JPH0291059A - Production of 7-substituted indole compounds - Google Patents
Production of 7-substituted indole compoundsInfo
- Publication number
- JPH0291059A JPH0291059A JP24234288A JP24234288A JPH0291059A JP H0291059 A JPH0291059 A JP H0291059A JP 24234288 A JP24234288 A JP 24234288A JP 24234288 A JP24234288 A JP 24234288A JP H0291059 A JPH0291059 A JP H0291059A
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- formula
- group
- substituted indole
- indole compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 7-substituted indole compounds Chemical class 0.000 title claims abstract description 17
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 claims abstract 2
- 239000012046 mixed solvent Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 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 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- PSTIYGCBZXFIJN-UHFFFAOYSA-N acetyl acetate;n,n-dimethylformamide Chemical compound CN(C)C=O.CC(=O)OC(C)=O PSTIYGCBZXFIJN-UHFFFAOYSA-N 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 13
- 239000000203 mixture Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 abstract description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000365 copper sulfate Inorganic materials 0.000 abstract 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 abstract 2
- 150000004686 pentahydrates Chemical class 0.000 abstract 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 5
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ORVPXPKEZLTMNW-UHFFFAOYSA-N 1h-indol-7-ol Chemical class OC1=CC=CC2=C1NC=C2 ORVPXPKEZLTMNW-UHFFFAOYSA-N 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 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Substances CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 229910052716 thallium Inorganic materials 0.000 description 4
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 4
- 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 3
- ZKDWNMWTHCDVSN-UHFFFAOYSA-N 1-(7-hydroxy-2,3-dihydroindol-1-yl)ethanone Chemical compound C1=CC(O)=C2N(C(=O)C)CCC2=C1 ZKDWNMWTHCDVSN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- ZMXDDKWLCZADIW-WFVSFCRTSA-N 1-deuterio-n,n-dimethylformamide Chemical compound [2H]C(=O)N(C)C ZMXDDKWLCZADIW-WFVSFCRTSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012776 electronic material Substances 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000005730 ring rearrangement reaction Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- JHFAEUICJHBVHB-UHFFFAOYSA-N 1h-indol-2-ol Chemical compound C1=CC=C2NC(O)=CC2=C1 JHFAEUICJHBVHB-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
- MSVCQAUKLQEIJJ-UHFFFAOYSA-N 7-nitro-2,3-dihydro-1h-indole Chemical class [O-][N+](=O)C1=CC=CC2=C1NCC2 MSVCQAUKLQEIJJ-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 238000006641 Fischer synthesis reaction Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 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
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 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
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012156 elution solvent Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical group C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 150000002476 indolines Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005839 oxidative dehydrogenation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 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７−置換インドール化合物類の
製造法に係り、特に７−位にヒドロキシ基又はニトロ基
を有するインドール化合物類の製造法に関する。Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a method for producing 7-substituted indole compounds useful as raw materials or bulk materials in the fields of medicines, agricultural chemicals, electronic materials, etc. The present invention relates to a method for producing indole compounds having a hydroxy group or a nitro group at the -position.
［従来の技術］
７−ヒドロキシインドール類やＩ−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。[Prior Art] 7-hydroxyindoles and I-nitroindoles are important as raw materials for medicines, agricultural chemicals, electronic materials, and the like.
例えば７−ヒドロキシインドール類は、最近その骨格を
有する多くの薬理活性天然物が発見されており、また、
７−ニトロインドール類は、現在写真薬の発色剤の原料
として用いられている。For example, many pharmacologically active natural products with 7-hydroxyindoles have recently been discovered, and
7-Nitroindoles are currently used as raw materials for color formers in photographic drugs.
そして、これらの化合物の製造法としては、例えば、７
−ヒドロキシインドールの場合には、■Ｎ−アセチルイ
ンドリンを出発原料として６エ程で製造する方法（Ｊ、
Ｏｒｑ、 Ｃｈｅｍ、、 ２０．１５３８（１９５５
）、Ｊ。As a method for producing these compounds, for example, 7
- In the case of hydroxyindole, ■Production method using N-acetylindoline as a starting material in 6 steps (J,
Orq, Chem, 20.1538 (1955
), J.
Ｏｒｇ、 Ｃｈｅｍ、、 ２８．２７９４（１９６３）
）が知られており、また、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（Ｆｉｓｃｈ
ｅｒ）反応によりインドール環を形成し、次いで脱炭酸
反応を行なう方法（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（丁ｒ、 ）ｌｏｓｋ、 Ｔ
ｅｋｈｎｏｌ、 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なうことにより製造する方法（
Ｃｈｅｍ、 Ｂｅｒ、 ９５．２２０５（１９６２））
が知られている。Org, Chem, 28.2794 (1963)
) is known, and in the case of 7-nitroindole, Fisch
er) A method of forming an indole ring by reaction and then performing a decarboxylation reaction (J, Am, Chem, Soc
,, 80.4261 (1958)), and ■ a method of forming an indole ring using 5-nitro β-naphthol as a starting material through ring opening and rearrangement (Cross, )losk, T
Ekhnol, In5t, 1973.74)
, ■Production method using indole as a starting material and nitration via indoline sulfonate (
Chem, Ber, 95.2205 (1962))
It has been known.
また、インドール化合物の４−位に置換基を導入する反
応例としては、インドール−３−アルデヒドの４−位に
−ＴＩ（ＯＣＯＣＦ３） ２基を導入し、この４−位の
−Ｔｌ（ＯＣＯＣＦ３） ２基を水酸基に置換する例（
ｔｈｅｔｅｒｏｃｙｃｌｅｓ、 ２４．３０６５（１９
６５）が知られている。Furthermore, as a reaction example for introducing a substituent into the 4-position of an indole compound, two groups of -TI(OCOCF3) are introduced into the 4-position of indole-3-aldehyde, and -Tl(OCOCF3) at the 4-position is Example of substituting 2 groups with hydroxyl groups (
theterocycles, 24.3065 (19
65) is known.
［発明が解決しようとする課題］
しかしながら、これら従来の技術においては、原料及び
反応収率において欠点が挙げられている。[Problems to be Solved by the Invention] However, these conventional techniques have drawbacks in terms of raw materials and reaction yield.
７−ヒドロキシインドールの製造法である■の方法では
、工程数が長く、かつ、７−位に置換基を導入するため
に、５−位の臭素化を行ない、そして脱臭素を行なうと
いった経済的に効率のよいものではない。また、７−ニ
トロインドールの製造法でめる■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閉環収率
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
れた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。Method (2), which is a method for producing 7-hydroxyindole, requires a long number of steps, and in order to introduce a substituent at the 7-position, bromination is performed at the 5-position, and then debromination is performed, which is an economical process. It is not very efficient. In addition, in method (2) for the production of 7-nitroindole, the cost of starting materials and auxiliary materials is high, and the ring closure yield of the Fischer reaction is low. The problem is that the yields of the ring-opening reaction and rearrangement reaction are low, and in method The problem is that the selectivity for nitration at the 7-position is low.
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工程で収率良く、しかも
、位置選択的に７−置換インドール化合物類を製造し得
る方法を見い出し、本発明に到達した。As a result of repeated research to solve the above-mentioned problems, the present inventors found that using an indole compound having two -Tl(OCOCF3) groups at the 7-position as a raw material, a high yield can be achieved in one step, and the regioselective The inventors have discovered a method for producing 7-substituted indole compounds, and have arrived at the present invention.
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−位にヒドロキシ基やニトロ基を有する７−置
換インドール化合物類を位置選択的に製造する方法を提
供することにある。Therefore, an object of the present invention is to provide a method for regioselectively producing 7-substituted indole compounds having a hydroxyl group or a nitro group at the 7-position in a high yield and in a short production process.
［課題を解決するための手段］
すなわち、本発明は、下記一般式（２）（但し、式中Ｒ
１は−ＣＯＲ３であってＲ３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で、下記一般式（１ａ）又は（
１ｂ）
（但し、式中Ｒ１は水素又は−ＣＯＲ３でおってＲ２、
Ｒ３及びｎは前記と同じであり、また、Ｒ４はヒドロキ
シ基又はニトロ基である）で表される化合物を製造する
１−置換インドール化合物類の製造法である。[Means for Solving the Problems] That is, the present invention solves the problem by solving the following general formula (2) (wherein R
1 is -COR3, R3 is a monovalent group, R2 is a substituent, and n is O or an integer of 1 to 5) as an intermediate, and the following general formula ( 1a) or (
1b) (However, in the formula, R1 is hydrogen or -COR3, and R2,
R3 and n are the same as above, and R4 is a hydroxy group or a nitro group.
本発明方法において、一般式（２）で示される化合物は
、その置換基Ｒ１が水素又は−ＣＯＲ３で表されるカル
ボニル基を有する置換基であり、このＲ３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
又はアミノ基等の１価の基であって、好ましくは炭素数
１〜３のアルキル基、フェニル基、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
シ基又はアミノ基である。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 substituent R1 of the compound represented by the general formula (2) is hydrogen or a substituent having a carbonyl group represented by -COR3, and this R3 is hydrogen, a lower alkyl group, an aryl group. , a monovalent group such as an alkoxy group, a hydroxyl group or an amino group, preferably an alkyl group having 1 to 3 carbon atoms, a phenyl group, an aryl group substituted with an alkyl group having 1 to 3 carbon atoms, and an aryl group substituted with an alkyl group having 1 to 3 carbon atoms. 3 is 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.
また、本発明方法において、一般式（１ａ）又は（１ｂ
）で表される７−置換インドール化合物類は、その置換
Ｉ Ｒ１、Ｒ２及びｎは上記と同様であり、また、７−
位に導入される置換基Ｒ４はヒドロキシ基又はニトロ基
である。Furthermore, in the method of the present invention, general formula (1a) or (1b
), the substituted I R1, R2 and n are the same as above, and the 7-substituted indole compounds are
The substituent R4 introduced at the position is a hydroxy group or a nitro group.
ざらに、本発明方法において、出発原料である一般式（
２）の化合物の合成は、例えば、ｃｈｅｍ。In general, in the method of the present invention, the starting material, the general formula (
The compound 2) can be synthesized using, for example, chem.
Ｐｈａｒｍ、 Ｂｕｌｌ、、 ３５．３１４６（１９８
７）に記載の方法で行うことができる。Pharm, Bull, 35.3146 (198
It can be carried out by the method described in 7).
そして、本発明方法において、７−ヒドロキシインドー
ル化合物類を製造する場合には、好ましくは、出発原料
である一般式（２）の化合物に対し、硫酸銅・五水和物
１〜１０当蟻、好ましくは５当量程度と、反応溶媒とし
てのＮ、Ｎ−ジメチルホルム７ ミド（ＯＨＦ）−水（
１／１． Ｖ／Ｖ）１合溶媒５〜４０重量部、好ましく
は１５〜３０重量部とを使用し、反応温度８０〜１３０
℃、好ましくは１２５℃程度で行うのがよい。また、７
−二トロインドール化合物類を製造する場合には、好ま
しくは、出発原料である一般式（２）の化合物に対し、
硝酸銅・三水和物１〜５当串、好ましくは２〜３当量程
度と、反応溶媒としてのＮ、Ｎ−ジメチルホルムアミド
（Ｄ）ＩＦ）−無水酢酸（１／１． Ｖ／Ｖ）混合溶媒
５〜４０重量部、好ましくは１５〜３０重量部とを使用
し、反応温度６０〜１２０℃、好ましくは８０℃程度で
行うのがよい。In the method of the present invention, when producing 7-hydroxyindole compounds, preferably copper sulfate pentahydrate 1 to 10 compounds are added to the compound of general formula (2) as a starting material, Preferably about 5 equivalents and N,N-dimethylform7amide (OHF)-water (
1/1. 5 to 40 parts by weight, preferably 15 to 30 parts by weight of V/V)1 combined solvent, and the reaction temperature is 80 to 130 parts by weight.
The temperature is preferably about 125°C. Also, 7
- When producing ditroindole compounds, preferably, for the compound of general formula (2) as a starting material,
A mixture of 1 to 5 equivalents, preferably 2 to 3 equivalents, of copper nitrate trihydrate and N,N-dimethylformamide (D)IF)-acetic anhydride (1/1.V/V) as a reaction solvent. It is preferable to use 5 to 40 parts by weight of a solvent, preferably 15 to 30 parts by weight, and to carry out the reaction at a reaction temperature of 60 to 120°C, preferably about 80°C.
本発明方法における反応は、ヒドロキシ化及びニトロ化
のいずれにおいても、銅塩の二価の銅とベンゼン環がπ
−錯体を形成し、この錯体内で水分子及び硝酸イオンと
無水酢酸により生成するニトロニウムイオンによってタ
リウム−炭素結合が水酸基及びニトロ基に置換されるこ
とで反応が進行し、目的物を得る。In the reaction in the method of the present invention, in both hydroxylation and nitration, the divalent copper of the copper salt and the benzene ring are
- A complex is formed, and within this complex, the thallium-carbon bond is replaced by a hydroxyl group and a nitro group by water molecules, nitronium ions generated from nitrate ions, and acetic anhydride, and the reaction proceeds to obtain the desired product.
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、７−ヒトロキシイントリン類の製造法として、Ｃ
ｈｅｍ、 Ｐｈａｒｍ、 Ｂｕｌｌ、、 ３５．３１４
６（１９８７）に記載の方法で一般式（２）の化合物を
合成し、次いでこの化合物を単離精製することなく１工
程で一般式（１ａ）で示される７−ヒトロキシイントリ
ン類を製造することができる。つまり、この方法によれ
ば、インドリン類から１工程で７−ヒトロキシイントリ
ン類を製造することができる。In addition, as a method for producing 7-hydroxyintrins, C
hem, Pharm, Bull,, 35.314
6 (1987) to synthesize the compound of general formula (2), and then produce 7-hydroxyintrins represented by general formula (1a) in one step without isolating and purifying this compound. can do. That is, according to this method, 7-hydroxyintolins can be produced from indolines in one step.
また、生成した７−ヒドロキシ及び７−ニトロインドリ
ン類は、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７−ヒドロキシ及び７−ニトロインドール類
に変換することができる。Further, the generated 7-hydroxy and 7-nitroindolines can be easily converted into the corresponding 7-hydroxy and 7-nitroindoles by oxidative dehydrogenation according to a conventional method.
［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.
実施例１
（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２９０゜２９
を、Ｎ、Ｎ−ジメチルホルムアミド（Ｄ）ＩＦ） ２ｄ
と水２ｒｎ１の混合溶媒中に溶解し、得られた溶液中に
さらに硫酸銅・五水和物６１４．０ｍｇを添加し、攪拌
下に１２５℃で６時間反応させた。反応終了後、減圧下
に溶媒を留去し、得られた残留物に塩化メチレン−メタ
ノール（９５：５． Ｖ／Ｖ）混合溶媒と飽和食塩水と
を加え、不溶性の固形物を濾過して除去した。有機層を
分離し、飽和食塩水で洗浄した俊、硫酸ナトリウムで脱
水乾燥し、溶媒を留去して残留物を得た。得られた残留
物を塩化メチレン−メタノール混合溶媒を溶出溶媒とす
るシリカゲルカラムクロマトグラフィーにより精製し、
ざらにメタノール−水混合溶媒で再結晶し、無色針状結
晶の１−アセチル−７−ヒトロキシインドリン５３．９
ｆＩｔｇ（収率６２％）を得た。Example 1 (1-acetyl-2,3-dihydroindol-7-yl)thallium pitrifluoroacetate 290°29
, N,N-dimethylformamide (D)IF) 2d
614.0 mg of copper sulfate pentahydrate was further added to the resulting solution, and the mixture was reacted at 125° C. for 6 hours with stirring. After the reaction, the solvent was distilled off under reduced pressure, and a methylene chloride-methanol (95:5.V/V) mixed solvent and saturated saline were added to the resulting residue, and insoluble solids were filtered. Removed. The organic layer was separated, washed with saturated brine, dehydrated and dried over sodium sulfate, and the solvent was distilled off to obtain a residue. The obtained residue was purified by silica gel column chromatography using a methylene chloride-methanol mixed solvent as an elution solvent,
Recrystallize from a methanol-water mixed solvent to obtain colorless needle-like crystals of 1-acetyl-7-hydroxyindoline, 53.9
fItg (yield 62%) was obtained.
得られた結晶について、その融点、赤外吸収スペクトル
、’Ｈ−ＮＭＲ，質量分析及び元素分析を行った。結果
を以下に示す。The obtained crystals were subjected to melting point, infrared absorption spectrum, 'H-NMR, mass spectrometry, and elemental analysis. The results are shown below.
融点１１４．５〜１１５℃
ＩＲ（にＢｒ）： ３４４３．１６３２．１６０３．１
５７１．１４７３ ｃｍ−’１Ｈ−ＮＭＲ（ＣＤＣｌ２
）δ： ２．２１（３Ｈ，Ｓ）、 ３．０５（２Ｎ、
ｔ。Melting point 114.5-115℃ IR (Br): 3443.1632.1603.1
571.1473 cm-'1H-NMR (CDCl2
) δ: 2.21 (3H, S), 3.05 (2N,
t.
Ｊ＝８．３Ｈ２）、 ３．９２（２Ｎ、 ｔ、 Ｊ＝８
．３Ｈ７）、 ６．５１（ＩＨ。J=8.3H2), 3.92(2N, t, J=8
．． 3H7), 6.51 (IH.
ｂｒ−ｄ、 Ｊ＝８ｔ！ｚ）、 ６．６２（ＩＨ，ｂｒ
−ｄ、 Ｊ＝６．４Ｈｚ）。br-d, J=8t! z), 6.62 (IH, br
-d, J=6.4Hz).
６．８８（ＩＨ，ｄｄ、 Ｊ＝８ ａｎｄ ６．４Ｈｚ
）、 １１．３０（ＩＨ，ｓ。6.88 (IH, dd, J=8 and 6.4Hz
), 11.30 (IH, s.
ＯＨ）ｐｐｍ
）１ｓ（ｍ／Ｚ）： １７７［Ｈ１
元素分析” Ｃｌ０Ｈ１１ＮＯ２として計算値：Ｃ：６
７．７８； Ｈ：６．２６； Ｎニア、９０測定値：
Ｃ：６７．７０；旧６．３６； Ｎニア、８９実施例２
〜６
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１と同様にして１−アセチル−７−ヒドロキシイ
ンドリンの合成を行った。そのときの収率を第１表に示
す。OH) ppm ) 1s (m/Z): 177 [H1 elemental analysis” Calculated value as Cl0H11NO2: C: 6
7.78; H: 6.26; N near, 90 measured value:
C: 67.70; Old 6.36; N Near, 89 Example 2
~6 1-Acetyl-7-hydroxyindoline was synthesized in the same manner as in Example 1 above, except that the reaction conditions were changed as shown in Table 1. The yield at that time is shown in Table 1.
実施例７
１−アセチルインドリンを原料と１ハＣｈｅｍ、 Ｐｈ
ａｒｍ、 Ｂｕｌｌ、、 ３５．３１４６（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）タリウムご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−アセデルインド
リンがら１工程で目的物を合成した。以下、具体的に説
明する。Example 7 1-acetylindoline as raw material and 1-Ha Chem, Ph
arm, Bull, 35.3146 (1987)
(1-acetyl-2,3-dihydroindol-7-yl)thallium trifluoroacetate was synthesized according to the method of Example 1, and the obtained product was then synthesized in the same manner as in Example 1 above without isolation and purification. The target product was synthesized in one step from , 1-acedelindoline. This will be explained in detail below.
１−アセチルインドリン２０３．６！ｒｔ！ｊをトリフ
ルオロ酢酸３．０ｄに溶解し、次いで得られた溶液に０
．８８モル濃度のタリウムトリストリフルオロ酢酸溶液
２．３ｒｒＩＲ（１，６モル当量）を加えて室温で攪拌
下に２４時間反応させた。反応終了後、減圧下に溶媒を
留去し、得られた残留物にＤＨＦ４゜Ｏｄ及び水４．０
ｍを加え、さらに硫酸銅・五水和物１．５７９９を加え
、攪拌下に１２５℃で６時間反応させた。反応終了後、
溶媒を留去して得られた残留物（塩化メチレン−メタノ
ール（９５二５゜Ｖ／Ｖ）混合溶媒と飽和食塩水とを加
え、不溶性の固形物を濾過して除去した。有機層を分離
し、飽和食塩水で洗浄した後、硫酸ナトリウムで脱水乾
燥し、溶媒を留去して残留物を得た。得られた残留物を
塩化メチレン−メタノール混合溶媒を溶出溶媒とするシ
リカゲルカラムクロマトグラフィーにより精製し、１−
アセチル−７−ヒトロキシインドリン９４．８ＩＩｔｇ
（収率４２％）を得た。1-acetylindoline 203.6! rt! j was dissolved in 3.0 d of trifluoroacetic acid, and then 0
．． 2.3 rrIR (1.6 molar equivalent) of an 88 molar concentration thallium trifluoroacetic acid solution was added, and the mixture was allowed to react for 24 hours with stirring at room temperature. After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was mixed with 4°Od of DHF and 4.0°Od of water.
1.5799 of copper sulfate pentahydrate was added, and the mixture was reacted at 125° C. for 6 hours with stirring. After the reaction is complete,
The residue obtained by distilling off the solvent (methylene chloride-methanol (95-25° V/V) mixed solvent and saturated brine was added, and insoluble solids were removed by filtration. The organic layer was separated. After washing with saturated brine, dehydration and drying over sodium sulfate, the solvent was distilled off to obtain a residue.The obtained residue was subjected to silica gel column chromatography using a methylene chloride-methanol mixed solvent as an eluent. Purified by 1-
Acetyl-7-hydroxyindoline 94.8IItg
(yield 42%).
実施例８
（１−７セチルー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２９０゜０Ｗ
Ｊ（０，４９ｎ＋ ｍｏｌｅ）をＤＨＦ ２．０ｍｊ！
に溶解し、さらに硝酸銅・三水和物２３７ 、５ｆｆｌ
ＳＦ（０，９８ｍ ｍｏｌｅ）と無水酢１２．ＯＮＲと
を一１８℃に冷却しながら攪拌下に添加し、次いで室温
に戻し、さらに８０℃で攪拌下に５時間反応させた。反
応終了後、減圧下に溶媒を留去し、得られた残留物に塩
化メチレン−メタノール（９５：５． Ｖ／Ｖ）混合溶
媒及び飽和食塩水を添加し、不溶性の固形物を濾過して
除去した。有機図を分離し、飽和食塩水で洗浄した後、
硫酸ナトリウムで脱水乾燥し、溶媒を留去して残留物を
得た。得られた残留物をｎ−ヘキサン−酢酸エチルエス
テル混合溶媒を溶出溶媒とするシリカゲルカラムクロマ
トグラフィーで精製し、さらにメタノールで再結晶して
淡黄色プリズム状の１−アセチル−７−ニトロインドリ
ン４６．６ｍｙ（収率４６％）を得た。Example 8 (1-7 cetyl-2,3-dihydroindol-7-yl)thallium pitrifluoroacetate 290°0W
J (0,49n+ mole) to DHF 2.0mj!
Copper nitrate trihydrate 237, 5ffl
SF (0.98 m mole) and anhydrous vinegar 12. ONR was added under stirring while cooling the mixture to -18°C, and then the mixture was returned to room temperature and reacted at 80°C with stirring for 5 hours. After the reaction, the solvent was distilled off under reduced pressure, and a methylene chloride-methanol (95:5.V/V) mixed solvent and saturated saline were added to the resulting residue, and insoluble solids were filtered. Removed. After separating the organic diagram and washing with saturated saline,
After dehydration and drying over sodium sulfate, the solvent was distilled off to obtain a residue. The obtained residue was purified by silica gel column chromatography using a mixed solvent of n-hexane and ethyl acetate as an eluent, and further recrystallized from methanol to obtain pale yellow prismatic 1-acetyl-7-nitroindoline 46. 6my (yield 46%) was obtained.
得られた結晶について、その融点、赤外吸収スペクトル
、’Ｈ−Ｎ Ｍ Ｒ１質量分析及び元素分析を行った。The obtained crystal was subjected to melting point, infrared absorption spectrum, 'H-NMR1 mass spectrometry, and elemental analysis.
結果を以下に示す。The results are shown below.
融点：１６３〜１６４°Ｃ
ＩＲ（ＫＢｒ）： １６７３．１５２０．１３９１ ｃ
ｍ−１１Ｈ−ｔ４ＭＲ（ＣＤＣｌ２＞δ：２．２Ｂ（３
Ｈ，Ｓ）、 ３．１７（２Ｈ，ｔＪ＝７．８１１ｚ）、
４．２０（２Ｈ，ｔ、 Ｊ＝７．８Ｈｚ）、 ７．８
（ＩＨ。Melting point: 163-164°C IR (KBr): 1673.1520.1391 c
m-11H-t4MR(CDCl2>δ:2.2B(3
H, S), 3.17 (2H, tJ=7.811z),
4.20 (2H, t, J=7.8Hz), 7.8
(IH.
ｔ、 Ｊ＝７．９Ｈｚ）、 ７゜３７（ＩＨ，ｂｒ−ｄ
、 Ｊ＝７．９Ｈｚ）、 ７゜６０（ＩＨ，ｂｒ−ｄ、
Ｊ＝７．９Ｈｚ）ｐｐｍＭＳ（ｍ／Ｚ）： ２０６［
Ｈ］
元素分析：Ｃ１ｏＨ１ｏＮ２０３として計紳値：Ｃ：５
８．２５； ｌｌ：４．８９； Ｎ、１３．５８測定値
：Ｃ：５８．０５； Ｈ：４．８８； Ｎ：１３．５９
実施例９〜１０
第２表に示すように硝酸銅・三水和物の使用最を変えた
以外は、上記実施例８と同様にして１−アセチル−７−
ニトロインドリンの合成を行った。そのときの収率を第
２表に示すご
第２表
［発明の効果］
本発明方法によれば、入手困難である７−位にヒドロキ
シ基あφいはニトロ基を有する７−置換インドール化合
物類を短い製造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、工業的な製造が可能になり、製造コス
トの面で極めて経済的である。t, J=7.9Hz), 7°37(IH, br-d
, J=7.9Hz), 7゜60(IH,br-d,
J=7.9Hz)ppmMS(m/Z): 206[
H] Elemental analysis: Calculated value as C1oH1oN203: C:5
8.25; ll: 4.89; N, 13.58 Measured value: C: 58.05; H: 4.88; N: 13.59
Examples 9 to 10 1-Acetyl-7-
Nitroindoline was synthesized. The yield at that time is shown in Table 2. [Effects of the Invention] According to the method of the present invention, a 7-substituted indole compound having a hydroxy group, φ or nitro group at the 7-position, which is difficult to obtain, can be obtained. can be produced in a short production process and in a regioselective manner with good yields, making industrial production possible and extremely economical in terms of production costs.
特許出願人 新日鐵化学株式会社Patent applicant: Nippon Steel Chemical Co., Ltd.
Claims (4)
価の基を示し、Ｒ＿２は置換基であり、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て、下
記一般式（１ａ）又は（１ｂ） ▲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） （但し、式中Ｒ＿１は水素又は−ＣＯＲ＿３であつてＲ
＿２、Ｒ＿３及びｎは前記と同じであり、また、Ｒ＿４
はヒドロキシ基又はニトロ基である）で表される化合物
を製造することを特徴とする７−置換インドール化合物
類の製造法。(1) The following general formula (2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) (However, in the formula, R_1 is -COR_3 and R_3 is 1
represents a valent group, R_2 is a substituent, and n is 0 or 1 to
The compound represented by the following general formula (1a) or (1b) (indicates an integer of 5) is used as an intermediate. 1b) (However, in the formula, R_1 is hydrogen or -COR_3 and R
_2, R_3 and n are the same as above, and R_4
is a hydroxy group or a nitro group.
チルホルムアミド−水系混合溶媒で行う請求項１記載の
７−置換インドール化合物類の製造法。(2) The method for producing 7-substituted indole compounds according to claim 1, wherein the reaction is carried out in an N,N-dimethylformamide-water mixed solvent in the presence of copper sulfate pentahydrate.
チルホルムアミド−無水酢酸系混合溶媒で行う請求項１
記載の７−置換インドール化合物類の製造法。(3) Claim 1: The reaction is carried out in the presence of copper nitrate trihydrate in an N,N-dimethylformamide-acetic anhydride mixed solvent.
Methods for producing the described 7-substituted indole compounds.
く反応に使用される請求項１記載の７−置換インドール
化合物類の製造法。(4) The method for producing 7-substituted indole compounds according to claim 1, wherein the compound represented by general formula (2) is used in the reaction without being purified.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24234288A JPH0291059A (en) | 1988-09-29 | 1988-09-29 | Production of 7-substituted indole compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24234288A JPH0291059A (en) | 1988-09-29 | 1988-09-29 | Production of 7-substituted indole compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0291059A true JPH0291059A (en) | 1990-03-30 |
Family
ID=17087771
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24234288A Pending JPH0291059A (en) | 1988-09-29 | 1988-09-29 | Production of 7-substituted indole compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0291059A (en) |
-
1988
- 1988-09-29 JP JP24234288A patent/JPH0291059A/en active Pending
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