JPH0248547A - Production of 4-acetyloxy-1-(2-substituted ethoxy)benzene - Google Patents
Production of 4-acetyloxy-1-(2-substituted ethoxy)benzeneInfo
- Publication number
- JPH0248547A JPH0248547A JP19720088A JP19720088A JPH0248547A JP H0248547 A JPH0248547 A JP H0248547A JP 19720088 A JP19720088 A JP 19720088A JP 19720088 A JP19720088 A JP 19720088A JP H0248547 A JPH0248547 A JP H0248547A
- Authority
- JP
- Japan
- Prior art keywords
- ketene
- group
- formula
- benzene
- hydroxy
- 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
- -1 4-acetyloxy-1-(2-substituted ethoxy)benzene Chemical class 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- 239000011541 reaction mixture Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002904 solvent Substances 0.000 abstract description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 abstract description 5
- 150000002430 hydrocarbons Chemical group 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 abstract description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract description 2
- 239000005977 Ethylene Substances 0.000 abstract description 2
- 239000002220 antihypertensive agent Substances 0.000 abstract description 2
- 229940030600 antihypertensive agent Drugs 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 239000000810 peripheral vasodilating agent Substances 0.000 abstract description 2
- 229960002116 peripheral vasodilator Drugs 0.000 abstract description 2
- 238000000197 pyrolysis Methods 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 150000001555 benzenes Chemical class 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-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
- 239000012345 acetylating agent Substances 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- RECUKUPTGUEGMW-UHFFFAOYSA-N carvacrol Chemical compound CC(C)C1=CC=C(C)C(O)=C1 RECUKUPTGUEGMW-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000001302 tertiary amino group Chemical group 0.000 description 2
- 238000005979 thermal decomposition reaction Methods 0.000 description 2
- SMRXWRRCRTYVKL-UHFFFAOYSA-N 2-methyl-5-propan-2-ylphenol hydrochloride Chemical compound Cl.CC(C)C1=CC=C(C)C(O)=C1 SMRXWRRCRTYVKL-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 239000004129 EU approved improving agent Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000000397 acetylating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- HHTWOMMSBMNRKP-UHFFFAOYSA-N carvacrol Natural products CC(=C)C1=CC=C(C)C(O)=C1 HHTWOMMSBMNRKP-UHFFFAOYSA-N 0.000 description 1
- 235000007746 carvacrol Nutrition 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940117927 ethylene oxide Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- WYXXLXHHWYNKJF-UHFFFAOYSA-N isocarvacrol Natural products CC(C)C1=CC=C(O)C(C)=C1 WYXXLXHHWYNKJF-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
〔発明の目的］
（産業上の利用分野）
本発明は、４−アセチルオキシ−１−（２−置換エトキ
シ）ベンゼン類の製造方法に関するものである。Detailed Description of the Invention [Object of the Invention] (Industrial Application Field) The present invention relates to a method for producing 4-acetyloxy-1-(2-substituted ethoxy)benzenes.
（従来の技術及びその問題点）
次式（Ａ）：
で示される置換アミノエトキシカルバクロール誘導体は
、末梢血管拡張剤、血圧降下剤、脳循環代謝改善剤、抗
喘息剤として有用であり、例えば、Ｒ５−１？ｉ＝Ｈ，
Ｒｔ＝アラルキル基の構造を有する４（Ｎ−モノアラル
キルアミノエトキシ）カルバクロールが特開昭５６−１
００７４５号公報に開示されている。また、Ｉ？、＝ア
セチル基、Ｒｈ ＝ Ｒ？ ＝メチル基の構造を有する
モキシシリトの塩酸塩は、循環器系用医薬品として有用
な化合物として知られている。(Prior art and its problems) Substituted aminoethoxycarvacrol derivatives represented by the following formula (A) are useful as peripheral vasodilators, antihypertensive agents, cerebral circulation and metabolism improving agents, and anti-asthmatic agents, such as , R5-1? i=H,
4(N-monoaralkylaminoethoxy)carvacrol having a structure of Rt=aralkyl group is disclosed in JP-A-56-1
It is disclosed in Japanese Patent No. 00745. Also, I? , = acetyl group, Rh = R? Moxisilito hydrochloride having a =methyl group structure is known as a compound useful as a pharmaceutical for the cardiovascular system.
これらの医薬品の製法においては、化学式（ｎ）で示さ
れる４−ヒドロキシ−１−（２−置換エトキシ）ベンゼ
ン類をアセチル化する工程が重要となる場合がある。特
に、上記モキシシリトの塩酸塩の場合、このアセチル化
が最終工程となるため生成物の純度に多大な影響を与え
る。In the manufacturing method of these pharmaceuticals, the step of acetylating 4-hydroxy-1-(2-substituted ethoxy)benzenes represented by chemical formula (n) may be important. In particular, in the case of the above-mentioned moxisilite hydrochloride, this acetylation is the final step and has a great effect on the purity of the product.
現在までに様々な方法が提示されているが、大別すると
２種の方法に分けられる。Various methods have been proposed up to now, but they can be roughly divided into two types.
１つは、アセチル化剤と塩基を用いる方法で、無水酢酸
とピリジンもしくはキノリンを用いる方法が、特開昭４
９−４５０２９号公報に開示されている。この方法では
、塩基であるピリジンやキノリン及び、それらの酢酸塩
が生成物に混入し、精製操作が煩雑となり工業的な製法
としては不利である。One is a method using an acetylating agent and a base, and a method using acetic anhydride and pyridine or quinoline was disclosed in Japanese Patent Application Laid-open No. 4
It is disclosed in Japanese Patent No. 9-45029. In this method, bases such as pyridine, quinoline, and their acetate salts are mixed into the product, and the purification operation is complicated, which is disadvantageous as an industrial production method.
いま１つは、アセチル化剤を単独で用いる方法で、無水
酢酸を用いる方法が開示されている。しかし、何れもア
セチル化の進行に伴って酸が副生じ生成物を汚染するた
め、やはり精製操作が煩雑となっていた。Another method uses an acetylating agent alone, and a method using acetic anhydride has been disclosed. However, as the acetylation progresses, acid contaminates the by-products, making the purification operation complicated.
特に、塩化アセチルを用いる際には出発原料（化学構造
式（ＩＩ））の塩酸塩が析出し易く、生成物の分離・精
製をさらに煩雑なものとしていた。In particular, when acetyl chloride is used, the hydrochloride of the starting material (chemical structural formula (II)) tends to precipitate, making separation and purification of the product even more complicated.
この原料（Ｕ）の塩酸塩の副生をおさえるためには大量
の溶媒を必要とし、工業的に不利な方法となっている。In order to suppress the by-product of the hydrochloride of the raw material (U), a large amount of solvent is required, making this method industrially disadvantageous.
また、これらのアシル化剤は容易に加水分解をうけるた
め、原料及び溶媒は充分に脱水されたものを用いるか、
加水分解を見込んで過剰のアシル化剤を用いる等の操作
が必要なっていた。さらに、塩基を使わずにアシル化す
る際には、通常、加熱により、反応を加速することが必
要で、反応系が汚れ易い等の欠点があった。In addition, since these acylating agents are easily hydrolyzed, the raw materials and solvent must be sufficiently dehydrated or
In anticipation of hydrolysis, operations such as using an excess of acylating agent were required. Furthermore, when performing acylation without using a base, it is usually necessary to accelerate the reaction by heating, which has the disadvantage that the reaction system is easily contaminated.
本発明者等は、前記の種々の問題を解決するべく研究を
重ねた結果、原料として次式（ＩＩ）：（式中Ｒ１、Ｒ
２及びＲ３は水素原子又は炭化水素基を表し、Ｘは、反
応混合物に対し不活性な官能基を示す。）で示される４
−ヒドロキシ−１−（２−置換エトキシ）ベンゼン類を
ケテンと反応させることにより、ヒドロキシ基からアシ
ルオキシＷへの変換を簡便かつ好収率で行うことができ
ることを見出し、本発明を完成するに至った。As a result of repeated research in order to solve the various problems mentioned above, the present inventors have found that the following formula (II): (wherein R1, R
2 and R3 represent a hydrogen atom or a hydrocarbon group, and X represents a functional group inert to the reaction mixture. ) indicated by 4
The present inventors have discovered that by reacting -hydroxy-1-(2-substituted ethoxy)benzenes with ketene, a hydroxy group can be easily converted to acyloxy W in a good yield, and the present invention has been completed. Ta.
〔発明の構成］
（問題点を解決するための手段）
すなわち、本発明は、次式（ＩＩ）：
（式中Ｒ１％ Ｒ２及びＲ１は水素原子又は炭化水素基
を表し、Ｘは、反応混合物に対し不活性な官能基を示す
。）で示される４−ヒドロキシ−１−（２−置換エト片
シ）ベンゼン類をケテンで処理することを特徴とする
次式（１）：
（式中、Ｒ１、Ｒ２、Ｒ３及びＸは、前記と同義である
。[Structure of the Invention] (Means for Solving the Problems) That is, the present invention provides the following formula (II): (wherein R1% R2 and R1 represent a hydrogen atom or a hydrocarbon group, and X represents a reaction mixture The following formula (1) is characterized by treating 4-hydroxy-1-(2-substituted ethyl)benzenes represented by (representing a functional group inert to) with ketene: (in the formula, R1, R2, R3 and X have the same meanings as above.
）で示される４−アセチルオキシ−１−（２−置換エト
キシ）−・ンゼン頚の製造方法を提供するものである。) Provides a method for producing 4-acetyloxy-1-(2-substituted ethoxy)-.
前記式（＋）及び（ＩＩ）において、Ｒ１、Ｒ２及びＲ
３で表される炭化水素基としては、アルキル基もしくは
アリール基が挙げられる。このアルキル基は、通常、炭
素数１〜１０、好ましくは炭素数１〜６のアルキル基で
あり、例えばメチル基、エチル基、プロピル基、イソプ
ロピル基、ブチル基、イソブチル基、５ｅｃ−ブチル基
、ｔｅｒ ｔ−ブチル基、ペンチル基、イソペンチル基
、ネオペンチル基、ヘキシル基、イソヘキシル基、ネオ
ヘキシル基等が挙げられる。In the formulas (+) and (II), R1, R2 and R
Examples of the hydrocarbon group represented by 3 include an alkyl group and an aryl group. This alkyl group is usually an alkyl group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec-butyl group, Examples include tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group, neohexyl group, and the like.
同様に、アリール基としては、例えばフェニル基、トリ
ル基、クメニル基、キシリル基、メシチル基、ベンジル
基等が挙げられる。Similarly, examples of the aryl group include phenyl group, tolyl group, cumenyl group, xylyl group, mesityl group, benzyl group, and the like.
前記アルキル基及びアリール基は、適当な置換基で置換
されていてもよい。ここで、適当な置換基とは本発明の
製造方法における反応条件下において安定な置換基をい
い、例えばハロゲン原子、アルコキシ基、アルキル基、
ニトロ基等が挙げられる。The alkyl group and aryl group may be substituted with a suitable substituent. Here, an appropriate substituent refers to a substituent that is stable under the reaction conditions in the production method of the present invention, such as a halogen atom, an alkoxy group, an alkyl group,
Examples include nitro group.
前記式（１）及び（ＩＩ）においてＸで表される官能基
としては、ハロゲン原子、３級アミノ基、適当な酸と塩
を形成している３級アミノ基、アルキルスルホニルオキ
シ基、アリールスルホニルオキシ基等が挙げられる。The functional group represented by X in the above formulas (1) and (II) includes a halogen atom, a tertiary amino group, a tertiary amino group forming a salt with an appropriate acid, an alkylsulfonyloxy group, and an arylsulfonyl group. Examples include oxy group.
前記式（１）で示される４−アセチルオキシ−１（２−
置換エトキシ）ベンゼン類は、前記式（ＩＩ）で示され
る４−ヒドロキシ−１−（２，置換エトキシ）ベンゼン
類をケテンで処理することにより製造することができる
。4-acetyloxy-1(2-
Substituted ethoxy)benzenes can be produced by treating 4-hydroxy-1-(2, substituted ethoxy)benzenes represented by formula (II) with ketene.
ここで、用いるケテンは、通常の方法により、アセトン
の熱分解により発生させたものであり、不純物としてエ
チレンや一酸化炭素が含まれていても構わない。ジケテ
ンを熱分解して発生させると、さらに高純度ケテンを得
ることができ、より好ましく用いることができる。発生
させたケテンをそのまま用いても、−度トラップに集め
てもちいても構わない。また、不活性気体で希釈して用
いても何らさしつかえない。The ketene used here is generated by thermal decomposition of acetone by a normal method, and may contain ethylene and carbon monoxide as impurities. When diketene is generated by thermal decomposition, even higher purity ketene can be obtained and can be used more preferably. The generated ketene may be used as it is or collected in a -degree trap. Moreover, there is no problem even if it is used diluted with an inert gas.
用いる溶媒は、原料（Ｉ［）を溶解するものであれば、
いかなるものでもよく、例えばクロロホルム、塩化メチ
レン、ベンゼン、トルエン、酢酸エチル、アセトン、エ
ーテル、イソプロピルエーテル、ジメチルホルムアミド
、ジメチルスルホギシド等が挙げられ、特に塩化メチレ
ン、イソプロピルエーテル、ジメチルホルムアミド等が
好ましい。The solvent used is one that dissolves the raw material (I[),
Any solvent may be used, and examples thereof include chloroform, methylene chloride, benzene, toluene, ethyl acetate, acetone, ether, isopropyl ether, dimethylformamide, dimethyl sulfoside, etc., and methylene chloride, isopropyl ether, dimethylformamide, etc. are particularly preferred.
反応温度は、通常−３０〜１００°Ｃ１好ましくは０〜
６０°Ｃである。The reaction temperature is usually -30 to 100°C, preferably 0 to 100°C.
It is 60°C.
ケテンの使用量は、上記（ＩＩ）に対し、等量販上あれ
ばよく、好ましくは１．２〜１０倍等量である。The amount of ketene used may be an equivalent amount, preferably 1.2 to 10 times the amount of (II) above.
過剰のケテンは副反応を起こすことなく、系外に放出さ
れる。Excess ketene is released from the system without causing any side reactions.
さらに反応は触媒存在下、もしくは無触媒で進行し、触
媒としては、硫酸、塩酸もしくはベンゼンスルホン酸、
ｐ−トルエンスルホン酸及ヒこれらの水和物が挙げられ
、好ましくは硫酸、ｐ−トルエンスルホン酸が挙げられ
る。Furthermore, the reaction proceeds in the presence of a catalyst or without a catalyst, and the catalysts include sulfuric acid, hydrochloric acid, benzenesulfonic acid,
Examples include p-toluenesulfonic acid and hydrates thereof, preferably sulfuric acid and p-toluenesulfonic acid.
触媒の使用量は、４−ヒドロキシ−１−（２−置換エト
キシ）−、ンゼン類（Ｉ［）に対し、通常０．００１〜
１重景％好ましくは０．０１〜０．５重量％である。The amount of the catalyst used is usually 0.001 to 4-hydroxy-1-(2-substituted ethoxy)-, based on the benzenes (I[).
1% by weight, preferably 0.01 to 0.5% by weight.
反応の進行は、反応溶媒の一部をガスクロマトグラフィ
ーにより分析することにより追跡することができる。原
料（ＩＩ）が消費された時点でケテンの導入を終了し、
溶媒を留去すると粗４−アセチルオキシ−１−（２−置
換エトキシ）ベンゼン類（旧が得られる。必要に応じて
カラムクロマトグラフィー、再結晶、蒸留の方法を用い
て精製する。The progress of the reaction can be monitored by analyzing a portion of the reaction solvent by gas chromatography. The introduction of ketene is terminated when the raw material (II) is consumed,
When the solvent is distilled off, crude 4-acetyloxy-1-(2-substituted ethoxy)benzenes (old) are obtained. Purification is performed using column chromatography, recrystallization, and distillation as necessary.
（発明の実施例）
以下、実施例により本発明を更に詳細に説明するが、以
下の実施例は本発明の範囲を何ら制限するものではない
。(Examples of the Invention) Hereinafter, the present invention will be explained in more detail with reference to Examples, but the following Examples do not limit the scope of the present invention in any way.
実施例１゜
４−〔アセチルオキシ−１−（２−置換エトキシ）−、
ンゼン類（１）の合成
原料の４− （２−（ジメチルアミノ）エトキシツー２
メチル−５−（１−メチルエチル）−フェノール（式（
％式％
メチルアミノ３）２．３７ｇ、（１０ミリモル）をイソ
プロピルエーテル５０緘中に溶解し、２５°Ｃでケテン
と窒素の混合気体をケテンが０．８２ ミリモル、７分
の割合になるように１００分間吹き込む。Example 1゜4-[acetyloxy-1-(2-substituted ethoxy)-,
4-(2-(dimethylamino)ethoxy2), a raw material for the synthesis of enzymes (1)
Methyl-5-(1-methylethyl)-phenol (formula (
% Formula % Methylamino 3) 2.37 g (10 mmol) was dissolved in 50 ml of isopropyl ether, and mixed gas of ketene and nitrogen was added at 25°C so that the ratio of ketene was 0.82 mmol and 7 minutes. Blow in for 100 minutes.
ガスクロマトグラフィーにより反応が完結していること
を確認した後、溶媒を留去して、定量的に粗モキシシリ
トを得た。After confirming the completion of the reaction by gas chromatography, the solvent was distilled off to quantitatively obtain crude moxysilite.
未反応物としては、原料の４− （２−（ジメチルアミ
ノ）エトキシ〕−２−メチル−５−（１−メチルエチル
）−フェノールが、副性物としてはジケテンが生成する
が、その量は極めてわずかである。The raw material 4-(2-(dimethylamino)ethoxy]-2-methyl-5-(1-methylethyl)-phenol is produced as an unreacted product, and diketene is produced as a by-product, but the amount is Very little.
次に、１．２Ｎ塩酸水溶液１０ｍ１と、エタノール２０
ｍ１を加え塩酸塩とした後、溶媒を留去し、アセトニト
リル１０ｄより再結晶を行い、塩酸モキンシリトの白色
結晶２．０２ｇを得た。母液を濃縮し、アセトニトリル
で再び再結晶を行い上記化合物の結晶０．９６ｇを得た
。 合計２．９８ｇ（収率９４．３％）このようにして
得られた化合物は、標準試料との赤外吸収スペクトルの
比較によって化学構造を確認した。Next, add 10 ml of 1.2N hydrochloric acid aqueous solution and 20 ml of ethanol.
After adding m1 to form a hydrochloride, the solvent was distilled off and recrystallization was performed from 10 d of acetonitrile to obtain 2.02 g of white crystals of mokinsilito hydrochloride. The mother liquor was concentrated and recrystallized again with acetonitrile to obtain 0.96 g of crystals of the above compound. A total of 2.98 g (yield: 94.3%) The chemical structure of the thus obtained compound was confirmed by comparing its infrared absorption spectrum with a standard sample.
赤外吸収スペクトル（ｃｍ−’）
２９６９、２８６０．２８１０．２７６０．１７５０
（カルボニル基）１２１０（−０−） 、 １１７０（
−０−） 、 １０５０．１０１０．９１０実施例２゜
４−アセチル−１−（２−置換エトキシ）ベンゼン類（
Ｉ）の合成
原料の４− （２−（ジメチルアミノ）エトキシ］−２
メチル−５−（１−メチルエチル）−フェノール塩酸塩
（式（ＩＩ）；Ｒ＋＝メチル、Ｒ２＝イソプロピル、Ｒ
３＝Ｈ，Ｘ＝ニジメチルアミノ酸塩）２．７４ｇ（１０
ミリモル）をジメチルホルムアミド１２ｍ１中に溶解し
、２５°Ｃでケテンが０．８２ミリモル／分の割合にな
るように１２０分間吹き込む。生成した固体にイソプロ
ピルエーテル４０ｍ！で洗浄し、真空下で乾燥すると目
的物が３．１６ｇ（粗収率６２．０％）を得た。Infrared absorption spectrum (cm-') 2969, 2860.2810.2760.1750
(Carbonyl group) 1210(-0-), 1170(
-0-), 1050.1010.910 Example 2゜4-acetyl-1-(2-substituted ethoxy)benzenes (
4-(2-(dimethylamino)ethoxy)-2, a raw material for synthesis of I)
Methyl-5-(1-methylethyl)-phenol hydrochloride (formula (II); R+=methyl, R2=isopropyl, R
3=H, X=nidimethyl amino acid salt) 2.74 g (10
mmol) in 12 ml of dimethylformamide and bubbled in at 25° C. for 120 minutes at a rate of 0.82 mmol/min of ketene. 40m of isopropyl ether in the generated solid! The product was washed with water and dried under vacuum to obtain 3.16 g (crude yield: 62.0%) of the desired product.
このようにして得られた化合物は、標準試料との赤外吸
収スペクトルとの比較によって化学構造を確認した。The chemical structure of the compound thus obtained was confirmed by comparing its infrared absorption spectrum with that of a standard sample.
赤外吸収スペクトル（ｃｌｌ−’）
３４００．２９５０，２５５０，２４３０．１７５０（
カルボニル基）１２５０（−０−）、１１７０（−０−
）、９２０〔発明の効果〕
本発明によれば、４−アセチルオキシ−１−（２−置換
エトキシ）ベンゼン類をケテンを用いることにより簡便
かつ高純度で得ることができ、医薬として有用な置換ア
ミノエトキシカルバクロール誘導体を効率よく提供する
ことが出来る。Infrared absorption spectrum (cll-') 3400.2950, 2550, 2430.1750 (
carbonyl group) 1250 (-0-), 1170 (-0-
), 920 [Effects of the Invention] According to the present invention, 4-acetyloxy-1-(2-substituted ethoxy)benzenes can be easily obtained with high purity by using ketene, and are substituted with pharmaceutically useful substances. Aminoethoxycarvacrol derivatives can be efficiently provided.
特許出願人 宇部興産株式会社Patent applicant: Ube Industries Co., Ltd.
Claims (1)
素基を表し、Ｘは、反応混合物に対し不活性な官能基を
示す。）で示される４−ヒドロキシ−１−（２−置換エ
トキシ）ベンゼン類をケテンで処理することを特徴とす
る 次式（ I ）： ▲数式、化学式、表等があります▼（ I ） （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３及びＸは、前記と同義
である。 ）で示される４−アセチルオキシ−１−（２−置換エト
キシ）ベンゼン類の製造方法。(1) Following formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R_1, R_2 and R_3 represent a hydrogen atom or a hydrocarbon group, and X represents an inert group to the reaction mixture. The following formula (I), which is characterized by treating 4-hydroxy-1-(2-substituted ethoxy)benzenes (representing a functional group) with ketene: ▲Mathematical formulas, chemical formulas, tables, etc.▼( I) A method for producing 4-acetyloxy-1-(2-substituted ethoxy)benzenes represented by (wherein R_1, R_2, R_3 and X have the same meanings as above).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19720088A JPH0248547A (en) | 1988-08-09 | 1988-08-09 | Production of 4-acetyloxy-1-(2-substituted ethoxy)benzene |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19720088A JPH0248547A (en) | 1988-08-09 | 1988-08-09 | Production of 4-acetyloxy-1-(2-substituted ethoxy)benzene |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0248547A true JPH0248547A (en) | 1990-02-19 |
Family
ID=16370481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP19720088A Pending JPH0248547A (en) | 1988-08-09 | 1988-08-09 | Production of 4-acetyloxy-1-(2-substituted ethoxy)benzene |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0248547A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4945029A (en) * | 1972-08-02 | 1974-04-27 |
-
1988
- 1988-08-09 JP JP19720088A patent/JPH0248547A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4945029A (en) * | 1972-08-02 | 1974-04-27 |
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