JPH0143743B2 - - Google Patents

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Publication number
JPH0143743B2
JPH0143743B2 JP10802481A JP10802481A JPH0143743B2 JP H0143743 B2 JPH0143743 B2 JP H0143743B2 JP 10802481 A JP10802481 A JP 10802481A JP 10802481 A JP10802481 A JP 10802481A JP H0143743 B2 JPH0143743 B2 JP H0143743B2
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Japan
Prior art keywords
compound
general formula
reaction
production
methyl
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
Application number
JP10802481A
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Japanese (ja)
Other versions
JPS5810566A (en
Inventor
Hiroshi Ishikawa
Tetsuyuki Uno
Kazuyuki Nakagawa
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Otsuka Pharmaceutical Co Ltd
Original Assignee
Otsuka Pharmaceutical Co Ltd
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Priority to JP10802481A priority Critical patent/JPS5810566A/en
Publication of JPS5810566A publication Critical patent/JPS5810566A/en
Publication of JPH0143743B2 publication Critical patent/JPH0143743B2/ja
Granted legal-status Critical Current

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

【発明の詳现な説明】 本発明は新芏なむンドヌル誘導䜓に関する。[Detailed description of the invention] The present invention relates to novel indole derivatives.

本発明のむンドヌル誘導䜓は、䞋蚘䞀般匏
で衚わされる。 The indole derivative of the present invention is represented by the following general formula (I).

〔匏䞭R1及びR2は倫々䜎玚アルキル基を、X1、
X2及びX3は倫々ハロゲン原子を瀺す〕 䞊蚘䞀般匏で衚わされる本発明のむンド
ヌル誘導䜓は、䟋えば抗菌剀ずしお有甚であるこ
ずの知られおいる−ゞヒドロ−6H〔
−ij〕キノリン−−カルボン酞誘導䜓の
合成䞭間䜓ずしお有甚であり、たた該化合物自䜓
抗菌掻性を有しおおり医療甚及び蟲園芞甚の抗菌
剀ずしお利甚できるものである。䞊蚘本発明化合
物から抗菌剀有効成分化合物を誘導するための方
法は埌蚘する通りである。 [In the formula, R 1 and R 2 each represent a lower alkyl group, X 1 ,
X 2 and X 3 each represent a halogen atom] The indole derivative of the present invention represented by the above general formula (I) is, for example, 1,2-dihydro-6H[3 
2,1-ij] is useful as a synthetic intermediate for quinoline-5-carboxylic acid derivatives, and the compound itself has antibacterial activity and can be used as an antibacterial agent for medical and agricultural and horticultural purposes. The method for deriving the antibacterial active ingredient compound from the above-mentioned compound of the present invention is as described below.

䞊蚘䞀般匏䞭R1及びR2で定矩される䜎
玚アルキル基ずしおは、具䜓的には、メチル、゚
チル、プロピル、む゜プロピル、ブチル、tert−
ブチル、ペンチル、ヘキシル等の各基を、たた
X1、X2及びX3で定矩されるハロゲン原子ずしお
は、塩玠、北玠、臭玠及び沃玠原子を、倫々挙げ
るこずができる。 Specifically, the lower alkyl group defined by R 1 and R 2 in the above general formula (I) includes methyl, ethyl, propyl, isopropyl, butyl, tert-
Each group such as butyl, pentyl, hexyl, etc.
The halogen atoms defined by X 1 , X 2 and X 3 include chlorine, fluorine, bromine and iodine atoms, respectively.

本発明化合物は、代衚的には䞋蚘反応行皋匏−
に瀺す方法により補造される。 The compound of the present invention is typically produced by the following reaction scheme -
It is manufactured by the method shown in I.

〔反応行皋匏−〕 〔各匏䞭R1、R2、X1、X2及びX3は䞊蚘に同じ。
X4はハロゲン原子を瀺す。〕 即ち本発明化合物は䞀般匏で衚わされる
アニリン誘導䜓を出発原料ずし、これをたずハロ
ゲン化剀ず反応させ、次いで埗られる䞀般匏
で衚わされる化合物に、䞀般匏で衚
わされるチオ化合物を反応させるこずにより埗ら
れる。[Reaction formula-1] [In each formula, R 1 , R 2 , X 1 , X 2 and X 3 are the same as above.
X 4 represents a halogen atom. ] That is, the compound of the present invention uses an aniline derivative represented by the general formula () as a starting material, which is first reacted with a halogenating agent, and then the compound represented by the general formula () obtained is added to the aniline derivative represented by the general formula (). Obtained by reacting thio compounds.

䞊蚘においお䞀般匏のアニリン誘導䜓ず
ハロゲン化剀ずの反応は、通垞適圓な溶媒䞭で行
なわれる。溶媒ずしおは反応に悪圱響を䞎えない
通垞の各皮溶媒をいずれも䜿甚できる。その代衚
䟋ずしおは䟋えばクロロホルム、塩化メチレン等
のハロゲン化炭化氎玠類、ゞオキサン、ゞ゚チル
゚ヌテル、テトラヒドロフラン等の゚ヌテル類、
ベンれン、トル゚ン、キシレン等の芳銙族炭化氎
玠類、メタノヌル、゚タノヌル、む゜プロパノヌ
ル等の䜎玚アルコヌル類、ゞメチルスルホキシ
ド、ヘキサメチルリン酞トリアミド、アセトニト
リル等の極性溶剀を䟋瀺できる。たた䞊蚘反応に
甚いられるハロゲン化剀は、通垞のハロゲン化反
応に利甚される各皮化合物をいずれも䜿甚でき
る。その代衚䟋ずしおは䟋えば−ブロムコハク
酞むミド、−クロロコハク酞むミド、次亜臭玠
酞ナトリりム、次亜塩玠酞ナトリりム、サラシ
粉、塩化チオニル、tert−ブチルハむポクロリド
等を䟋瀺できる。之等ハロゲン化剀の䜿甚量は通
垞出発原料化合物に察し少なくずも等モル量、奜
たしくは玄〜1.5倍モル量ずするのがよい。反
応枩床は䞀般に−78〜℃、奜たしくは−60〜−
10℃皋床ずされ、反応は瞬時通垞数分以内に完結
する。 In the above, the reaction between the aniline derivative of general formula () and the halogenating agent is usually carried out in a suitable solvent. As the solvent, any of the usual various solvents that do not adversely affect the reaction can be used. Typical examples include halogenated hydrocarbons such as chloroform and methylene chloride, ethers such as dioxane, diethyl ether, and tetrahydrofuran;
Examples include aromatic hydrocarbons such as benzene, toluene, and xylene, lower alcohols such as methanol, ethanol, and isopropanol, and polar solvents such as dimethyl sulfoxide, hexamethylphosphoric triamide, and acetonitrile. Further, as the halogenating agent used in the above reaction, any of various compounds used in ordinary halogenation reactions can be used. Representative examples include N-bromosuccinimide, N-chlorosuccinimide, sodium hypobromite, sodium hypochlorite, mustard powder, thionyl chloride, tert-butylhypochloride, and the like. The amount of the halogenating agent used is usually at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the starting material compound. The reaction temperature is generally -78 to 0°C, preferably -60 to -
The temperature is approximately 10°C, and the reaction is instantaneous and usually complete within a few minutes.

かくしお䞀般匏で衚わされる䞭間䜓を埗
る。これは反応系より取り出しお匕き続く反応に
䟛しおもよいが、通垞反応系から分離するこずな
く、次いで䞀般匏のチオ化合物ずの反応に
䟛せられる。 In this way, an intermediate represented by the general formula () is obtained. Although this may be taken out from the reaction system and subjected to the subsequent reaction, it is usually subjected to the reaction with the thio compound of general formula () without being separated from the reaction system.

䞊蚘䞀般匏の䞭間䜓ず䞀般匏のチ
オ化合物ずの反応は適圓な塩基性化合物の存圚䞋
に、通垞前蚘䟋瀺の溶媒ず同䞀の溶媒䞭同枩床条
件䞋に行なわれる。甚いられる塩基性化合物ずし
おは、䟋えば炭酞カリりム、炭酞ナトリりム、氎
酞化ナトリりム、炭酞氎玠ナトリりム、ナトリり
ムアミド、氎玠化ナトリりム等の無機塩基性化合
物及びトリ゚チルアミン、トリプロピルアミン、
ピリゞン、キノリン等の第䞉玚アミン類等の有機
塩基性化合物が奜たしく䟋瀺できる。この反応に
おける䞀般匏の䞭間䜓に察する䞀般匏
の化合物の䜿甚量は、䞀般に少なくずも等
モル量、奜たしくは玄〜1.5倍モル量ずすれば
よい。たた反応は通垞玄〜時間で完結する。
かくしお本発明の䞀般匏で衚わされるむン
ドヌル誘導䜓を収埗できる。 The reaction between the intermediate of the above general formula () and the thio compound of the general formula () is carried out in the presence of a suitable basic compound, usually in the same solvent as the above-mentioned exemplified solvent and under the same temperature conditions. Examples of the basic compounds used include inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogen carbonate, sodium amide, and sodium hydride, and triethylamine, tripropylamine,
Preferred examples include organic basic compounds such as tertiary amines such as pyridine and quinoline. The amount of the compound of general formula () to be used in this reaction is generally at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the intermediate of general formula (). Further, the reaction is usually completed in about 1 to 5 hours.
In this way, the indole derivative represented by the general formula (I) of the present invention can be obtained.

䞊蚘反応行皋匏−においお甚いられる各化合
物は、いずれも公知のものであるが、䞀般匏
で衚わされる化合物は、その眮換基により
䞀郚新芏化合物を含んでいる。この䞀般匏
の化合物は、䟋えば䞋蚘反応行皋匏−に瀺す方
法により容易に補造するこずができる。 All of the compounds used in the above reaction scheme-1 are known, but the compound represented by the general formula () contains some new compounds due to its substituents. This general formula ()
The compound can be easily produced, for example, by the method shown in Reaction Scheme-2 below.

〔反応行皋匏−〕 〔各匏䞭X1、X2及びX3は䞊蚘に同じ。R3は䜎玚
アルカノむル基を瀺す。〕 䞀般匏のアニリン誘導䜓のアシル化反応
は適圓なアシル化剀䟋えばアセチルクロラむド、
プロピオニルクロラむド、−ブチリルブロマむ
ド等の䜎玚アルカン酞ハロゲン化物、無氎酢酞等
の䜎玚アルカン酞無氎物を甚いお、適圓な溶媒
䞭、䟋えば氎、゚タノヌル、メタノヌル等のアル
コヌル類、ベンれン、トル゚ン、キシレン等の芳
銙族炭化氎玠類、ゞ゚チル゚ヌテル、テトラヒド
ロフラン等の゚ヌテル類、その他酢酞、ピリゞン
等又は之等の混合溶媒䞭で、反応枩床〜100℃
䞋に、玄10分〜時間で終了する。䜿甚されるア
シル化剀は䞀般匏の化合物に察しお通垞少
なくずも等モル奜たしくは〜1.5倍モル量ずさ
れるのがよい。[Reaction formula-2] [In each formula, X 1 , X 2 and X 3 are the same as above. R 3 represents a lower alkanoyl group. ] The acylation reaction of the aniline derivative of general formula (V) is carried out using a suitable acylating agent such as acetyl chloride,
Using a lower alkanoic acid halide such as propionyl chloride, n-butyryl bromide, or a lower alkanoic acid anhydride such as acetic anhydride, in an appropriate solvent, for example, water, an alcohol such as ethanol or methanol, benzene, toluene, or xylene. in a mixed solvent such as aromatic hydrocarbons such as, ethers such as diethyl ether and tetrahydrofuran, and acetic acid, pyridine, etc., at a reaction temperature of 0 to 100°C.
As shown below, it takes about 10 minutes to 5 hours to complete. The acylating agent used is usually at least equimolar, preferably 1 to 1.5 times the molar amount of the compound of general formula (V).

䞀般匏の化合物ずハロゲン化剀ずの反応
は、適圓な溶媒䞭又は非溶媒䞭奜たしくは非溶媒
䞭でルむス酞の存圚又は非存圚䞋で行うこずが出
来る。ここで䜿甚されるハロゲン化剀ずしおは、
塩玠、臭玠、−ブロムコハク酞むミド、−ク
ロロコハク酞むミド等を䟋瀺できる。たたルむス
酞ずしおは、䟋えば塩化アルミニりム、塩化亜
鉛、塩化鉄、塩化錫、䞉臭化硌玠、䞉北化硌玠、
濃硫酞、硫酞銀等が挙げられる。䜿甚される溶媒
ずしおは、塩化メチレン、クロロホルム、ゞクロ
ロ゚タン、トリクロロ゚タン等の芳銙族炭化氎玠
類、クロロベンれン、ベンれン、トル゚ン、キシ
レン等の芳銙族炭化氎玠類、硫酞等が挙げられ
る。反応枩床は玄〜250℃奜たしくは玄〜200
℃であり、反応は分〜時間皋床で終了する。
ハロゲン化剀の䜿甚量は、䞀般匏の化合物
に察しお通垞〜倍モル量奜たしくは〜倍
モル量ずするのがよく、ルむス酞の䜿甚量は、䞀
般匏の化合物に察しお〜倍モル量ずす
るのがよい。 The reaction between the compound of general formula () and the halogenating agent can be carried out in a suitable solvent or non-solvent, preferably in the presence or absence of a Lewis acid. The halogenating agent used here is
Examples include chlorine, bromine, N-bromosuccinimide, N-chlorosuccinimide, and the like. Examples of Lewis acids include aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride,
Examples include concentrated sulfuric acid and silver sulfate. Examples of the solvent used include aromatic hydrocarbons such as methylene chloride, chloroform, dichloroethane, and trichloroethane, aromatic hydrocarbons such as chlorobenzene, benzene, toluene, and xylene, and sulfuric acid. The reaction temperature is about 0-250℃, preferably about 0-200℃
℃, and the reaction is completed in about 2 minutes to 3 hours.
The amount of the halogenating agent to be used is usually 1 to 8 times the molar amount, preferably 1 to 5 times the molar amount of the compound of the general formula (), and the amount of the Lewis acid to be used is the amount of the compound of the general formula (). The amount is preferably 1 to 5 times the molar amount of the compound.

䞀般匏の化合物の加氎分解反応は、氎、
メタノヌル、゚タノヌル、む゜プロパノヌル等の
アルコヌル䞭で氎酞化ナトリりム、氎酞化カリり
ム、炭酞氎玠ナトリりム等の無機塩基又は塩酞、
硫酞等の酞を甚いお玄〜200℃奜たしくは玄50
〜100℃の枩床䞋に玄30分〜時間を芁しお行な
い埗る。 The hydrolysis reaction of the compound of general formula () is water,
Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, or hydrochloric acid in alcohols such as methanol, ethanol, and isopropanol;
Using an acid such as sulfuric acid, the temperature is about 0 to 200℃, preferably about 50℃.
This can be carried out at a temperature of ~100°C for about 30 minutes to 3 hours.

以䞋本発明むンドヌル誘導䜓からの抗菌剀有効
成分である−ゞヒドロ−6H〔−
ij〕キノリン−−カルボン酞誘導䜓の補造に぀
き䞋蚘反応行皋匏−に埓い詳述する。 Below, 1,2-dihydro-6H [3,2,1-
ij] The production of the quinoline-5-carboxylic acid derivative will be explained in detail according to the following reaction scheme-3.

〔反応行皋匏−〕 〔各匏䞭R1、R2、X1、X2及びX3は䞊蚘に同じ。
R4は氎玠原子、䜎玚アルキル基又は䜎玚アルカ
ノむル基を瀺す。〕 目的ずする抗菌剀有効成分は、䞊蚘に
瀺す通り䞀般匏の本発明化合物より、䞀般
匏の化合物、䞀般匏の化合物、䞀般
匏の化合物及び䞀般匏XIの化合物を経
お、又は䞊蚘においお䞀般匏の化合物を経
るこずなく、補造するこずができる。各反応は以
䞋のようにしお実斜される。[Reaction scheme-3] [In each formula, R 1 , R 2 , X 1 , X 2 and X 3 are the same as above.
R 4 represents a hydrogen atom, a lower alkyl group or a lower alkanoyl group. ] As shown above, the target antibacterial active ingredient (X) is a compound of the general formula (), a compound of the general formula (), a compound of the general formula (X), and a compound of the general formula (I). It can be produced via the compound of general formula (XI) or without passing through the compound of general formula () in the above. Each reaction is carried out as follows.

䞀般匏の本発明むンドヌル誘導䜓の脱硫
反応䞀般匏の化合物の補造反応は、通
垞適圓な觊媒の存圚䞋に溶媒䞭で行なわれる。觊
媒ずしおは䟋えばアルミニりム−アマルガム、リ
チりム−䜎玚アルキルアミン、ラネヌニツケル、
ラネヌコバルト、トリ゚チルホスフアむト、トリ
プニルホスフむン等を䟋瀺でき、奜たしくはラ
ネヌニツケルを挙げるこずが出来る。溶媒ずしお
はメタノヌル、゚タノヌル、む゜プロパノヌル等
のアルコヌル類、ゞオキサン、テトラヒドロフラ
ン、ゞ゚チル゚ヌテル等の゚ヌテル類等を䟋瀺出
来る。反応枩床は玄〜200℃奜たしくは宀枩付
近ずされ、反応は玄〜時間皋床で終了する。
觊媒䜿甚量は、䞀般匏のむンドヌル誘導䜓
に察しお通垞玄〜10倍重量ずするのがよい。 The desulfurization reaction of the indole derivative of the present invention represented by the general formula (I) (the reaction for producing the compound represented by the general formula ()) is usually carried out in a solvent in the presence of a suitable catalyst. Examples of catalysts include aluminum amalgam, lithium lower alkylamine, Raney nickel,
Examples include Raney cobalt, triethyl phosphite, triphenylphosphine, and Raney nickel is preferred. Examples of solvents include alcohols such as methanol, ethanol and isopropanol, and ethers such as dioxane, tetrahydrofuran and diethyl ether. The reaction temperature is about 0 to 200°C, preferably around room temperature, and the reaction is completed in about 1 to 5 hours.
The amount of catalyst used is usually about 1 to 10 times the weight of the indole derivative of general formula (I).

かくしお埗られる䞀般匏の化合物の脱ハ
ロゲン反応䞀般匏の化合物の補造反応
は、通垞の脱ハロゲン化反応方法ず同様にしお実
斜できる。䟋えば、酢酞䞭亜鉛末を甚いる反応方
法、接觊還元方法等により行ない埗る。酢酞䞭亜
鉛末を甚いる反応は、通垞玄50〜150℃の反応枩
床䞋に玄〜時間を芁しお行なわれる。ここで
䜿甚される亜鉛末の量は、䞀般匏の化合物
に察しお通垞玄〜倍モル量ずするのがよい。
たた接觊還元法は、メタノヌル、゚タノヌル、む
゜プロパノヌル等のアルコヌル類、ゞ゚チル゚ヌ
テル、ゞオキサン、テトラヒドロフラン等の゚ヌ
テル類、酢酞等の適圓な溶媒䞭でパラゞりム炭
玠、パラゞりム黒等の觊媒を甚いお有利に行なわ
れる。その反応は℃〜宀枩付近の枩床䞋、〜
気圧皋床の圧力䞋に玄0.5〜時間皋床を芁し
お行なわれる。觊媒の䜿甚量は通垞の觊媒量でよ
く、これは䟋えば䞀般匏の化合物の玄
10〜20重量倍皋床ずされる。䞊蚘接觊還元反
応時には、たたナトリりムアセチレヌト等を添加
するこずも可胜である。 Dehalogenation reaction of the compound of the general formula () obtained in this way (manufacturing reaction of the compound of the general formula ())
can be carried out in the same manner as a normal dehalogenation reaction method. For example, it can be carried out by a reaction method using zinc powder in acetic acid, a catalytic reduction method, etc. The reaction using zinc powder in acetic acid is usually carried out at a reaction temperature of about 50 to 150° C. and takes about 2 to 5 hours. The amount of zinc dust used here is usually about 2 to 5 times the molar amount of the compound of general formula ().
The catalytic reduction method is advantageously carried out using a catalyst such as palladium on carbon or palladium black in an appropriate solvent such as an alcohol such as methanol, ethanol or isopropanol, an ether such as diethyl ether, dioxane or tetrahydrofuran, or acetic acid. . The reaction takes place at temperatures around 0°C to room temperature, from 1 to
The process is carried out under a pressure of about 3 atmospheres and takes about 0.5 to 3 hours. The amount of the catalyst to be used may be a usual catalytic amount, for example, about 1/1 of the amount of the compound of general formula ().
It is said to be about 10 to 1/20 times the weight. During the above catalytic reduction reaction, it is also possible to add sodium acetylate or the like.

たた䞀般匏の化合物は、䞀般匏の
むンドヌル誘導䜓より盎接補造するこずもでき
る。この反応は通垞適圓な溶媒䞭觊媒を甚いお行
なわれる。溶媒ずしおは䞊蚘脱硫反応で䟋瀺した
溶媒をいずれも䜿甚出来る。たた觊媒ずしおはト
リ゚チルホスフアむト、トリプニルホスフむ
ン、ラネヌニツケル等奜たしくはラネヌニツケル
等を䜿甚出来る。反応枩床は通垞〜200℃奜た
しくは玄50〜100℃ずされる。その他の条件は䞊
蚘脱硫反応のそれず同様である。 Moreover, the compound of general formula () can also be directly produced from the indole derivative of general formula (I). This reaction is usually carried out in a suitable solvent using a catalyst. As the solvent, any of the solvents exemplified in the above desulfurization reaction can be used. Further, as a catalyst, triethyl phosphite, triphenylphosphine, Raney nickel, and preferably Raney nickel can be used. The reaction temperature is usually 0 to 200°C, preferably about 50 to 100°C. Other conditions are the same as those for the desulfurization reaction described above.

かくしお埗られる䞊蚘䞀般匏の化合物か
らの目的化合物の補造反応は、いずれも公知に属
し、この公知反応ず同䞀条件、同䞀操䜜により行
なわれる。 The reaction for producing the target compound from the compound of the general formula () thus obtained is all known, and is carried out under the same conditions and by the same operations as the known reaction.

本発明のむンドヌル誘導䜓を利甚しお、䞊蚘反
応行皋匏−を瀺す䞀連の反応を経お目的ずする
抗菌剀有効成分を補造する方法は、特に本発明誘
導䜓が簡単な操䜜で容易に䞔぀高玔床及び高収率
で埗られるものであるず共に、該誘導䜓からの䞀
般匏の化合物の補造も亊簡単な操䜜で容易
に実斜でき高玔床及び高収率で所望化合物を収埗
できるものであるため、工業的実斜に適しおお
り、之等むンドヌル誘導䜓及び䞀般匏で衚
わされる化合物を経由するこずに基づいお、目的
物の収率及び玔床も高く、極めお有甚なものであ
る。 The method for producing the desired antibacterial active ingredient using the indole derivative of the present invention through a series of reactions shown in the above-mentioned reaction scheme 3 is particularly useful because the indole derivative of the present invention can be easily and highly purified by simple operations. and can be obtained in high yield, and the compound of general formula () can be easily produced from the derivative by simple operations, and the desired compound can be obtained with high purity and high yield. , is suitable for industrial implementation, and is extremely useful because it provides a high yield and purity of the target product based on the use of indole derivatives and compounds represented by the general formula ().

䞊蚘反応行皋匏−乃至−に瀺す倫々の行皋
での目的化合物は、通垞の分離手段により単離粟
補するこずができる。該分離手段ずしおは䟋えば
溶媒抜出法、垌釈法、再結晶法、カラムクロマト
グラフむヌ、プレパラテむブ薄局クロマトグラフ
むヌ等を䟋瀺できる。 The target compounds in each step shown in the above reaction schemes -1 to -3 can be isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

以䞋本発明のむンドヌル誘導䜓を補造するため
の原料化合物䞀般匏の化合物の補造䟋
及び本発明化合物から抗菌剀有効成分化合物を埗
るための化合物䞀般匏の化合物の補造
䟋を倫々参考䟋ずしお挙げ、たた本発明化合物の
補造䟋を実斜䟋ずしお挙げる。 The following is an example of manufacturing a raw material compound (compound of general formula ()) for manufacturing the indole derivative of the present invention, and a manufacturing example of a compound (compound of general formula ()) for obtaining an active ingredient compound of an antibacterial agent from the compound of the present invention. are listed as Reference Examples, and production examples of the compounds of the present invention are listed as Examples.

参考䟋  䞀般匏の化合物からの䞀般匏の
化合物の補造 −クロロ−−フルオロアニリン3.2Kgを酢
酞及び氎の混液に溶解させ、宀枩にお無
氎酢酞2.3Kgを加え、70℃で30分間加枩する。反
応埌氷氎10䞭に反応物を投入し、析出する結晶
を過する。氎掗埌也燥しお4.25Kgの−クロロ
−−フルオロ−アセトアニリドを埗る。Reference Example 1 (Production of a compound of general formula () from a compound of general formula (V)) 3.2 kg of 3-chloro-4-fluoroaniline was dissolved in a mixture of 6 acetic acid and 4 parts water, and 2.3 kg of acetic anhydride was dissolved at room temperature. Kg and heat at 70℃ for 30 minutes. After the reaction, the reactant was poured into 10 g of ice water, and the precipitated crystals were filtered off. After washing with water and drying, 4.25 kg of 3-chloro-4-fluoro-acetanilide was obtained.

mp 111〜112℃ 癜色針状晶 参考䟋  䞀般匏の化合物からの䞀般匏の
化合物の補造 参考䟋ず同様にしお−ゞフルオロアニ
リン129gから−ゞフルオロアセトアニリ
ド162.5gを埗る。 mp 111-112°C White needle crystals Reference Example 2 (Production of compound of general formula () from compound of general formula (V)) 3,4- 162.5 g of difluoroacetanilide are obtained.

mp 124〜125℃ 癜色針状晶 参考䟋  䞀般匏の化合物からの䞀般匏の
化合物の補造 −クロロ−−フルオロアセトアニリドKg
に無氎塩化アルミニりム4.3Kgを加え内枩130℃に
加熱しお溶液状にする。぀ぎに内枩130〜140℃に
お臭玠715mlを滎䞋する。滎䞋埌、反応物を10
の氷氎䞭に投入し、析出する結晶を取する。゚
タノヌル−氎で再結晶しお、−ブロム−−フ
ルオロ−−クロロ−アセトアニリド2.7Kgを埗
る。 mp 124-125℃ White needle crystal reference example 3 (Production of compound of general formula () from compound of general formula ()) 3-chloro-4-fluoroacetanilide 2 kg
Add 4.3 kg of anhydrous aluminum chloride to the solution and heat to an internal temperature of 130°C to form a solution. Next, 715 ml of bromine is added dropwise at an internal temperature of 130 to 140°C. After dropping, add the reactant to 10
into ice water and remove the precipitated crystals. Recrystallization from ethanol-water yields 2.7 kg of 2-bromo-4-fluoro-5-chloro-acetanilide.

mp 146〜148℃ 癜色皜状晶 参考䟋  䞀般匏の化合物からの䞀般匏の
化合物の補造 −ゞフルオロアセトアニリド134gを濃
ç¡«é…ž1.1に溶解し、次に硫酞銀123gを加え、氎
冷䞭、臭玠45mlを45分間で滎䞋する。滎䞋埌氷冷
䞋に時間反応させた埌氷氎に投入し、クロ
ロホルムで抜出する。硫酞マグネシりムで也
燥し、濃瞮しお、−ブロム−−ゞフルオ
ロ−アセトアニリド190gを埗る。 mp 146-148℃ White edge-shaped crystals Reference example 4 (Production of compound of general formula () from compound of general formula ()) 134 g of 3,4-difluoroacetanilide was dissolved in 1.1 g of concentrated sulfuric acid, and then 123 g of silver sulfate was dissolved. was added, and 45 ml of bromine was added dropwise over 45 minutes while cooling with water. After the dropwise addition, the reaction mixture was allowed to react for 1 hour under ice-cooling, then poured into ice water (5) and extracted with chloroform (4). Dry over magnesium sulfate and concentrate to obtain 190 g of 2-bromo-4,5-difluoro-acetanilide.

mp 103〜104℃ 癜色針状晶 参考䟋  䞀般匏の化合物からの䞀般匏の
化合物の補造 −ブロム−−フルオロ−−クロロアセト
アニリド1.57Kgをメタノヌル15に溶解し、氎酞
化カリりムKgã‚’æ°Ž1.5に溶解した溶液を加え
る。反応混合物を時間加熱還流する。反応埌混
合物を1/5たで枛圧濃瞮し、残枣に氎10加え、
析出結晶を取する。也燥埌、−ブロム−−
フルオロ−−クロロ−アニリン1.2Kgを埗る。 mp 103-104℃ White needle crystals Reference example 5 (Production of compound of general formula () from compound of general formula ()) Dissolve 1.57 kg of 2-bromo-4-fluoro-5-chloroacetanilide in methanol 15. , add a solution of 2 kg of potassium hydroxide dissolved in 1.5 kg of water. The reaction mixture is heated to reflux for 1 hour. After the reaction, the mixture was concentrated to 1/5 under reduced pressure, and 10% of water was added to the residue.
Take the precipitated crystals. After drying, 2-bromo-4-
1.2 Kg of fluoro-5-chloro-aniline are obtained.

mp 63〜65℃ 無色針状晶 参考䟋  䞀般匏の化合物からの䞀般匏の
化合物の補造 参考䟋ず同様にしお、−ブロム−−
ゞフルオロアセトアニリド180gから、−ブロ
ム−−ゞフルオロアニリン128.8gを埗る。 mp 63-65℃ Colorless needle crystals Reference example 6 (Production of a compound of general formula () from a compound of general formula ()) In the same manner as in Reference example 5, 2-bromo-4,5-
128.8 g of 2-bromo-4,5-difluoroaniline are obtained from 180 g of difluoroacetanilide.

mp 35〜37℃ 無色針状晶 参考䟋  本発明化合物からの䞀般匏の化合物の
補造 −メチル−−メチルチオ−−ゞフル
オロ−−ブロムむンドヌル174gを゚タノヌル
に溶解したのち、ラネヌニツケル1.5Kgを加
え、゚タノヌル加熱還流䞋時間反応させる。反
応埌冷华し、ラネヌニツケルを去する。液を
濃瞮するこずにより−メチル−−ゞフル
オロむンドヌル85.5gを埗る。 mp 35-37°C Colorless needle crystals Reference example 7 (Production of compound of general formula () from the compound of the present invention) 174 g of 2-methyl-3-methylthio-4,5-difluoro-7-bromuindole was dissolved in ethanol 3 After dissolving, 1.5 kg of Raney nickel was added, and the mixture was allowed to react under heating and refluxing with ethanol for 3 hours. After the reaction, the mixture is cooled and the Raney nickel is removed. By concentrating the liquid, 85.5 g of 2-methyl-4,5-difluoroindole was obtained.

mp 72〜74℃ 淡黄色皜状晶 参考䟋  本発明化合物からの䞀般匏の化合物の
補造 −メチル−−゚チルチオ−−クロロ−
−フルオロ−−ブロムむンドヌル700gã‚’ã‚šã‚¿
ノヌル12に溶解したのち、ラネヌニツケルKg
を加え、゚タノヌル加熱還流䞋、時間反応させ
る。反応埌冷华し、ラネヌニツケルを去する。
液を濃瞮するこずにより、−メチル−−ク
ロロ−−フルオロむンドヌル338gを埗る。 mp 72-74°C Pale yellow edge-shaped crystals Reference Example 8 (Production of compound of general formula () from the compound of the present invention) 2-Methyl-3-ethylthio-4-chloro-5
- After dissolving 700 g of fluoro-7-bromiindole in 12 ethanol, 7 kg of Raney nickel was added.
was added, and the mixture was allowed to react for 4 hours under heating and refluxing with ethanol. After the reaction, the mixture is cooled and the Raney nickel is removed.
By concentrating the liquid, 338 g of 2-methyl-4-chloro-5-fluoroindole was obtained.

mp 70〜71℃ 淡黄色皜状晶 参考䟋  本発明化合物からの䞀般匏の化合物の
補造 −メチル−−メチルチオ−−クロロ−
−フルオロ−−ブロムむンドヌル50gをゞオキ
サンに溶解させ、぀ぎにラネヌニツケル
400gを加え、宀枩で時間反応させる。反応埌
ラネヌニツケルを過し、液を枛圧濃瞮する。
残枣を゚タノヌル−氎で再結晶しお、−メチル
−−クロロ−−フルオロ−−ブロムむンド
ヌル30.2gを埗る。 mp 70-71°C Pale yellow edge-shaped crystals Reference Example 9 (Production of compound of general formula () from the compound of the present invention) 2-Methyl-3-methylthio-4-chloro-5
-Dissolve 50g of fluoro-7-bromiindole in 1 part of dioxane, then add
Add 400g and react at room temperature for 4 hours. After the reaction, the mixture is filtered through Raney nickel, and the liquid is concentrated under reduced pressure.
The residue is recrystallized from ethanol-water to obtain 30.2 g of 2-methyl-4-chloro-5-fluoro-7-bromuindole.

該化合物の生成はNMR分析により確認され
る。分析結果は次の通りである。 The production of the compound is confirmed by NMR analysis. The analysis results are as follows.

NMRCDCl3分析結果 ÎŽppm2.40、3H 6.2〜6.4、2H 7.0、1H、Hz 参考䟋 10 䞀般匏の化合物からの䞀般匏の
化合物の補造 −メチル−−クロロ−−フルオロ−−
ブロムむンドヌル20gを゚タノヌル200mlに溶解
し、パラゞりム−炭玠1gを加え、さらに20
氎酞化ナトリりム氎溶液15ml加え垞圧、宀枩に
お接觊還元を行う。理論量の氎玠玄1.7を
吞収したずころで反応を止め、觊媒を去し、濃
瞮する。残枣をシリカゲルカラムクロマトグラフ
むヌワコヌゲル −200、溶出液クロロホル
ム−ヘキサンで粟補し、−メチル
−−クロロ−−フルオロむンドヌル11.5gを
埗る。 NMR (CDCl 3 ) analysis results ÎŽppm = 2.40 (s, 3H) 6.2 - 6.4 (m, 2H) 7.0 (d, 1H, J = 9Hz) Reference example 10 (from the compound of general formula ()) Production of compound) 2-methyl-4-chloro-5-fluoro-7-
Dissolve 20g of bromoindole in 200ml of ethanol, add 1g of 5% palladium-carbon, and add 20g of bromoindole to 200ml of ethanol.
Add 15 ml of % sodium hydroxide aqueous solution and perform catalytic reduction at normal pressure and room temperature. When the theoretical amount of hydrogen (approximately 1.7) has been absorbed, the reaction is stopped, the catalyst is removed, and the mixture is concentrated. The residue was purified by silica gel column chromatography (Wakogel C-200, eluent chloroform:n-hexane 5:1) to obtain 11.5 g of 2-methyl-4-chloro-5-fluoroindole.

mp 70〜71℃ 淡黄色皜状晶 参考䟋 11 䞀般匏の化合物からの䞀般匏の
化合物の補造 −メチル−−ゞフルオロむンドヌル
93gを酢酞1.5に溶解する。これに金属錫200gを
加え、酢酞還流する。還流䞋、濃塩酞1.5を
時間で滎䞋する。滎䞋埌、同枩床で時間反応さ
せる。反応埌、溶媒を枛圧留去する。残枣に氎
を加え、20Kl氎酞化ナトリりム溶液でPH13ずし
たのち、゚ヌテルを加え、撹拌埌䞍溶物を
過する。液より゚ヌテル局を分別し、無氎炭酞
カリりムで也燥する。゚ヌテルを枛圧留去しお、
−メチル−−ゞフルオロむンドリン80g
を埗る。 mp 70-71℃ Pale yellow edge-shaped crystals Reference example 11 (Production of compound of general formula (X) from compound of general formula ()) 2-Methyl-4,5-difluoroindole
Dissolve 93 g in 1.5 acetic acid. Add 200 g of metal tin to this and reflux acetic acid. Under reflux, add 1.5 to 1 part of concentrated hydrochloric acid.
Drip in time. After dropping, the mixture is allowed to react at the same temperature for 2 hours. After the reaction, the solvent is distilled off under reduced pressure. 1 water to the residue
After adjusting the pH to 13 with 20 Kl sodium hydroxide solution, 1 ether was added, and after stirring, the insoluble matter was filtered out. Separate the ether layer from the liquid and dry with anhydrous potassium carbonate. Distill the ether under reduced pressure,
2-Methyl-4,5-difluoroindoline 80g
get.

該化合物の生成はNMR分析により確認した。
その結果は次の通りである。 The production of the compound was confirmed by NMR analysis.
The results are as follows.

NMRCDCl3分析結果 ÎŽppm1.25、3H、Hz 2.0〜3.2、2H 3.4〜4.2、2H 5.8〜6.8、2H 参考䟋 12 䞀般匏の化合物からの䞀般匏の
化合物の補造 −メチル−−クロロ−−フルオロむンド
ヌル330gを氷酢酞に溶解し、金属錫650gを
加え、酢酞加熱還流䞋、濃塩酞を滎䞋する。
反応時間埌、酢酞及び氎を枛圧留去し、残枣に
20氎酞化ナトリりム氎溶液を加え、PH12ずした
のち、゚ヌテルで抜出する。䞍溶物を去
埌、゚ヌテル局を無氎炭酞カリりムで也燥する。
濃瞮埌、−メチル−−クロロ−−フルオロ
むンドリン273.5gを埗る。 NMR (CDCl 3 ) analysis results ÎŽppm=1.25 (d, 3H, J=6Hz) 2.0 to 3.2 (m, 2H) 3.4 to 4.2 (m, 2H) 5.8 to 6.8 (m, 2H) Reference example 12 (General formula ( ) 330 g of 2-methyl-4-chloro-5-fluoroindole was dissolved in 4 glacial acetic acid, 650 g of metal tin was added, and while heating the acetic acid under reflux, concentrated hydrochloric acid 4 drip.
After 4 hours of reaction, acetic acid and water were distilled off under reduced pressure, and the residue
Add 20% aqueous sodium hydroxide solution to adjust the pH to 12, then extract with ether 3. After removing the insoluble matter, the ether layer is dried over anhydrous potassium carbonate.
After concentration, 273.5 g of 2-methyl-4-chloro-5-fluoroindoline are obtained.

該化合物の生成はNMR分析で確認した。その
結果は次の通りである。 The production of this compound was confirmed by NMR analysis. The results are as follows.

NMRCDCl4分析結果 ÎŽppm1.23、3H、Hz 2.3〜3.4、2H 3.48、1H 3.6〜4.2、1H 6.01dd、1H、Hz、Hz 6.5、1H、Hz 実斜䟋  −ブロム−−ゞフルオロアニリン
116gを塩化メチレンに溶解し、ドラむアむ
ス−アセトン济にお−50℃以䞋に冷华する。同枩
床でtert−ブチルハむポクロラむド60gを滎䞋す
る。この時反応系内は䞍均䞀から均䞀な溶液に倉
化する。次に、メチルチオ−−プロパノン67g
を滎䞋し、同枩床で時間反応させる。続いおト
リ゚チルアミン80mlを滎䞋する。滎䞋埌、埐々に
宀枩に戻す。宀枩に戻した埌の氎を加え塩化
メチレン局を分液する。硫酞ナトリりムで也燥す
る。枛圧濃瞮埌゚タノヌル−氎で再結晶しお−
メチル−−メチルチオ−−ゞフルオロ−
−ブロムむンドヌル151.5gを埗る。 NMR (CDCl 4 ) analysis results ÎŽppm = 1.23 (d, 3H, J = 6Hz) 2.3 - 3.4 (m, 2H) 3.48 (s, 1H) 3.6 - 4.2 (m, 1H) 6.01 (dd, 1H, J = 4Hz , 8Hz) 6.5 (d, 1H, J=8Hz) Example 1 2-bromo-4,5-difluoroaniline
Dissolve 116 g in methylene chloride 1 and cool to below -50°C in a dry ice-acetone bath. At the same temperature, 60 g of tert-butyl hypochloride is added dropwise. At this time, the inside of the reaction system changes from a non-uniform solution to a homogeneous solution. Next, 67g of methylthio-2-propanone
was added dropwise and allowed to react at the same temperature for 2 hours. Subsequently, 80 ml of triethylamine is added dropwise. After dropping, gradually return to room temperature. After returning to room temperature, add water from step 1 to separate the methylene chloride layer. Dry with sodium sulfate. After concentrating under reduced pressure, recrystallize with ethanol-water to obtain 2-
Methyl-3-methylthio-4,5-difluoro-
151.5 g of 7-bromoindole are obtained.

mp 104〜105℃ 淡黄色皜状晶 実斜䟋  −ブロム−−フルオロ−−クロロアニリ
ン720gを也燥塩化メチレンに溶解し、−60℃
たで冷华する。次に−ブチルハむポクロラむド
350gの塩化メチレン溶液500mlを同枩床で滎䞋す
る。続いお゚チルチオ−−プロパノン680gの
ゞクロロメタン溶液を滎䞋する。滎䞋埌時
間同枩床で反応埌、さらにトリ゚チルアミン
325gの塩化メチレン溶液を滎䞋する。滎䞋
埌、埐々に宀枩に戻す。぀ぎに氎を加えお撹
拌埌、塩化メチレン局を分離し、硫酞マグネシり
ムで也燥する。枛圧濃瞮埌−メチル−−゚チ
ルチオ−−クロロ−−フルオロ−−ブロム
むンドヌルKgを埗る。 mp 104-105℃ Pale yellow edge-shaped crystal Example 2 720g of 2-bromo-4-fluoro-5-chloroaniline was dissolved in dry methylene chloride 4 and heated to -60℃.
Cool until cool. Next, t-butyl hypochloride
Add 500 ml of a solution of 350 g of methylene chloride dropwise at the same temperature. Subsequently, a solution of 680 g of ethylthio-2-propanone in dichloromethane (1) is added dropwise. After dropping, react at the same temperature for 2 hours, and then add triethylamine.
325 g of methylene chloride solution 1 are added dropwise. After dropping, gradually return to room temperature. Next, water 5 is added and after stirring, the methylene chloride layer is separated and dried over magnesium sulfate. After concentration under reduced pressure, 1 kg of 2-methyl-3-ethylthio-4-chloro-5-fluoro-7-bromuindole was obtained.

該化合物の生成はNMR分析により確認した。
その結果は次の通りである。 The production of the compound was confirmed by NMR analysis.
The results are as follows.

NMRCDCl3分析結果 ÎŽppm1.1、3H、Hz 2.46、3H 3.63、2H、Hz 6.87、1H、Hz 8.2bs、1H NMR (CDCl 3 ) analysis results ÎŽppm=1.1 (t, 3H, J=7Hz) 2.46 (s, 3H) 3.63 (q, 2H, J=7Hz) 6.87 (d, 1H, J=8Hz) 8.2 (bs, 1H) )

Claims (1)

【特蚱請求の範囲】  䞀般匏 〔匏䞭R1及びR2は倫々䜎玚アルキル基を、X1、
X2及びX3は倫々ハロゲン原子を瀺す〕 で衚わされるむンドヌル誘導䜓。[Claims] 1. General formula [In the formula, R 1 and R 2 each represent a lower alkyl group, X 1 ,
X 2 and X 3 each represent a halogen atom] An indole derivative represented by:
JP10802481A 1981-07-09 1981-07-09 Indole derivative Granted JPS5810566A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP10802481A JPS5810566A (en) 1981-07-09 1981-07-09 Indole derivative

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP10802481A JPS5810566A (en) 1981-07-09 1981-07-09 Indole derivative

Publications (2)

Publication Number Publication Date
JPS5810566A JPS5810566A (en) 1983-01-21
JPH0143743B2 true JPH0143743B2 (en) 1989-09-22

Family

ID=14474030

Family Applications (1)

Application Number Title Priority Date Filing Date
JP10802481A Granted JPS5810566A (en) 1981-07-09 1981-07-09 Indole derivative

Country Status (1)

Country Link
JP (1) JPS5810566A (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0417779Y2 (en) * 1986-03-19 1992-04-21
JPH0771728B2 (en) * 1989-10-02 1995-08-02 本田技研工業株匏䌚瀟 Cylinder head and mold for cylinder head
WO1999003465A1 (en) * 1997-07-16 1999-01-28 Eisai Co., Ltd. Antibiotics containing indole derivatives

Also Published As

Publication number Publication date
JPS5810566A (en) 1983-01-21

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