063B2 (en) | 1989-04-03 |
Family
ID=16546389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58207840A Granted JPS60100536A (en) | 1983-11-04 | 1983-11-04 | Preparation of 2-(p-isobutylphenyl)propionic acid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60100536A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63162655A (en) * | 1986-12-25 | 1988-07-06 | Daicel Chem Ind Ltd | Separation of phenylpropionic acid isomer |
| DE4305696A1 (en) * | 1993-02-25 | 1994-09-01 | Hoechst Ag | Detection method for the identification of inhibitors |
| BRPI1007861A2 (en) | 2009-02-25 | 2016-11-29 | Council Scient Ind Res | process for the ecological preparation of 3,5-dibromo 4-hydroxybenzonitrile |
| DE102009035648B3 (en) * | 2009-07-29 | 2011-03-17 | Siemens Aktiengesellschaft | A process for the preparation of a radiolabeled carboxylate and the use of a microelectrode for the electrochemical synthesis of a radiolabeled carboxylate |
| CN113136593A (en) * | 2021-04-14 | 2021-07-20 | 赤峰学院 | Method for synthesizing ibuprofen |
-
1983
- 1983-11-04 JP JP58207840A patent/JPS60100536A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60100536A (en) | 1985-06-04 |
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