JPH02264757A - Production of nitroindoles - Google Patents
Production of nitroindolesInfo
- Publication number
- JPH02264757A JPH02264757A JP8579389A JP8579389A JPH02264757A JP H02264757 A JPH02264757 A JP H02264757A JP 8579389 A JP8579389 A JP 8579389A JP 8579389 A JP8579389 A JP 8579389A JP H02264757 A JPH02264757 A JP H02264757A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reaction
- solvent
- nitroindoles
- 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
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- HCGYMSSYSAKGPK-UHFFFAOYSA-N 2-nitro-1h-indole Chemical class C1=CC=C2NC([N+](=O)[O-])=CC2=C1 HCGYMSSYSAKGPK-UHFFFAOYSA-N 0.000 title claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 10
- 229910000365 copper sulfate Inorganic materials 0.000 claims abstract description 5
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 5
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 7
- -1 indole compound Chemical class 0.000 abstract description 7
- 125000003118 aryl group Chemical group 0.000 abstract description 6
- 125000000217 alkyl group Chemical group 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003905 agrochemical Substances 0.000 abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 abstract description 3
- 239000012776 electronic material Substances 0.000 abstract description 3
- 230000000802 nitrating effect Effects 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 238000000034 method Methods 0.000 description 22
- 239000000243 solution Substances 0.000 description 11
- 229910052716 thallium Inorganic materials 0.000 description 7
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- RNTCWULFNYNFGI-UHFFFAOYSA-N 1-(2,3-dihydroindol-1-yl)ethanone Chemical compound C1=CC=C2N(C(=O)C)CCC2=C1 RNTCWULFNYNFGI-UHFFFAOYSA-N 0.000 description 5
- LAVZKLJDKGRZJG-UHFFFAOYSA-N 4-nitro-1h-indole Chemical class [O-][N+](=O)C1=CC=CC2=C1C=CN2 LAVZKLJDKGRZJG-UHFFFAOYSA-N 0.000 description 5
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 5
- NBKQRVSGHYZUOR-UHFFFAOYSA-N indoline-3-carbaldehyde Natural products C1=CC=C2C(C=O)CNC2=C1 NBKQRVSGHYZUOR-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 244000309464 bull Species 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LZJGQIVWUKFTRD-UHFFFAOYSA-N 7-nitro-1h-indole Chemical class [O-][N+](=O)C1=CC=CC2=C1NC=C2 LZJGQIVWUKFTRD-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- CGXVTWQTGQAMMX-UHFFFAOYSA-N 4-nitro-1h-indole-3-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(C=O)=CN2 CGXVTWQTGQAMMX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000012746 preparative thin layer chromatography Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000005730 ring rearrangement reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- VJGCLZJLDHAMQI-UHFFFAOYSA-N 1-(7-nitro-2,3-dihydroindol-1-yl)ethanone Chemical compound C1=CC([N+]([O-])=O)=C2N(C(=O)C)CCC2=C1 VJGCLZJLDHAMQI-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- ZLOXFEJDHGQNOG-UHFFFAOYSA-N 1-nitroindole Chemical class C1=CC=C2N([N+](=O)[O-])C=CC2=C1 ZLOXFEJDHGQNOG-UHFFFAOYSA-N 0.000 description 1
- FQJRFSYYZAPSAU-UHFFFAOYSA-N 2,3-dihydroindole-1-sulfonic acid Chemical compound C1=CC=C2N(S(=O)(=O)O)CCC2=C1 FQJRFSYYZAPSAU-UHFFFAOYSA-N 0.000 description 1
- AAPRNHKWNGDTOT-DVRVPOOOSA-N 2-[(3s)-3-(aminomethyl)piperidine-1-carbonyl]-n-[1-(cyclononen-1-ylmethyl)piperidin-4-yl]-9h-xanthene-9-carboxamide Chemical compound C1[C@H](CN)CCCN1C(=O)C1=CC=C(OC=2C(=CC=CC=2)C2C(=O)NC3CCN(CC=4CCCCCCCC=4)CC3)C2=C1 AAPRNHKWNGDTOT-DVRVPOOOSA-N 0.000 description 1
- 238000006641 Fischer synthesis reaction Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- JWAZRIHNYRIHIV-UHFFFAOYSA-N beta-hydroxynaphthyl Natural products C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- SXTLQDJHRPXDSB-UHFFFAOYSA-N copper;dinitrate;trihydrate Chemical compound O.O.O.[Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O SXTLQDJHRPXDSB-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 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、医薬、農薬、電子材料等の分野においてその
原料や原体として有用なニトロインドール類の製造方法
に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for producing nitroindoles useful as raw materials or bulk materials in the fields of medicines, agricultural chemicals, electronic materials, etc.
［従来の技術］
７−ニトロインドール類ヤ４−ニトロインドール類は、
医薬、農薬、電子材料等の原料として重要である。例え
ば１−ニトロインドール類は現在写真薬の発色材の原料
として用いられており、また、４−二トロインドール類
は医薬の原料として用いられている。そして、これらの
化合物のＨａ六方法しては、例えば、７−ニトロインド
ールの場合には、■２−ニトロアニリンから合成された
２−二トロフェニルヒドラジンを原料にフィッシャー（
ＦｉＳＣｈｅｒ）反応によりインドール環を形成し、次
いで脱炭酸反応を行う方法（Ｊ、 Ａｍ、 Ｃｈｅｍ、
Ｓｏｃ、、 ８０．４２６１（１９５８））や、■５
−ニトローβ−ナフトールを出発原料に、開環、転位を
経てインドール環を形成させる方法（Ｔｒ、 ）ｌｏｓ
ｋ、 Ｔｅｋｈｒｉｏｌ、 Ｉｎ５ｔ、、 １９７３．
７４）や、■インドールを出発原料とし、インドリンス
ルホン酸塩を経てニトロ化を行うことにより製造する方
法（Ｃｈｅｍ、 Ｂｅｒ、 ９５．２２０５（ｔ９６２
））が知られている。[Prior art] 7-nitroindoles and 4-nitroindoles are:
It is important as a raw material for medicines, agricultural chemicals, electronic materials, etc. For example, 1-nitroindoles are currently used as raw materials for coloring materials for photographic drugs, and 4-nitroindoles are used as raw materials for pharmaceuticals. For example, in the case of 7-nitroindole, the Ha6 method for these compounds is as follows:
A method in which an indole ring is formed by a reaction (FiSCher) and then a decarboxylation reaction (J, Am, Chem,
Soc,, 80.4261 (1958)), ■5
- A method of forming an indole ring using nitro β-naphthol as a starting material through ring opening and rearrangement (Tr, )los
K, Tekriol, In5t, 1973.
74), and ■ a method of producing by using indole as a starting material and performing nitration via indoline sulfonate (Chem, Ber, 95.2205 (t962
))It has been known.
また、４−ニトロインドールの場合には、■２，６−シ
ニトロトルエンを原料として三工程で製造する方法（Ｃ
ｈｅｍ、 Ｐｈａｒｍ、 Ｂｕｌｌ、、 ２９．３１４
５（１９８１）。In the case of 4-nitroindole, a three-step manufacturing method using 2,6-sinitrotoluene as a raw material (C
hem, Pharm, Bull,, 29.314
5 (1981).
Ｏｒｇａｎｉｃ ５ｙｎｔｈｅｓｉｓ、 ６５．１４６
（ｔ９８７））が知られている。Organic 5ynthesis, 65.146
(t987)) is known.
ざらに、先に我々が提案した■７−又は４−位に−ＴＩ
（ＯＣＯＣＦ３） ２基を有するインドール化合物を原
料に、硝酸銅・三水和物の存在下にＮ、Ｎ−ジメチルホ
ルムアミド−無水酢酸系混合溶媒で各々対応するニトロ
化合物を製造する方法がある（特願昭６３−２４２ 、
３４２号出願）。Roughly, the ■7- or 4-position that we proposed earlier - TI
(OCOCF3) There is a method of producing corresponding nitro compounds using an indole compound having two groups as a raw material in a mixed solvent of N,N-dimethylformamide and acetic anhydride in the presence of copper nitrate trihydrate (specially Gansho 63-242,
Application No. 342).
しかしながら、これら従来の方法においては原料及び反
応収率において欠点が挙げられている。However, these conventional methods have drawbacks in terms of raw materials and reaction yield.
すなわち、７−二トロインドールの！！造方法である■
の方法では出発原料及び副原料のコストが高く、フィッ
シャー反応の開環収率が低いことが問題であり、■の方
法では出発原料を合成することが難しく、開環反応及び
転位反応の収率が低いことが問題であり、また、■の方
法ではインドールスルホン塩のニトロ化反応の際に５−
位にニトロ基が導入されるものがその主生成物であり、
７−位のニトロ化の選択性が低いことが問題である。さ
らに、４−ニトロインドールの製造方法である■では出
発原料及び副原料のコストが高く、反応の再現性が難し
いことが問題である。That is, 7-nitroindole! ! ■ It is a manufacturing method.
The problem with method (2) is that the cost of starting materials and auxiliary materials is high and the ring-opening yield of the Fischer reaction is low, and with method (2), it is difficult to synthesize the starting material and the yield of ring-opening reaction and rearrangement reaction is low. The problem is that the amount of 5-
The main product is one in which a nitro group is introduced into the position,
The problem is that the selectivity for nitration at the 7-position is low. Furthermore, the method (1) for producing 4-nitroindole has problems in that the cost of starting materials and auxiliary materials is high and the reproducibility of the reaction is difficult.
以上の■〜■の方法の問題点を解決すべく、我々が提案
した■の方法は、一応上記■〜■の問題点を解決し・、
その反応収率もこれら■〜■の方法よりも高いが、それ
でも４０〜５０％程度であり、充分に満足できる結果で
はない。In order to solve the problems of the above methods ■~■, the method ■ we proposed solves the problems of the above ■~■,
Although the reaction yield is higher than those of methods 1 to 2, it is still only about 40 to 50%, which is not a fully satisfactory result.
［発明が解決しようとする課題］
本発明者らは、上記の問題点を解決すべく研究を重ねた
結果、７−位又は４−位に−Ｔｌ（ＯＣＯＣＦ３ ＞
２基を有するインドール化合物を原料に、１工程で高収
率に、しかも、位置選択的に７−位又は４−位にニトロ
基を有するインドールを製造することができる改良方法
を見い出し、本発明に到達した。[Problems to be Solved by the Invention] As a result of repeated research to solve the above problems, the present inventors found that -Tl (OCOCF3 >
We have discovered an improved method that can regioselectively produce indole having a nitro group at the 7- or 4-position in one step in a high yield using an indole compound having two groups as a raw material, and the present invention reached.
従って、本発明の目的は、収率良く、しかも、短い製造
工程で７−位又は４−位にニトロ基を有するインドール
類を位置選択的に製造することができる方法を提供する
ことにある。Therefore, an object of the present invention is to provide a method for regioselectively producing indoles having a nitro group at the 7-position or 4-position in a high yield and in a short production process.
［課題を解決するための手段］
すなわら、本発明は、下記一般式［２ａ１又は［２ｂ１
Ｆ３ＣＯＣＯ＼１０ＣＯＣＦ３
丁１
Ｈ［２ｂ ］
（但し、式中Ｒは１価の基を示し、Ｒ２は置換基であり
、ｎはＯ又は１〜５の整数を示す）で表される化合物を
中間体として、下記一般式［１ａｌ。[Means for Solving the Problems] In other words, the present invention solves the problems by the following general formula [2a1 or [2b1
F3COCO\10COCF3 D1 H[2b] (However, in the formula, R represents a monovalent group, R2 is a substituent, and n represents O or an integer from 1 to 5) as an intermediate. As, the following general formula [1al.
【１ｂ１又は［１Ｃ１
Ｈ（１ｃｌ
（但し、式中Ｒ３ハ水素又バーＣ０Ｒ１テＩ） Ｖ）、
Ｒ１、Ｒ２及びｎは前記と同じである〉で表される化合
物を得るニトロインドール化合物類のＴＩＡ造方法でお
る。[1b1 or [1C1 H(1cl (However, in the formula, R3 is hydrogen or C0R1 is V),
This is a TIA production method for nitroindole compounds to obtain a compound represented by R1, R2 and n are the same as above.
本発明方法において、一般式［２ａ１及び［２ｂｌで示
される化合物は、−ＣＯＲ１で示されるカルボニル基を
有するインドール誘導体であり、このＲ１としては水素
、低級アルキル基、アリール基、アルコキシ基、水酸基
又はアミン基等の１価の基であって、好ましくは炭素数
１〜３のアルキル基が置換したアリール基、炭素数１〜
３のアルコキシ基又はアミノ基が挙げられる。また、置
換基Ｒ２は、好ましくは低級アルキル基又はアリール基
であり、ｎはＯ又は１〜５の整数である。In the method of the present invention, the compounds represented by the general formulas [2a1 and [2bl] are indole derivatives having a carbonyl group represented by -COR1, where R1 is hydrogen, a lower alkyl group, an aryl group, an alkoxy group, a hydroxyl group, or A monovalent group such as an amine group, preferably an aryl group substituted with an alkyl group having 1 to 3 carbon atoms, and an aryl group having 1 to 3 carbon atoms.
3, an alkoxy group or an amino group. Further, the substituent R2 is preferably a lower alkyl group or an aryl group, and n is O or an integer of 1 to 5.
一般式［２ａ１の化合物から得られる一般式［１ａ］又
は［１ｂ１で示されるニトロインドール類及び一般式［
２ｂ１の化合物から得られる一般式［１ｃ］で示される
ニトロインドール類は、４−位にニトロ基を有する化合
物であり、Ｒ３は水素又は−ＣＯＲ１である。そして、
Ｒ１、Ｒ２及びｎは前記と同様のものを示す。Nitroindoles represented by the general formula [1a] or [1b1 obtained from the compound of the general formula [2a1] and the general formula [
The nitroindoles represented by the general formula [1c] obtained from the compound 2b1 are compounds having a nitro group at the 4-position, and R3 is hydrogen or -COR1. and,
R1, R2 and n are the same as above.
さらに、本発明方法において、中間体である一般式［２
ａｌ及び［２ｂ１の化合物の合成は、例えばＣｈｅｍ、
Ｐｈａｒｍ、 Ｂｕｌｌ、、 ３５．３１４６（１
９８７）の記載の方法で行うことができる。Furthermore, in the method of the present invention, an intermediate of the general formula [2
Synthesis of al and [2b1 compounds can be performed, for example, in Chem.
Pharm, Bull, 35.3146 (1
987).
そして、本発明方法において、ニトロインドール類を製
造する場合には、中間体である一般式［２ａｌ又は［２
ｂ１の化合物に対して、硫酸銅１〜１゜当量、好ましく
は１〜３当間及び亜硝酸ナトリウム４〜１２当母、好ま
しくは６〜１０当量と、反応溶媒としてのＮ、Ｎ−ジメ
チルホルムアミド５〜４０中４部、好ましくは１０〜２
０重量部とを使用し、反応温度は８０〜１４０’Ｃ１好
ましくは１００〜１２０″Ｃ程度で行うのがよい。In the method of the present invention, when producing nitroindoles, intermediates of the general formula [2al or [2
1 to 1 equivalents of copper sulfate, preferably 1 to 3 equivalents, and 4 to 12 equivalents, preferably 6 to 10 equivalents of sodium nitrite, and N,N-dimethylformamide as a reaction solvent, relative to the compound b1. 4 parts in 5-40, preferably 10-2
0 parts by weight, and the reaction temperature is preferably about 80 to 140'C, preferably about 100 to 120'C.
反応終了後は、溶媒を留去してハロゲン系有機溶媒で抽
出した後、不溶性の無機物を濾過して飽和食塩水で洗浄
し、硫酸ナトリウムで脱水乾燥させ、次いで溶媒を留去
した後、得られた粗生成物を再結晶やカラムクロマトグ
ラフィー等の手段により精製する。After the reaction is completed, the solvent is distilled off and extracted with a halogenated organic solvent, and the insoluble inorganic substances are filtered and washed with saturated brine, dehydrated and dried over sodium sulfate, and the solvent is distilled off. The resulting crude product is purified by means such as recrystallization and column chromatography.
なお、一般式［２ａ１の化合物から上記方法により製造
される一般式［１ａ１の化合物は、常法に従って酸化脱
水素することにより容易に対応する一般式［１ｂ］の化
合物に変換することができる。In addition, the compound of general formula [1a1 produced by the above method from the compound of general formula [2a1] can be easily converted into the corresponding compound of general formula [1b] by oxidative dehydrogenation according to a conventional method.
［作 用］
本発明における反応は、銅塩の■価の鋼とベンゼン環と
がπ錯体を形成し、このπ銘体内でニトロソ化が先ず進
行し、次いで生成したニトロソ体が税離し、■価のタリ
ウムによる酸化によりニトロ体が生成し、目的物が１ｑ
られると考えられる。[Function] In the reaction of the present invention, the steel with a valence of copper salt and the benzene ring form a π complex, nitrosation first proceeds within this π integer, and then the generated nitroso form is separated from tax, and Oxidation with valent thallium produces a nitro body, and the target product is 1q
It is thought that it will be possible.
［実施例］
以下、実施例に基づいて、本発明方法を具体的に説明す
る。[Example] Hereinafter, the method of the present invention will be specifically explained based on Examples.
なお、当量とあるのは、主原料のはを１当Ｗとしたどき
の値である。It should be noted that the term "equivalent" refers to a value based on 1 equivalent W of the main raw material.
実施例１
ＣＯ３Ｏ４−５８２０７６６，１Ｒｇ（９，１当Ｍ）を
Ｎ、Ｎ−ジメチルホルムアミド９ｄに溶解した液にＮａ
ＮＯ２５６７，５ｆｆｉｇ（２４当量）を加え、室温下
に１５分間攪拌した。得られた溶液中に一般式［２ａ］
においてＲ，＝ＣＨ３、ｎ＝０の（１−アセチル−２，
３−ジヒドロインドール−７−イル）タリウムビス（ト
リフルオロアセテート＞２００．３１ｒＩｇ（１当量）
をＮ、Ｎ−ジメチルホルムアミド２ｄに溶かした溶液を
加え、攪拌下に１００℃で２４時間反応させた。Example 1 Na
NO2567.5ffig (24 equivalents) was added and stirred at room temperature for 15 minutes. In the resulting solution, general formula [2a]
(1-acetyl-2,
3-dihydroindol-7-yl)thallium bis(trifluoroacetate >200.31 rIg (1 equivalent)
A solution prepared by dissolving N,N-dimethylformamide 2d was added thereto, and the mixture was reacted at 100° C. for 24 hours with stirring.
反応終了後、減圧下に溶媒を留去し、得られた残留物に
メタノール−酢酸エチルエステル（５：９５゜Ｖ／Ｖ）
混合溶媒を加え、不溶性の固形物を濾別し除去した。濾
液を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾
燥し、減圧下に溶媒を留去した。After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with methanol-ethyl acetate (5:95°V/V).
A mixed solvent was added and insoluble solids were filtered and removed. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
このようにして得られた結晶性の残留物を、塩化メチレ
ン−メタノール（９９：１．Ｖ／Ｖ）混合溶媒を展開溶
媒とするシリカゲル分取薄層クロマトグラフィーニヨリ
精製し、Ｒｆ （Ｉａｏ、４２〜０．２７（７）バンド
より得られた結晶をメタノール−水混合溶媒で再結晶し
、融点１１４．５〜１１５℃である無色針状晶の１−ア
セチル−２，３−ジヒドロ−７−二トロインドール５９
．９ｍｃＪ（収率８６％）を得た。The crystalline residue thus obtained was purified by preparative thin layer chromatography on silica gel using a mixed solvent of methylene chloride and methanol (99:1.V/V) as a developing solvent. The crystals obtained from the ~0.27(7) band were recrystallized from a methanol-water mixed solvent to produce 1-acetyl-2,3-dihydro-7- as colorless needle-like crystals with a melting point of 114.5-115°C. nitro indole 59
．． 9 mcJ (yield 86%) was obtained.
実施例２
１−アセチル−２，３−ジヒドロインドールを原料とし
、Ｃｈｅｍ Ｐｈａｒｍ、 Ｂｕｌｌ、、 ３５．３１
４６（１９８７）の方法に従って（１−アセチル−２，
３−ジヒドロインドール７−イル）タリウムピストリフ
ルオロアセテートを合成し、次いで得られた生成物を単
離精製することなく、上記実施例１と同様にして１−ア
セチル−２，３−ジヒドロインドールから１工程で目的
物を合成した。Example 2 Using 1-acetyl-2,3-dihydroindole as a raw material, Chem Pharm, Bull, 35.31
46 (1987) (1-acetyl-2,
3-dihydroindol (7-yl) thallium pistriefluoroacetate was synthesized, and then the obtained product was synthesized from 1-acetyl-2,3-dihydroindole in the same manner as in Example 1 above without isolation and purification. The target product was synthesized in one step.
すなわち、１−アセチル−２，３−ジヒドロインドール
８４．０ｍＦＪをトリフルオロ酢酸１ｍｌに溶解した１
麦、この溶液中に０．８８モル濃度のタリウムトリスト
リフルオロ酢酸溶液０．８９ｄ（１，５当量）を加え、
室温下に６０時間攪拌して反応させた。That is, 1-acetyl-2,3-dihydroindole 84.0 mFJ was dissolved in 1 ml of trifluoroacetic acid.
wheat, add 0.89 d (1,5 equivalents) of 0.88 molar thallium tristrifluoroacetic acid solution to this solution,
The reaction mixture was stirred at room temperature for 60 hours.
反応終了後、減圧下に溶媒を留去し、ｊｑられた残留物
をＮ、Ｎ〜ジメチルボルムアミド５．０ｍｌに溶解した
。得られた溶液中に、ＣｕＳＯ４５ｔ１２０１ 、１８
３．７ｍｇ（ｇ当量）及びＮａＮＯ２１、８１０，３ｍ
ｙ（５０当母）をＮ、Ｎ−ジメチルホルムアミド１５ｍ
に溶解して得られた溶液を加え、攪拌下に１００’Ｃで
２４時間反応させた。After the reaction was completed, the solvent was distilled off under reduced pressure, and the hydrated residue was dissolved in 5.0 ml of N,N-dimethylbormamide. In the resulting solution, CuSO45t1201,18
3.7 mg (g equivalent) and NaNO21,810.3m
y (50 units) to N,N-dimethylformamide 15m
The solution obtained by dissolving in was added, and the mixture was reacted at 100'C for 24 hours with stirring.
反応終了後、減圧下に溶媒を留去して得られた残留物を
実施例１と同様に処理し、１−アセチル−２，３−ジヒ
ドロ−７−二トロインドール６１．８＃ｌび（５７，５
％）を得た。After the reaction, the solvent was distilled off under reduced pressure and the resulting residue was treated in the same manner as in Example 1 to obtain 61.8 #l of 1-acetyl-2,3-dihydro-7-nitroindole ( 57,5
%) was obtained.
実施例３
ＣｕＳ０４５Ｈ２０７８７、１ｍｆｆ（９，０当量）を
Ｎ、Ｎ−ジメチルホルムアミド９ｄに溶解し、得られた
溶液にＮａＮＯ２５８０，２ｍＦＪ （２４当量）ヲ加
え７１５分間撹拌した。得られた溶液中に、一般式［２
旧においてＲ１＝Ｈ５ｎ＝ｏの（３−ホルミルインドー
ル−４−イル）タリウムビス（トリフルオロアセテート
＞２０１．５７７７ｙをＮ、Ｎ−ジメチルホルムアミド
２ｍｌに溶解して得られた溶液を加え、攪拌下に９５〜
１００’Ｃで２４時間反応させた。Example 3 1 mff (9.0 equivalents) of CuS045H20787 was dissolved in 9d of N,N-dimethylformamide, and 2 mFJ (24 equivalents) of NaNO2580 was added to the resulting solution and stirred for 715 minutes. In the obtained solution, general formula [2
A solution obtained by dissolving (3-formylindol-4-yl)thallium bis(trifluoroacetate>201.5777y with R1=H5n=o in 2 ml of N,N-dimethylformamide in the previous example) was added, and the mixture was stirred. 95～
The reaction was carried out at 100'C for 24 hours.
反応終了後、減圧下に溶媒を留去し、得られた残留物に
メタノール−酢酸エチルエステル（５：９５゜ν／Ｖ）
混合溶媒及び飽和食塩水を加え、良く攪拌した後、不溶
性の固形物を濾過して除去し、得られた濾液を分液して
有機層を得、この有機層を無水硫酸ナトリウムで乾燥し
た後、溶媒を留去して残留物を得た。After the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with methanol-ethyl acetate (5:95°ν/V).
After adding the mixed solvent and saturated saline and stirring well, insoluble solids were removed by filtration, the resulting filtrate was separated to obtain an organic layer, and this organic layer was dried over anhydrous sodium sulfate. , the solvent was distilled off to obtain a residue.
このようにして得られた残留物を、メタノール−塩化メ
チレン（５： ９５． Ｖ／Ｖ）混合溶媒を展開溶媒と
するシリカゲル分取薄層クロマトグラフィーにより精製
し、融点２０６〜２０７℃の４−二トロインドール１．
２ＩＩｔｇ（収率２．１％）、３−ホルミルインドール
２．４η（収率４．７％）及び融点１９６〜１９８℃の
４−ニトロ−３−ホルミルインドール４８．２ｍ！ｊ（
収率７２．３％）を得た。The residue thus obtained was purified by preparative thin layer chromatography on silica gel using a methanol-methylene chloride (5:95.V/V) mixed solvent as a developing solvent to obtain 4- Nitroindole 1.
2IItg (2.1% yield), 2.4η of 3-formylindole (4.7% yield) and 48.2m of 4-nitro-3-formylindole with a melting point of 196-198°C! j(
A yield of 72.3%) was obtained.
実施例４〜１３
反応条件を第１表に示すように変化させたほかは、上記
実施例３と同様にして４−ニトロ−３−ホルミルインド
ールを合成した。そのときの反応条（！１及び収率を第
１表に示す。Examples 4 to 13 4-nitro-3-formylindole was synthesized in the same manner as in Example 3, except that the reaction conditions were changed as shown in Table 1. The reaction conditions (!1) and yields at that time are shown in Table 1.
実施例１４
３−ホルミルインドールを原料とし、Ｃｈｃｍ、 Ｐｈ
ａｒｍ、 Ｂｕｌｌ、、 ３５．３１４６（ｔ９８７）
の方法を利用して（３−ホルミルインドール−４−イル
）タリウムビス（１〜リフルオロアセテート）を合成し
、次いで得られた生成物を単離精製することなく、上記
実施例３と同様にして、３−ホルミルインドールから１
工程で目的物を合成した。Example 14 Using 3-formylindole as a raw material, Chcm, Ph
arm, Bull, 35.3146 (t987)
(3-formylindol-4-yl)thallium bis(1-lifluoroacetate) was synthesized using the method of Example 3 above, and the resulting product was then synthesized in the same manner as in Example 3 above without isolation and purification. , 3-formylindole to 1
The target product was synthesized in the process.
すなわち、３−ホルミルインドール１４５．８ｍｇをト
ルフルオロ酢酸１ｄに溶解し、得られた溶液中に０．８
８モル濃度のタリウムトリストリフルオロ酢酸溶液１．
３６ｍ（１，２当量）を加え、室温下に２４時間攪拌し
て反応させた。That is, 145.8 mg of 3-formylindole was dissolved in 1 d of trifluoroacetic acid, and 0.8 mg of 3-formylindole was dissolved in 1 d of trifluoroacetic acid.
8 molar thallium tristrifluoroacetic acid solution 1.
36m (1.2 equivalents) was added, and the reaction was stirred at room temperature for 24 hours.
反応終了後、減圧下に溶媒を留去し、ｊｑられた残留物
をＮ、Ｎ−ジメチルホルムアミド６ｄに溶解し、コｈｋ
−ＣｕＳ’０４５Ｈ２０２，２８０，６ｍｆｆ（ｇ尚早
〉及びＮａＮＯ２１、６９４，６ｍｇ（２４当但）のＮ
、Ｎ−ジメチルホルムアミド２６ｍ溶液を加え、攪拌下
に１ｏｏ’ｃで２４時間反応させた。After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in N,N-dimethylformamide 6d.
-N of CuS'045H202,280,6mff (g is too early) and NaNO21,694,6mg (24 for now)
, 26 m of N-dimethylformamide solution was added thereto, and the mixture was allowed to react at 100°C for 24 hours with stirring.
反応終了後、減圧下に溶媒を留去し、（７られた残留物
を実施例３と同様に処理し、４−ニトロ−３−ポルミル
インドール１２５．０ｍｇ（収率６５．４％）を１９だ
。After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was treated in the same manner as in Example 3 to obtain 125.0 mg (yield 65.4%) of 4-nitro-3-pormylindole. It's 19.
［発明の効果］
本発明方法によれば、入手困難である７−位又は４−位
にニトロ基を有するインドール類を短い工程で、しかも
、位置選択的に収率良く製造することができ、これによ
ってその工業的な製造が可能になり、その製造コストの
大幅な低減を図ることができる。[Effects of the Invention] According to the method of the present invention, indoles having a nitro group at the 7-position or 4-position, which are difficult to obtain, can be produced in a short process and regioselectively with high yield. This makes it possible to manufacture it industrially, and the manufacturing cost can be significantly reduced.
特許出願人 新日鐵化学株式会社Patent applicant: Nippon Steel Chemical Co., Ltd.
Claims (2)
であり、ｎは０又は１〜５の整数を示す）で表される化
合物を中間体とし、下記一般式［１ａ］、［１ｂ］又は
［１ｃ］ ▲数式、化学式、表等があります▼［１ａ］ ▲数式、化学式、表等があります▼［１ｂ］ ▲数式、化学式、表等があります▼［１ｃ］ （但し、式中Ｒ＿３は水素又は−ＣＯＲ＿１であり、Ｒ
＿１、Ｒ＿２及びｎは前記と同じである）で表される化
合物を得ることを特徴とするニトロインドール類の製造
方法。(1) The following general formula [2a] or [2b] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [2a] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [2b] (However, in the formula, R_1 is a monovalent group , R_2 is a substituent, n is an integer of 0 or 1 to 5) as an intermediate, and the following general formula [1a], [1b] or [1c] ▲Mathematical formula, chemical formula , tables, etc. ▼ [1a] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [1b] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [1c] (However, R_3 in the formula is hydrogen or -COR_1, and R
_1, R_2 and n are the same as above) A method for producing nitroindoles, characterized by obtaining a compound represented by:
，Ｎ−ジメチルホルムアミドを溶媒として行う請求項１
記載のニトロインドール類の製造方法。(2) The reaction is carried out in the presence of copper sulfate and sodium nitrite.
, N-dimethylformamide as a solvent.Claim 1
A method for producing the described nitroindoles.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8579389A JPH02264757A (en) | 1989-04-06 | 1989-04-06 | Production of nitroindoles |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8579389A JPH02264757A (en) | 1989-04-06 | 1989-04-06 | Production of nitroindoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH02264757A true JPH02264757A (en) | 1990-10-29 |
Family
ID=13868766
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8579389A Pending JPH02264757A (en) | 1989-04-06 | 1989-04-06 | Production of nitroindoles |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH02264757A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| US9394285B2 (en) | 2013-03-15 | 2016-07-19 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
-
1989
- 1989-04-06 JP JP8579389A patent/JPH02264757A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8889730B2 (en) | 2012-04-10 | 2014-11-18 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
| US9394285B2 (en) | 2013-03-15 | 2016-07-19 | Pfizer Inc. | Indole and indazole compounds that activate AMPK |
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