JPH0215058A - Production of 2-substituted-4-oxotetrahydroindoles - Google Patents
Production of 2-substituted-4-oxotetrahydroindolesInfo
- Publication number
- JPH0215058A JPH0215058A JP16436688A JP16436688A JPH0215058A JP H0215058 A JPH0215058 A JP H0215058A JP 16436688 A JP16436688 A JP 16436688A JP 16436688 A JP16436688 A JP 16436688A JP H0215058 A JPH0215058 A JP H0215058A
- Authority
- JP
- Japan
- Prior art keywords
- water
- acylmethylcyclohexane
- diones
- aminating agent
- 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.)
- Granted
Links
- -1 2-substituted-4-oxotetrahydroindoles Chemical class 0.000 title claims description 13
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 10
- 239000002904 solvent Substances 0.000 abstract description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract description 4
- 238000007796 conventional method Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- WAQFIKLYRKTCPW-UHFFFAOYSA-N 1,2,3,3a-tetrahydroindol-4-one Chemical compound O=C1C=CC=C2NCCC12 WAQFIKLYRKTCPW-UHFFFAOYSA-N 0.000 description 2
- AXMUMWUDWVIQMZ-UHFFFAOYSA-N 2-(2-oxopropyl)cyclohexane-1,3-dione Chemical compound CC(=O)CC1C(=O)CCCC1=O AXMUMWUDWVIQMZ-UHFFFAOYSA-N 0.000 description 2
- XANCWULXXRCMBC-UHFFFAOYSA-N 2-(3-oxobutan-2-yl)cyclohexane-1,3-dione Chemical compound CC(=O)C(C)C1C(=O)CCCC1=O XANCWULXXRCMBC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000005065 mining Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- KWIPUXXIFQQMKN-UHFFFAOYSA-N 2-azaniumyl-3-(4-cyanophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C#N)C=C1 KWIPUXXIFQQMKN-UHFFFAOYSA-N 0.000 description 1
- FLDCSPABIQBYKP-UHFFFAOYSA-N 5-chloro-1,2-dimethylbenzimidazole Chemical compound ClC1=CC=C2N(C)C(C)=NC2=C1 FLDCSPABIQBYKP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000001741 Ammonium adipate Substances 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N Glycerol trioctadecanoate Natural products CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- 235000019293 ammonium adipate Nutrition 0.000 description 1
- 229940090948 ammonium benzoate Drugs 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 229940056585 ammonium laurate Drugs 0.000 description 1
- VBIXEXWLHSRNKB-UHFFFAOYSA-N ammonium oxalate Chemical compound [NH4+].[NH4+].[O-]C(=O)C([O-])=O VBIXEXWLHSRNKB-UHFFFAOYSA-N 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- VJCJAQSLASCYAW-UHFFFAOYSA-N azane;dodecanoic acid Chemical compound [NH4+].CCCCCCCCCCCC([O-])=O VJCJAQSLASCYAW-UHFFFAOYSA-N 0.000 description 1
- CHCFOMQHQIQBLZ-UHFFFAOYSA-N azane;phthalic acid Chemical compound N.N.OC(=O)C1=CC=CC=C1C(O)=O CHCFOMQHQIQBLZ-UHFFFAOYSA-N 0.000 description 1
- XJMWHXZUIGHOBA-UHFFFAOYSA-N azane;propanoic acid Chemical compound N.CCC(O)=O XJMWHXZUIGHOBA-UHFFFAOYSA-N 0.000 description 1
- YNTQKXBRXYIAHM-UHFFFAOYSA-N azanium;butanoate Chemical compound [NH4+].CCCC([O-])=O YNTQKXBRXYIAHM-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- OKUGAOMPLZNWRT-UHFFFAOYSA-N diazanium;pentanedioate Chemical compound [NH4+].[NH4+].[O-]C(=O)CCCC([O-])=O OKUGAOMPLZNWRT-UHFFFAOYSA-N 0.000 description 1
- FRRMMWJCHSFNSG-UHFFFAOYSA-N diazanium;propanedioate Chemical compound [NH4+].[NH4+].[O-]C(=O)CC([O-])=O FRRMMWJCHSFNSG-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000000543 intermediate 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、２−置換−４−オキソテトラヒドロインドー
ル類の効率的な製造方法に関する。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to an efficient method for producing 2-substituted-4-oxotetrahydroindoles.
（従来の技術）
（式中、Ｒ１は炭化水素残基、Ｒ２， Ｒ３， Ｒ
４及びＲ５は水素原子または炭化水素残基、Ｒ６は水素
原子または低級アルキル基を示す。）
て示される２−置換−４−オキソテＩ・ラヒトロイント
ール類は、循環器系治療剤［メビントロール」や「ボビ
ントロール」及びそれらの類縁体の合成中間体として有
用なことが知られている。かかる化合物の合成法として
、従来から後記−数式（ＩＩ）で示されるような１−ア
シルメチルシクロヘキサン−２，６−ジオン類と７ミノ
化剤とを無水メタノール中で高温、高圧下で反応させる
方法（Ｃｈｅｍ。(Prior art) (In the formula, R1 is a hydrocarbon residue, R2, R3, R
4 and R5 represent a hydrogen atom or a hydrocarbon residue, and R6 represents a hydrogen atom or a lower alkyl group. ) The 2-substituted-4-oxote I lahitrointols shown in the table are known to be useful as synthetic intermediates for cardiovascular treatment agents [Mevintrol], "Bovintrol", and their analogs. There is. Conventionally, as a method for synthesizing such compounds, 1-acylmethylcyclohexane-2,6-diones as shown in formula (II) below are reacted with a 7-mining agent in anhydrous methanol at high temperature and high pressure. Method (Chem.
Ｂｅｒ．８ｆ１ ２７＋（１９５５）他）が知られてい
る。Ber. 8f1 27+ (1955) and others) are known.
しかしながら、この方法では（１）目的物を収率良く得
ることができない、 （２）反応ｉｆｆから目的物を回
収するにあたり、まず反応液から溶剤や低沸点化合物を
減圧下に留去し、さらに残留物に水を加えて有機層を有
機溶剤で抽出し、次いて溶剤を留去するという極めて複
雑な操作を行わなけれはならない、 （３）高圧下で反
応を実施するために特殊な設備、装置が必要となり経済
的でない等の問題点があった。However, with this method, (1) the target product cannot be obtained in good yield; (2) in recovering the target product from the reaction if, first the solvent and low-boiling point compounds are distilled off from the reaction solution under reduced pressure; It is necessary to perform an extremely complicated operation of adding water to the residue, extracting the organic layer with an organic solvent, and then distilling off the solvent. (3) Special equipment to perform the reaction under high pressure; There were problems such as the need for equipment and uneconomical.
一方、４−オキソテトラヒドロクマロンカルホン酸、２
−アルコキシ−４−オキソヘキサヒドロクマロン、１−
（２，２−ジアルコキシエチル）シクロヘキサン−２，
６−シオン等の４−オキソテトラヒドロインドール類の
前駆体と水溶性アミノ化剤を高温下に水中で反応させ４
−オキソテトラヒドロインドール
２２８４５６号公報）が知られている。On the other hand, 4-oxotetrahydrocumaroncarphonic acid, 2
-Alkoxy-4-oxohexahydrocoumarone, 1-
(2,2-dialkoxyethyl)cyclohexane-2,
A precursor of 4-oxotetrahydroindole such as 6-cyone is reacted with a water-soluble aminating agent in water at high temperature.
-Oxotetrahydroindole No. 228456) is known.
しかしながら、この方法では実際に原料として使用され
ている前駆体は上記のものに限られており、１−アシル
メチルシクロヘキサン−２，６−ジオン構造のものにつ
いては具体的な報告がなく、このような前駆体を水中で
反応させたときにとのような挙動を示すかについての知
見は得られていなかった。However, the precursors actually used as raw materials in this method are limited to those mentioned above, and there are no specific reports on those with a 1-acylmethylcyclohexane-2,6-dione structure. No knowledge has been obtained as to whether such precursors exhibit the same behavior when reacted in water.
（発明が解決しようとする課題）
そこで本発明者らは従来技術のかがる欠点を解決すべく
鋭意検討を進めた結果、原料として１−アシルメチルシ
クロｌ＼キサン−２，６−ジオン類を、反応溶剤として
水を用いれは目的物を収率よく、且つ、後処理も容易に
得られること、又、常圧ないしは低圧下で反応を実施す
ることができろため特殊な設備、装置を必要としないこ
とを見い出し、その知見に基づいて本発明を完成するに
到った。(Problems to be Solved by the Invention) Therefore, the present inventors conducted intensive studies to solve the drawbacks of the conventional technology, and as a result, they found that 1-acylmethylcyclol\xane-2,6-diones were used as raw materials. When water is used as a reaction solvent, the desired product can be obtained in high yield and post-treatment is easy, and the reaction can be carried out under normal pressure or low pressure, so special equipment and equipment are required. The present invention was completed based on this finding.
（課題を解決するための手段）
かくして本発明によれは、１−アシルメチルシクロヘキ
サン−２，６−ジオン類と水溶性アミノ化剤を高温下に
水中で反応させ２−置換−４−オキソテトラヒドロイン
ドール類を合成した後、反応ｉαを冷却して２ ａｌ
！ｌｌ！＋４−オキソテトラヒドロインドール類を析出
し回収することを特徴とする２装置ＪｉＪー４ーオキソ
テトラヒドロインドール類の製造方法が提供される。(Means for Solving the Problems) Thus, according to the present invention, 1-acylmethylcyclohexane-2,6-diones and a water-soluble aminating agent are reacted in water at high temperature to produce 2-substituted-4-oxotetrahydrocarbons. After synthesizing the indoles, the reaction iα is cooled and 2 al
! ll! Provided is a two-apparatus method for producing JiJ-4-oxotetrahydroindole, which is characterized in that +4-oxotetrahydroindole is precipitated and recovered.
本発明において原料として用いられる１−アシルメチル
シクロｌスキサン−２，６−ジオン類は下記一般式（Ｉ
Ｉ）で示されるものである。The 1-acylmethylcycloscane-2,6-diones used as raw materials in the present invention have the following general formula (I
I).
（式中、Ｒ１は炭化水素残基、Ｒ２， Ｒ３， Ｒ
４及びＲ５は水素原子または炭化水素残基を示す。）一
般式（ｎ）におけるＲ１、Ｒ２， Ｒ３， Ｒ４及
びＲ５て示される炭化水素残基の具体的な例として、メ
チル基、エチル基、１１−プロピル基、ｉｓｏ−プロピ
ル基、ｎ−ブチル基、ｉｓｏ−ブチル基、１１−オクチ
ル基、シクロＪ＼キシルメチル基なとのアルキル基、シ
クロプロピル基、シクロペンチル基、シクロヘキシル基
なとのシクロアルキル基、フェニル基、トリル基、キシ
リル基などのアリール基、ベンジルフェニルエチル基、
ｎ−メチルペンシル基などのアラルキル基などを挙げる
ことができ、好ましくは炭素数１５以下のもの、さらに
好ましくは炭素数５以下のアルキル基である。(In the formula, R1 is a hydrocarbon residue, R2, R3, R
4 and R5 represent a hydrogen atom or a hydrocarbon residue. ) Specific examples of hydrocarbon residues represented by R1, R2, R3, R4 and R5 in general formula (n) include methyl group, ethyl group, 11-propyl group, iso-propyl group, n-butyl group. , iso-butyl group, 11-octyl group, alkyl group such as cycloJ\xylmethyl group, cycloalkyl group such as cyclopropyl group, cyclopentyl group, cyclohexyl group, aryl group such as phenyl group, tolyl group, xylyl group , benzylphenylethyl group,
Examples include aralkyl groups such as n-methylpencil group, preferably those having 15 or less carbon atoms, and more preferably alkyl groups having 5 or less carbon atoms.
本発明ではアミノ化剤として水溶性の７ミノ化剤が用い
られる。その具体的な例として、アンモニア、塩化アン
モニウム、臭化アンモニウム、炭酸アンモニウム、硫酸
アンモニウム、リン酸アンモニウムなどの無４［アンモ
ニウム塩、ギ酸アンモニウム、酢酸アンモニウム、プロ
ピオン酸アンモニウム、酪酸アンモニウム、ラウリン酸
アンモニウム、ステアリン酸アンモニウム、安息香酸ア
ンモニウム、シュウ酸アンモニウム、マロン酸アンモニ
ウム、グルタル酸アンモニウム、アジピン酸アンモニウ
ム、フタル酸アンモニウム、ｌ＼ンゼインルホン酸アン
モニウムなとの有機酸アンモニウム塩、メチルアミノ、
エチルアミノ、プロピルアミノ、ブチルアミノなとの低
級アミノ等が例示される。特に実用上、アンモニア水ま
たは無水アンモニアが好ましい。In the present invention, a water-soluble 7-mining agent is used as the aminating agent. Specific examples include ammonia, ammonium chloride, ammonium bromide, ammonium carbonate, ammonium sulfate, ammonium phosphate, ammonium salts, ammonium formate, ammonium acetate, ammonium propionate, ammonium butyrate, ammonium laurate, stearin. Ammonium salts of organic acids such as ammonium acid, ammonium benzoate, ammonium oxalate, ammonium malonate, ammonium glutarate, ammonium adipate, ammonium phthalate, ammonium zein sulfonate, methylamino,
Examples include lower amino such as ethylamino, propylamino, and butylamino. Particularly from a practical standpoint, aqueous ammonia or anhydrous ammonia is preferred.
アミノ化剤の使用量は１−アシルメチルシクロヘキサン
−２，６−ジオン類に対して、通常、１〜１０当竜、好
ましくは１〜５当潰てあり、特に好ましくは１．５〜３
．５当量である。アミノ化剤は多量使用しても特に差し
支えないが、大過剰量使用しても格別の意味がない。The amount of aminating agent used is usually 1 to 10, preferably 1 to 5, particularly preferably 1.5 to 3, per 1-acylmethylcyclohexane-2,6-dione.
．． It is 5 equivalents. Although there is no particular problem in using a large amount of the aminating agent, there is no particular meaning in using a large excess amount.
本発明においては、溶剤として水が用いられるが、本発
明の効果を本質的に妨げない限り水溶性有機溶剤を併用
してもよい。用いられる水溶性有機溶剤の具体的な例と
しては、例えはメタノール、エタノール、１】−プロパ
ツール、１ｓｏ−プロパツール、１１−ブタノ、−ル、
１ｓｏ−フタノール、ｔｅｒｔ−ブタノール、アミノ
アルコール、エチレングリコール、グリセリンなどのア
ルコール類、アセトン、メチルエチルケトンなどのケト
ン類、ジオキサン、テトラヒドロフラン、エチレングリ
コールモノフ′チルエーテルなとのエーテル失頁、酉ヤ
酸エチルなとのエステル類などが挙げられる。これら水
溶性有機溶剤の許容割合は、通常、水との合計機中５０
重量％以下、好ましくは３０重量％以下である。In the present invention, water is used as a solvent, but a water-soluble organic solvent may be used in combination as long as it does not essentially impede the effects of the present invention. Specific examples of water-soluble organic solvents used include methanol, ethanol, 1]-propertool, 1so-propertool, 11-butanol, -l,
Alcohols such as 1so-phthanol, tert-butanol, amino alcohol, ethylene glycol, glycerin, ketones such as acetone, methyl ethyl ketone, dioxane, tetrahydrofuran, ethylene glycol monophthyl ether, etc. Examples include esters of. The permissible proportion of these water-soluble organic solvents is usually 50% in total with water.
It is not more than 30% by weight, preferably not more than 30% by weight.
使用する溶剤の使用量は均一反応が可能で、かつ反応後
に系を冷却することにより生成した２−置換−４−オキ
ソテトラヒドロ、インドール類か析出しするような範囲
で選択される。その範囲は原料や溶剤の種類により必ず
しも一定ではないが、簡単な予備試験を行うことにより
適宜決定することができる。The amount of the solvent to be used is selected within a range that allows a homogeneous reaction and allows the 2-substituted-4-oxotetrahydro and indoles produced to be precipitated by cooling the system after the reaction. Although the range is not necessarily constant depending on the type of raw material and solvent, it can be appropriately determined by conducting a simple preliminary test.
その範囲は一般に１−アシルメチルシクロヘキサン−２
，６−シオンに対して１〜１００重量倍程度であり、好
ましくは４〜３０重重倍程度である。The range is generally 1-acylmethylcyclohexane-2
, 6-sion, about 1 to 100 times by weight, preferably about 4 to 30 times by weight.
反応は１−アシルメチルシクロヘキサン−２゜６−ジオ
ン類と溶剤から得られた溶液あるいはＨ＝、％濁液中ヘ
アミノ化剤を連続的あるいは断続的に添加していく方法
、アミノ化剤を反応開始時に全ｌ添加する方法、溶剤中
へ１−アシルメチルシクロヘキサン−２，６−ジオン類
とアミノ化剤を同時に添加する方法、溶剤とアミノ化剤
の混合溶液中に１−アシルメチルシクロヘキサン−２，
６−ジオン類を連続的あるいは断続的に添加する方法等
により行われる。The reaction is carried out by adding the hair aminating agent continuously or intermittently to a solution or H = % suspension obtained from 1-acylmethylcyclohexane-2゜6-diones and a solvent, or by adding the aminating agent continuously or intermittently. A method of adding all liters at the start, a method of adding 1-acylmethylcyclohexane-2,6-diones and the aminating agent to the solvent at the same time, a method of adding 1-acylmethylcyclohexane-2,6-diones and the aminating agent to a mixed solution of the solvent and the aminating agent. ，
This is carried out by adding 6-diones continuously or intermittently.
本発明における反応は系が均一になるような温度条件下
で行われる。反応系は高温になるほど均一化しやすいの
で、通常、５０〜２００°Ｃ１好ましくは７０〜１５０
℃の温度範囲が選択される。The reaction in the present invention is carried out under temperature conditions that make the system homogeneous. The higher the temperature of the reaction system, the easier it is to homogenize the reaction system.
A temperature range of °C is selected.
反応圧力は常圧もしくは加圧のいずれてもよく、加圧の
場合は数Ｋ ｇ ／ ｃ ｍ２程度までの範囲で選択さ
れる。The reaction pressure may be normal pressure or increased pressure, and in the case of increased pressure, it is selected within a range of up to several kg/cm2.
本発明においては、反応終了後、系を冷却することによ
り生成した２−置換−４−オキソテトラヒドロインドー
ル類の析出が行われる。冷却に際しての温度は、通常、
５０℃以下であり、好ましくは０〜２０℃の範囲である
。この操作で析出した２−置換−４−オキソテトラヒド
ロインドール類は、次いて常法にしたがって水層から分
離した後、必要に応じ冷却した水で洗浄後、乾燥される
。In the present invention, after the reaction is completed, the produced 2-substituted-4-oxotetrahydroindole is precipitated by cooling the system. The temperature for cooling is usually
The temperature is 50°C or less, preferably in the range of 0 to 20°C. The 2-substituted-4-oxotetrahydroindole precipitated in this operation is then separated from the aqueous layer in a conventional manner, washed with cooled water if necessary, and then dried.
（発明の効果）
かくして本発明によれば従来法に比して高収率で２−置
換−４−オキソテトラヒドロインドール類を得ることが
できる。このように目的物を高収率で得られるという効
果は前述の従来法からは予期できぬものである。(Effects of the Invention) Thus, according to the present invention, 2-substituted-4-oxotetrahydroindoles can be obtained in a higher yield than in the conventional method. The effect of obtaining the target product in high yield is unexpected from the conventional methods described above.
また、本発明では従来法に比してはるかに低圧力下で反
応を実施することができるために、特殊な設備や装置が
不要であり、経済的である。Furthermore, since the present invention allows the reaction to be carried out under much lower pressure than conventional methods, no special equipment or equipment is required, making it economical.
（実施例）
以下に実施例を挙げて本発明をさらに具体的に説明する
。なお、実施例、比較例及び参考例中の部及び％は特に
断わりのない限り重量基準である。(Example) The present invention will be described in more detail with reference to Examples below. Note that parts and percentages in Examples, Comparative Examples, and Reference Examples are based on weight unless otherwise specified.
実施例１
［２−メチ１ト４−オキソ−４，５，６，７’ｒ）ラヒ
ド０イツト−１１の合成］反応器に１−アセトニルシク
ロヘキサン−２゜６−ジオン１００部、水１０００部及
び２８％アンモニア水１１０部を入れ均一に溶解後、加
熱し１１０℃で３時間、１３０℃で１０時間反応させた
。反応器の内圧は最高３Ｋｇ／ｃｍ２を示した。Example 1 [Synthesis of 2-methyl-4-oxo-4,5,6,7'r)rahydride-11] 100 parts of 1-acetonylcyclohexane-2°6-dione and 1000 parts of water were placed in a reactor. After uniformly dissolving 110 parts of 28% ammonia water, the mixture was heated and reacted at 110°C for 3 hours and at 130°C for 10 hours. The internal pressure of the reactor showed a maximum of 3 kg/cm2.
反応終了後、５°Ｃまて冷却し析出した結晶を濾別し、
水洗、乾燥したところ２−メチル−４−オキソ−４，５
，６，７−チトラヒトロインｌζ−ル６２部を得た。融
点は２０５〜２０７℃、収率はｌ−アセトニルシクロヘ
キサン−２，６−シオン基準で７０モル％てあった。After the reaction was completed, the mixture was cooled to 5°C and the precipitated crystals were filtered out.
After washing with water and drying, 2-methyl-4-oxo-4,5
, 62 parts of 6,7-titrahydroin lζ-ru were obtained. The melting point was 205-207°C, and the yield was 70 mol% based on 1-acetonylcyclohexane-2,6-ion.
実施例２
［２−メツ１１４−オキソ−４，５，６，７−チトラヒ
ビロインド’−ＩＬの合成］２８％アンモニア水１１０
部に代えて酢酸アンモニラｌ、１１５部を用い還流下に
１５時間反応させること以外は実施例１と同様に操作を
行ったところ２−メチル−４−オキソ−４，５，６，７
−チトラヒドロイントール
２０／ｌ〜２０６°Ｃ１収率は１−アセトニルシクロヘ
キサン−２，６−ジオン基準で６５モル％であった。Example 2 [Synthesis of 2-meth114-oxo-4,5,6,7-titrahibiroindo'-IL] 28% aqueous ammonia 110
The same procedure as in Example 1 was carried out except that 115 parts of ammonyl acetate was used in place of 115 parts of ammonium acetate and the reaction was carried out under reflux for 15 hours. 2-Methyl-4-oxo-4,5,6,7
-Titrahydrointole 20/l~206°C1 yield was 65 mol% based on 1-acetonylcyclohexane-2,6-dione.
比較例１
［２−メチド４−オキソ−４，５，（３，７−チトラヒ
ド０インビールの合成コ反応器に１−アセトニルシクロ
ヘキサン−２゜６−ジオン１００部、無水メタノール１
０００部にアンモニア３０部を溶解したアンモニアのメ
タノール溶）夜を入れ、１５０°Ｃで１２時間反応させ
た。反応器の内圧は最高３０ Ｋ ｇ／ ｃ ｍ２を示
した。Comparative Example 1 Synthesis of [2-Methide 4-oxo-4,5,(3,7-titrahydro)] In a co-reactor, 100 parts of 1-acetonylcyclohexane-2°6-dione and 1 part of anhydrous methanol were added.
A methanol solution of 30 parts of ammonia in 1,000 parts of ammonia was added and reacted at 150°C for 12 hours. The internal pressure of the reactor showed a maximum of 30 K g/cm2.
反応終了後、メタノールを留去し残渣に水８００部を加
えてエーテル抽出を行った。エーテル留去後、水を加え
て再結晶を行ったところ２−メチル−４−オキソ−４，
５，６，７−チトラヒトロイント−ル３５部を得た。融
点は２０４〜２０７℃、収率は１−アセトニルシクロヘ
キサン−２，６−ジオン基準で４０モル％であった。After the reaction was completed, methanol was distilled off and 800 parts of water was added to the residue to perform ether extraction. After distilling off the ether, water was added to recrystallize, resulting in 2-methyl-4-oxo-4,
35 parts of 5,6,7-thitrahydrointole were obtained. The melting point was 204-207°C, and the yield was 40 mol% based on 1-acetonylcyclohexane-2,6-dione.
このように比較例１の方法では実施例１及び２の方法に
比べ目的物を収率良く得ることができないうえに、３０
Ｋ ｇ／ ｃ ｍ”というはるかに高圧下て反応を実
施しなけれはならなかった。As described above, the method of Comparative Example 1 cannot obtain the target product in a higher yield than the methods of Examples 1 and 2, and also
The reaction had to be carried out under much higher pressures of K g/cm".
実施例３
［２＋３−Ｊ−メチド４−オキソ−４，５，６，７−チ
トラヒトーロイントールの合成コ反応器に１−アセトニ
ルシクロヘキサン−２゜６−ジオンの代わりに１−（１
−メチルアセトニル）シクロヘキサン−２，６−ジオン
１００部を用いること以外は実施例１と同様に操作を行
ったところ２，３−ジメチル−４−オキソ−４，５゜６
．７−テトラヒドロインドール５９部を得た。Example 3 Synthesis of [2+3-J-methide 4-oxo-4,5,6,7-titrahytrointole] 1-(1
-Methylacetonyl) cyclohexane-2,6-dione was operated in the same manner as in Example 1 except for using 100 parts of 2,3-dimethyl-4-oxo-4,5゜6.
．． 59 parts of 7-tetrahydroindole were obtained.
融点は２２３〜２２５°Ｃ１収率は１−（ｌ−メチルア
セトニル）シクロヘキサン−２，６−ジオン基準て６６
モル％であった。Melting point: 223-225°C1 Yield: 66% based on 1-(l-methylacetonyl)cyclohexane-2,6-dione
It was mol%.
特許出願人 日本七オン株式会社Patent applicant Nippon Shichion Co., Ltd.
Claims (1)
ン類と水溶性アミノ化剤を高温下に水中で反応させ２−
置換−４−オキソテトラヒドロインドール類を合成した
後、反応液を冷却して２−置換−４−オキソテトラヒド
ロインドール類を析出し回収することを特徴とする２−
置換−４−オキソテトラヒドロインドール類の製造方法
。(1) 1-acylmethylcyclohexane-2,6-diones and a water-soluble aminating agent are reacted in water at high temperature, and 2-
2- characterized in that after synthesizing the substituted-4-oxotetrahydroindole, the reaction solution is cooled to precipitate and collect the 2-substituted-4-oxotetrahydroindole.
Method for producing substituted-4-oxotetrahydroindoles.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63164366A JP2704267B2 (en) | 1988-07-01 | 1988-07-01 | Method for producing 2-substituted-4-oxotetrahydroindoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63164366A JP2704267B2 (en) | 1988-07-01 | 1988-07-01 | Method for producing 2-substituted-4-oxotetrahydroindoles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0215058A true JPH0215058A (en) | 1990-01-18 |
| JP2704267B2 JP2704267B2 (en) | 1998-01-26 |
Family
ID=15791778
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63164366A Expired - Fee Related JP2704267B2 (en) | 1988-07-01 | 1988-07-01 | Method for producing 2-substituted-4-oxotetrahydroindoles |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2704267B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070477A1 (en) * | 2001-03-01 | 2002-09-12 | Ono Pharmaceutical Co., Ltd. | 2-methylindole-4-acetic acid, process for producing the same, and process for producing intermediate therefor |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3467755A (en) * | 1966-05-11 | 1969-09-16 | Endo Lab | Compositions and methods for producing sedation and tranquilization with substituted 4,5,6,7- tetrahydro-4-oxindoles |
-
1988
- 1988-07-01 JP JP63164366A patent/JP2704267B2/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3467755A (en) * | 1966-05-11 | 1969-09-16 | Endo Lab | Compositions and methods for producing sedation and tranquilization with substituted 4,5,6,7- tetrahydro-4-oxindoles |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070477A1 (en) * | 2001-03-01 | 2002-09-12 | Ono Pharmaceutical Co., Ltd. | 2-methylindole-4-acetic acid, process for producing the same, and process for producing intermediate therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2704267B2 (en) | 1998-01-26 |
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