JPH0262549B2 - - Google Patents
Info
- Publication number
- JPH0262549B2 JPH0262549B2 JP59083895A JP8389584A JPH0262549B2 JP H0262549 B2 JPH0262549 B2 JP H0262549B2 JP 59083895 A JP59083895 A JP 59083895A JP 8389584 A JP8389584 A JP 8389584A JP H0262549 B2 JPH0262549 B2 JP H0262549B2
- Authority
- JP
- Japan
- Prior art keywords
- ammonia
- reaction
- solvent
- oxo
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 33
- 229910021529 ammonia Inorganic materials 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- -1 4-oxotetrahydrocoumarone-3-carboxylic acids Chemical class 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- WAQFIKLYRKTCPW-UHFFFAOYSA-N 1,2,3,3a-tetrahydroindol-4-one Chemical class O=C1C=CC=C2NCCC12 WAQFIKLYRKTCPW-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- FABBWECRHZNMDQ-UHFFFAOYSA-N 4-oxo-4,5,6,7-tetrahydrobenzo[b]furan-3-carboxylic acid Chemical compound C1CCC(=O)C2=C1OC=C2C(=O)O FABBWECRHZNMDQ-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 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
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- KCKIKSJECTZLJA-UHFFFAOYSA-N indol-4-one Chemical class O=C1C=CC=C2N=CC=C12 KCKIKSJECTZLJA-UHFFFAOYSA-N 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- VPBZZPOGZPKYKX-UHFFFAOYSA-N 1,2-diethoxypropane Chemical compound CCOCC(C)OCC VPBZZPOGZPKYKX-UHFFFAOYSA-N 0.000 description 1
- LEEANUDEDHYDTG-UHFFFAOYSA-N 1,2-dimethoxypropane Chemical compound COCC(C)OC LEEANUDEDHYDTG-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KASJZXHXXNEULX-UHFFFAOYSA-N 1,5,6,7-tetrahydroindol-4-one Chemical compound O=C1CCCC2=C1C=CN2 KASJZXHXXNEULX-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- POAOYUHQDCAZBD-UHFFFAOYSA-N 2-butoxyethanol Chemical compound CCCCOCCO POAOYUHQDCAZBD-UHFFFAOYSA-N 0.000 description 1
- RDTZWOOKIBKFCJ-UHFFFAOYSA-N 2-methyl-4-oxo-6,7-dihydro-5h-1-benzofuran-3-carboxylic acid Chemical compound C1CCC(=O)C2=C1OC(C)=C2C(O)=O RDTZWOOKIBKFCJ-UHFFFAOYSA-N 0.000 description 1
- QQPMDRGNNFKVEL-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid Chemical compound C1CCCC2=C1OC=C2C(=O)O QQPMDRGNNFKVEL-UHFFFAOYSA-N 0.000 description 1
- 239000005973 Carvone Substances 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 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
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000002243 cyclohexanonyl group Chemical class *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 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
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 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
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 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
- 229960004592 isopropanol Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Indole Compounds (AREA)
Description
【発明の詳細な説明】
本発明は４−オキソテトラヒドロインドール類
の効率的な製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an efficient method for producing 4-oxotetrahydroindoles.
一般式（）
K0282
〔式中、R1，R2，R3及びR4は水素原子または
炭化水素残基を表わす。〕
で示される４−オキソテトラヒドロインドール類
は、循環器系治療剤「ピンドロール」およびその
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、次のような
方法が提案されている。General formula () K0282 [In the formula, R 1 , R 2 , R 3 and R 4 represent a hydrogen atom or a hydrocarbon residue. ] The 4-oxotetrahydroindoles shown below are known to be useful as synthetic intermediates for the cardiovascular treatment drug "pindolol" and its analogs. The following methods have been proposed as methods for synthesizing such compounds.
(1) ４−オキソテトラヒドロクマロン−３−カル
ボン酸を加圧下に無水メタノールでアミノ化剤
と反応させる方法。〔特開昭54−19971号〕
(2) シクロヘキサノン誘導体をアミノ化剤と反応
させる方法。〔特開昭57−4970号〕
しかし、これらの公知方法では、一般に加圧下
で反応が行われており、装置上、操作上の問題点
があつた。また反応性の点でも必ずしも充分でな
く、反応に半日以上の長時間を必要としたり、反
応速度を高めるため反応温度を上昇すると高沸点
の副生物が増加するという問題があつた。(1) A method in which 4-oxotetrahydrocoumarone-3-carboxylic acid is reacted with an aminating agent in anhydrous methanol under pressure. [JP 54-19971] (2) A method of reacting a cyclohexanone derivative with an aminating agent. [Unexamined Japanese Patent Publication No. 57-4970] However, in these known methods, the reaction is generally carried out under pressure, which poses problems in equipment and operation. In addition, the reactivity is not necessarily sufficient, and there are problems in that the reaction requires a long time of half a day or more, and when the reaction temperature is raised to increase the reaction rate, high-boiling-point by-products increase.
そこで本発明者らは従来技術のかかる欠点を解
消すべく鋭意検討を進めた結果、特定なアミノ化
剤と溶媒とを組合せることによつて常圧下の緩和
な反応条件下で高収率かつ高選択率で４−オキソ
テトラヒドロインドール類を製造しうることを見
い出し、本発明を完成するに到つた。 Therefore, the present inventors conducted intensive studies to solve these drawbacks of the prior art, and found that by combining a specific aminating agent and a solvent, high yield and high yield under mild reaction conditions under normal pressure. The present inventors have discovered that 4-oxotetrahydroindoles can be produced with high selectivity, and have completed the present invention.
かくして本発明によれば、４−オキソテトラヒ
ドロクマロン−３−カルボン酸をアミノ化剤と反
応して４−オキソテトラヒドロインドール類を合
成するに際し、アミノ化剤としてアンモニアを使
用し、かつアンモニアと親和性のある溶剤中で前
記前駆体とアンモニアを常圧下に70〜110℃で反
応せしめることを特徴とする４−オキソテトラヒ
ドロインドール類の製造法が提供される。 Thus, according to the present invention, when reacting 4-oxotetrahydrocoumarone-3-carboxylic acid with an aminating agent to synthesize 4-oxotetrahydroindoles, ammonia is used as the aminating agent, and a compound having an affinity for ammonia is used. The present invention provides a method for producing 4-oxotetrahydroindoles, which comprises reacting the precursor with ammonia at 70 to 110[deg.] C. under normal pressure in a neutral solvent.
本発明において原料として用いられる４−オキ
ソテトラヒドロクマロン−３−カルボン酸類は、
一般式（）で示されるものである。 The 4-oxotetrahydrocumaron-3-carboxylic acids used as raw materials in the present invention are:
It is represented by the general formula ().
K0283
〔式中、R1，R2，R3，R4は水素原子もしくは
炭化水素残基を表わす。〕
一般式（）におけるR1，R2，R3，R4で示さ
れる炭化水素基の具体的な例として、メチル，エ
チル，ｎ−プロピル，iso−プロピル，ｎ−ブチ
ル，iso−ブチル，ｎ−オクチル，シクロヘキシ
ルメチル基などのアルキル基、シクロプロピル，
シクロペンチル，シクロヘキシル等のシクロアル
キル基、フエニル、トリル、キシリル基等のアリ
ール基、ベンジルフエニルエチル，ｐ−メチルベ
ンジル基などのアラルキル基を挙げることがで
き、炭素数15以下、好ましくは５以下のものであ
る。 K0283 [In the formula, R 1 , R 2 , R 3 , and R 4 represent a hydrogen atom or a hydrocarbon residue. ] Specific examples of the hydrocarbon groups represented by R 1 , R 2 , R 3 , and R 4 in the general formula () include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, Alkyl groups such as n-octyl and cyclohexylmethyl groups, cyclopropyl,
Examples include cycloalkyl groups such as cyclopentyl and cyclohexyl, aryl groups such as phenyl, tolyl, and xylyl groups, and aralkyl groups such as benzyl phenylethyl and p-methylbenzyl groups, and have carbon atoms of 15 or less, preferably 5 or less. It is something.
一般式（）で示される化合物の例としては、
例えば４−オキソ−４，５，６，７−テトラヒド
ロクマロン−３−カルボン酸、４−オキソ−２−
メチル−４，５，６，７−テトラヒドロクマロン
−３−カルボン酸、４−オキソ−６−エチル−
４，５，６，７−テトラヒドロクマロン−３−カ
ルボン酸などが例示される。これら４−オキソテ
トラヒドロクマロン−３−カルボン酸類は各々単
独で、あるいは２種以上を混合して用いる事が出
来る。 Examples of compounds represented by the general formula () are:
For example, 4-oxo-4,5,6,7-tetrahydrocoumarone-3-carboxylic acid, 4-oxo-2-
Methyl-4,5,6,7-tetrahydrocoumarone-3-carboxylic acid, 4-oxo-6-ethyl-
Examples include 4,5,6,7-tetrahydrocoumarone-3-carboxylic acid. These 4-oxotetrahydrocumaron-3-carboxylic acids can be used alone or in combination of two or more.
本発明においてアミノ化剤としてアンモニアが
用いられる。これはアンモニア水あるいは無水ア
ンモニアとして使用される。従来からアミノ化剤
として無機または有機のアンモニウム塩を用いる
方法も知られているが、炭酸アンモニウムのよう
な無機塩を用いると、副生する炭酸ガスのために
反応内容物が系外へ同伴し、損失を増大させる。
また装置の冷却部分での炭酸アンモニウムの析出
が促進され、装置気相部分につまりが生じ易くな
る。 Ammonia is used as the aminating agent in the present invention. This is used as aqueous ammonia or anhydrous ammonia. Conventionally, methods using inorganic or organic ammonium salts as aminating agents have been known, but when inorganic salts such as ammonium carbonate are used, the reaction contents are entrained out of the system due to the carbon dioxide gas produced as a by-product. , increasing losses.
Further, the precipitation of ammonium carbonate in the cooling section of the device is promoted, making it easier for the gas phase section of the device to become clogged.
また酢酸アンモニウムのような有機塩を用いる
と、副生する酢酸など有機酸による副反応のため
収率低下が起こり、装置の腐食も発生しやすくな
る。 Furthermore, when an organic salt such as ammonium acetate is used, the yield decreases due to a side reaction caused by the organic acid such as acetic acid produced as a by-product, and the equipment is likely to be corroded.
アンモニアの使用量は４−オキソテトラヒドロ
クマロン−３−カルボン酸類に対し、通常、１〜
10当量、好ましくは１〜５当量であり、特に好ま
しくは1.5〜3.5当量である。アンモニアは多量使
用しても特に差支えないが、大過剰量を使用して
も格別の意味がない。 The amount of ammonia used is usually 1 to 1 to 4-oxotetrahydrocoumarone-3-carboxylic acids.
10 equivalents, preferably 1 to 5 equivalents, particularly preferably 1.5 to 3.5 equivalents. There is no particular problem in using ammonia in large amounts, but there is no particular meaning in using a large excess amount.
本発明においては反応溶媒としてアンモニアと
親和性のある溶媒を用いることが必須の要件であ
る。 In the present invention, it is essential to use a solvent with affinity for ammonia as the reaction solvent.
ここで「親和性のある溶媒」とはアンモニア水
あるいは無水アンモニアと良く混合し均一溶液と
なる溶媒を意味し、その具体的な例として、水，
メタノール，エタノール，ｎ−プロパノール，
iso−プロパノール，ｎ−ブタノール，iso−ブタ
ノール，tert−ブタノール，アミルアルコール，
ヘキサノール，オクタノール，シクロペンタノー
ル，シクロヘキサノール，エチレングリコール，
などのアルコール類、テトラヒドロフラン，ジオ
キサン，エチレングリコールモノブチルエーテ
ル，エチレングリコールジメチルエーテル，エチ
レングリコールジエチルエーテル，ジエチレング
リコールジエチルエーテル，プロピレングリコー
ルジメチルエーテル，プロピレングリコールジエ
チルエーテルなどのエーテル類が挙げられる。中
でも反応性、経済性の点で水、エタノール、プロ
パノール類、ブタノール類が好ましい。 Here, the term "compatible solvent" refers to a solvent that mixes well with aqueous ammonia or anhydrous ammonia to form a homogeneous solution; specific examples include water,
methanol, ethanol, n-propanol,
iso-propanol, n-butanol, iso-butanol, tert-butanol, amyl alcohol,
hexanol, octanol, cyclopentanol, cyclohexanol, ethylene glycol,
and ethers such as tetrahydrofuran, dioxane, ethylene glycol monobutyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, propylene glycol dimethyl ether, and propylene glycol diethyl ether. Among them, water, ethanol, propanols, and butanols are preferred from the viewpoint of reactivity and economy.
これに対し、ベンゼン、トルエン、キシレンな
どのごときアンモニアと親和性のない溶媒を使用
する場合には、収率が著しく低下する。 On the other hand, when a solvent that has no affinity for ammonia, such as benzene, toluene, or xylene, is used, the yield decreases significantly.
本発明では、かかる溶剤を４−オキソテトラヒ
ドロクマロン−３−カルボン酸類に対して通常１
〜100重量倍、好ましくは４〜30重量倍の割合で
使用する。また反応は、常圧下に溶媒を還流させ
ることによつて温度を制御しつつ行われる。反応
温度は、70〜110℃である。 In the present invention, such a solvent is usually used in a proportion of 1
It is used at a ratio of ~100 times by weight, preferably 4 to 30 times by weight. Further, the reaction is carried out while controlling the temperature by refluxing the solvent under normal pressure. The reaction temperature is 70-110°C.
反応の形式としては、４−オキソテトラヒドロ
クマロン−３−カルボン酸類と溶剤から成る溶液
あるいは懸濁液中へアンモニアを連続的あるいは
断続的に添加してゆく方法が好ましいが、アンモ
ニアを反応開始時に全量添加する方法、溶剤中で
４−オキソテトラヒドロクマロン−３−カルボン
酸類とアンモニアを同時に添加してゆく方法、溶
剤とアンモニアの混合溶液中に４−オキソテトラ
ヒドロクマロン−３−カルボン酸類を連続的ある
いは断続的に添加してゆく方法を用いることもで
きる。 As for the reaction format, it is preferable to add ammonia continuously or intermittently to a solution or suspension consisting of 4-oxotetrahydrocoumarone-3-carboxylic acids and a solvent. A method of adding the entire amount, a method of adding 4-oxotetrahydrocoumarone-3-carboxylic acids and ammonia simultaneously in a solvent, a method of adding 4-oxotetrahydrocoumarone-3-carboxylic acids continuously to a mixed solution of a solvent and ammonia. A method of adding it selectively or intermittently can also be used.
反応は従来法に比較してきわめて速やかに進行
し、通常、数時間以内で終了する。反応後、生成
した４−オキソインドール類は適宜分離される。
例えば、溶剤を一部留去後、冷却するなどの方法
で生成した４−オキソインドール類を純度の高い
結晶として得ることができる。 The reaction proceeds extremely quickly compared to conventional methods and is usually completed within several hours. After the reaction, the produced 4-oxoindoles are separated as appropriate.
For example, the 4-oxoindole produced can be obtained as highly pure crystals by partially distilling off the solvent and then cooling.
かくして本発明によれば、操作の容易な常圧下
での反応によつて従来法に比して極めて収率良く
４−オキソテトラヒドロインドール類を得ること
ができ、しかも副生物の発生を低く抑えることが
できる。 Thus, according to the present invention, 4-oxotetrahydroindoles can be obtained in extremely high yield compared to conventional methods through reaction under normal pressure, which is easy to operate, and the generation of by-products can be suppressed to a low level. Can be done.
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、実施例中の部は重量基準であ
る。 The present invention will be explained in more detail with reference to Examples below. Note that parts in the examples are based on weight.
実施例 １
撹拌器を備えた反応器に４−オキソ−４，５，
６，７−テトラヒドロクマロン−３−カルボン酸
180部および水1500部を加え、常圧下で95℃に加
熱した。さらに28％濃度のアンモニア水150部を
１時間かけて徐々に添加した後、４時間94〜97℃
で加熱撹拌した後、反応液をガスクロマトグラフ
イーおよび薄層クロマトグラフイーにより分析し
た所、４−オキソ−４，５，６，７−テトラヒド
ロインドール129.6部を含むことが判つた。４−
オキソ−４，５，６，７−テトラヒドロクマロン
−３−カルボン酸基準の収率は96％（モル数基
準）であつた。Example 1 4-oxo-4,5,
6,7-tetrahydrocoumarone-3-carboxylic acid
180 parts and 1500 parts of water were added and heated to 95°C under normal pressure. Furthermore, after gradually adding 150 parts of 28% ammonia water over 1 hour,
After heating and stirring, the reaction solution was analyzed by gas chromatography and thin layer chromatography and was found to contain 129.6 parts of 4-oxo-4,5,6,7-tetrahydroindole. 4-
The yield based on oxo-4,5,6,7-tetrahydrocoumarone-3-carboxylic acid was 96% (based on number of moles).
実施例 ２
撹拌器を備えた反応器に４−オキソ−５−メチ
ル−４，５，６，７−テトラヒドロクマロン−３
−カルボン酸194部およびｎ−プロパノール1440
部を加え、常圧下で95℃に加熱した後、実施例１
と同様の操作により反応した後、反応液を実施例
１と同様に分析した結果、４−オキソ−５−メチ
ル−４，５，６，７−テトラヒドロインドール
138.6部を含むことがわかつた。４−オキソ−５
−メチル−４，５，６，７−テトラヒドロクマロ
ン−３−カルボン酸基準の収率は93％（モル数基
準）であつた。Example 2 4-oxo-5-methyl-4,5,6,7-tetrahydrocumaron-3 was added to a reactor equipped with a stirrer.
- 194 parts of carboxylic acid and 1440 parts of n-propanol
Example 1
After reacting in the same manner as in Example 1, the reaction solution was analyzed in the same manner as in Example 1. As a result, 4-oxo-5-methyl-4,5,6,7-tetrahydroindole
It was found that it contained 138.6 parts. 4-oxo-5
The yield based on -methyl-4,5,6,7-tetrahydrocoumarone-3-carboxylic acid was 93% (based on the number of moles).
比較例 １
アンモニア水の代りに酢酸アンモニウム190部
を用い、反応温度を94℃および145℃にする以外、
実施例１と同様の操作で反応を行つた結果、４−
オキソ−４，５，６，７−テトラヒドロクマロン
−３−カルボン酸基準の収率（モル数基準％）は
それぞれ60％，78％であつた。Comparative Example 1 Except for using 190 parts of ammonium acetate instead of aqueous ammonia and changing the reaction temperature to 94°C and 145°C.
As a result of carrying out the reaction in the same manner as in Example 1, 4-
The yields (% based on moles) of oxo-4,5,6,7-tetrahydrocoumarone-3-carboxylic acid were 60% and 78%, respectively.
比較例 ２
溶媒として水の代りにトルエン1500部を用いる
こと以外、実施例１と同様の操作で反応を行つた
結果、４−オキソ−４，５，６，７−テトラヒド
ロクマロン−３−カルボン酸基準の収率は32％
（モル数基準）であつた。Comparative Example 2 A reaction was carried out in the same manner as in Example 1 except that 1500 parts of toluene was used instead of water as a solvent. As a result, 4-oxo-4,5,6,7-tetrahydrocumaron-3-carvone was obtained. Yield based on acid is 32%
(based on the number of moles).
Claims (1)
ボン酸類をアミノ化剤と反応して４−オキソテト
ラヒドロインドール類を合成するに際し、アミノ
化剤としてアンモニアを使用し、かつアンモニア
と親和性のある溶剤中で前記４−オキソテトラヒ
ドロクマロン−３−カルボン酸類とアンモニアを
常圧下に70〜110℃で反応せしめることを特徴と
する４−オキソテトラヒドロインドール類の製造
法。1 When reacting 4-oxotetrahydrocoumarone-3-carboxylic acids with an aminating agent to synthesize 4-oxotetrahydroindoles, ammonia is used as the aminating agent, and in a solvent with affinity for ammonia. A method for producing 4-oxotetrahydroindoles, which comprises reacting the 4-oxotetrahydrocoumarone-3-carboxylic acids and ammonia at 70 to 110°C under normal pressure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8389584A JPS60228455A (en) | 1984-04-27 | 1984-04-27 | Preparation of 4-oxotetrahydroindole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8389584A JPS60228455A (en) | 1984-04-27 | 1984-04-27 | Preparation of 4-oxotetrahydroindole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60228455A JPS60228455A (en) | 1985-11-13 |
| JPH0262549B2 true JPH0262549B2 (en) | 1990-12-26 |
Family
ID=13815364
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8389584A Granted JPS60228455A (en) | 1984-04-27 | 1984-04-27 | Preparation of 4-oxotetrahydroindole |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60228455A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5927869A (en) * | 1982-08-06 | 1984-02-14 | Sagami Chem Res Center | Preparation of 4-oxo-4,5,6,7-tetrahydroindole |
-
1984
- 1984-04-27 JP JP8389584A patent/JPS60228455A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5927869A (en) * | 1982-08-06 | 1984-02-14 | Sagami Chem Res Center | Preparation of 4-oxo-4,5,6,7-tetrahydroindole |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS60228455A (en) | 1985-11-13 |
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