JP2006241111A - New benzofuroxan and its synthesis method - Google Patents
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- 0 CC(*)=C(C=CC=C1)C1=N[C@]1C(C)=CC=CC1 Chemical compound CC(*)=C(C=CC=C1)C1=N[C@]1C(C)=CC=CC1 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N c(cc1)cc2c1nccn2 Chemical compound c(cc1)cc2c1nccn2 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- AWBOSXFRPFZLOP-UHFFFAOYSA-N c1cc2n[o]nc2cc1 Chemical compound c1cc2n[o]nc2cc1 AWBOSXFRPFZLOP-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明は、新規ベンゾフロキサン及びその合成方法に関するものである。 The present invention relates to a novel benzofuroxane and a method for synthesizing the same.
ベンゾフロキサン誘導体として、例えば、特開平６−３４０６４４号公報に記載されている。ベンゾフロキサン類はキノキサリン、フェナジン誘導体、ベンゾフラゾン誘導体などの有用物質の原料として知られている。キノキサリン誘導体は、抗菌性（例えば、薬学雑誌１１６巻６号４９１−４９６に記載）や低酸素細胞毒性を持つことが知られ（例えば、Oncology Reports 8, 679-684(2001)に記載）、フェナジン誘導体は抗菌作用を持つことが知られ(例えば、医学と生物学代１４２巻第１号５−９に記載）、ベンゾフラゾン誘導体は、スーパーオキシド増産作用により酸素毒性を持つことが知られている（例えば、Chem. Pharm. Bull., 1990, 38, 128-132に記載）。 Examples of the benzofuroxane derivatives are described in JP-A-6-340644. Benzofuroxanes are known as raw materials for useful substances such as quinoxaline, phenazine derivatives, and benzofurazone derivatives. Quinoxaline derivatives are known to have antibacterial properties (for example, described in Pharmaceutical Journal, Vol. 116, No. 6, 491-496) and hypoxic cytotoxicity (for example, described in Oncology Reports 8, 679-684 (2001)), and phenazine Derivatives are known to have an antibacterial action (for example, described in Medicine and Biology, Vol. 142, No. 1, No. 5-9), and benzofurazone derivatives are known to have oxygen toxicity due to a superoxide production-increasing action ( For example, as described in Chem. Pharm. Bull., 1990, 38, 128-132).
例えば、キノキサリン１，４−ジオキサイドは、従来トリエチルアミンなどの塩基性触媒下でベンゾフロキサンにβ−ジケトン化合物を付加させた後、脱水環化させるBeirut反応により合成されてきた。
既述の反応は、one pot反応で極めて簡便な合成法であるが、塩基性条件下で不安定な官能基を有する誘導体の合成は困難である。また、目的物の収率も十分ではなかった。 The above-described reaction is a one pot reaction and is a very simple synthesis method, but it is difficult to synthesize a derivative having a functional group that is unstable under basic conditions. Moreover, the yield of the target product was not sufficient.
そこで、本発明は、この課題が無く、キノキサリン、フェナジン誘導体などの目的物質をベンゾフロキサン化合物から製造可能な方法を提供する事を目的とする。本発明の別な目的は、この種のベンゾフロキサン化合物として新規なものを提供する事を特徴とするものである。本発明の他の目的は、新規なベンゾフロキサン化合物の合成方法を提供することにある。本発明の更に他の目的は、新規なベンゾフロキサン化合物から得られた有用な新規キノキサリン誘導体を提供する事にある。 Therefore, the present invention has no such problem, and an object of the present invention is to provide a method capable of producing a target substance such as quinoxaline or a phenazine derivative from a benzofuroxane compound. Another object of the present invention is to provide a novel benzofuroxane compound of this kind. Another object of the present invention is to provide a method for synthesizing a novel benzofuroxane compound. Still another object of the present invention is to provide a useful novel quinoxaline derivative obtained from a novel benzofuroxane compound.
既述の目的を達成する本発明は次のとおりである。本発明の第１は、下記化１の骨格を持つベンゾフロキサン誘導体と下記化２の骨格を持つβージケトン誘導体を、固体酸に吸着させて、次いで加熱して脱水環化反応を起こさせる事を特徴とするキノキサリン誘導体の合成方法である。 The present invention that achieves the above-described object is as follows. In the first aspect of the present invention, a benzofuroxan derivative having a skeleton of the following chemical formula 1 and a β-diketone derivative having a skeleton of the following chemical formula 2 are adsorbed on a solid acid and then heated to cause a dehydration cyclization reaction. This is a method for synthesizing a quinoxaline derivative.
固体酸とは、反応物にプロトンを与えるか、反応物質から電子対を受け取る固体のことであり、例えばシリカゲル、モレキュラーシーブが好適である。 The solid acid is a solid that gives a proton to the reactant or receives an electron pair from the reactant, and for example, silica gel and molecular sieve are preferable.
本発明の第２は、化１の構造式を持つベンゾフロキサン誘導体と下記化３の構造式を持つフェノール誘導体を固体酸に吸着させて、次いで加熱して脱水環化反応を起こさせる事を特徴とするフェナジン誘導体の合成方法である。 The second aspect of the present invention is to adsorb a benzofuroxane derivative having the structural formula of Chemical Formula 1 and a phenol derivative having the structural formula of Chemical Formula 3 below to a solid acid, and then heat to cause a dehydration cyclization reaction. This is a method for synthesizing a characteristic phenazine derivative.
本発明の第３は、下記化４の構造式を持つ、新規なベンゾフロキサン誘導体である。
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
新規なベンゾフロキサン誘導体の好適な例は、下記化５乃至化８での何れかから構成される。 Suitable examples of the novel benzofuroxane derivatives are composed of any of the following chemical formulas 5 to 8.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
前記還元剤としては、亜リン酸トリメチル（Ｐ（ＯＣＨ3））であることが好ましい。 The reducing agent is preferably trimethyl phosphite (P (OCH 3 )).
本発明の第５は、下記化１０で示される新規なキノキサリン１，４−ジオキサイド誘導体である。 The fifth of the present invention is a novel quinoxaline 1,4-dioxide derivative represented by the following chemical formula 10.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。Ｒ５は、メチル基、Ｒ６は、メチル基、メトキシ基、又はフェニル基である。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H. R5 is a methyl group, and R6 is a methyl group, a methoxy group, or a phenyl group.
本発明の第６は、下記化１１で示される新規なフェナジン誘導体である。 A sixth aspect of the present invention is a novel phenazine derivative represented by the following chemical formula 11.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
Ｒ５は、Ｈ、アルデヒド基、カルボン酸、アセチル基またはCOC2H5基
Ｒ６は、ＯＨ、メチル基、メトキシ基、
Ｒ７は、Ｈ、ＯＨである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
R5 is H, aldehyde group, carboxylic acid, acetyl group or COC2H5 group R6 is OH, methyl group, methoxy group,
R7 is H or OH.
本発明の第７は、下記化１２で示される新規なベンゾフラザン誘導体である。 A seventh aspect of the present invention is a novel benzofurazan derivative represented by the following chemical formula 12.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
本発明の第８は、下記化１３で示されるニトロアミノベンゼン誘導体を次亜塩素酸化合物と反応させて、下記化１４で示される既述の新規なベンゾフロキサン誘導体を製造する方法である。 The eighth of the present invention is a method for producing the above-described novel benzofuroxane derivative represented by the following chemical formula 14 by reacting the nitroaminobenzene derivative represented by the chemical formula 13 below with a hypochlorous acid compound.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
本発明の第９は、下記化１５で示されるニトロアミノベンゼン誘導体をアジド化して下記化１６で示される化合物を得、これを熱分解することにより、下記化１７で示される既述の新規なベンゾフロキサン誘導体を製造する方法。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
In the ninth aspect of the present invention, a nitroaminobenzene derivative represented by the following chemical formula 15 is azidated to obtain a compound represented by the following chemical formula 16, which is thermally decomposed, whereby the above-mentioned novel novel compound represented by the following chemical formula 17 is represented. A method for producing a benzofuroxane derivative.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
新規なベンゾフロキサン誘導体の好適な例は、下記化５乃至化８での何れかから構成される。 Suitable examples of the novel benzofuroxane derivatives are composed of any of the following chemical formulas 5 to 8.
本発明の第１０は、前記化１６で示されるアジド化ニトロベンゼン誘導体である。 The tenth aspect of the present invention is an azido nitrobenzene derivative represented by the formula 16.
本発明に新規なベンゾフロキサン誘導体の合成における反応工程は次のとおりである。 The reaction steps in the synthesis of a benzofuroxane derivative novel to the present invention are as follows.
5,6-Diethylbenzofuroxan(1)の合成
3,4-Diethyl-6-nitroaniline (90 mg)/メタノール溶液(10 ml)に50 ％水酸化ナトリウム水溶液(2ml)を加え、0 ℃で冷却しながら4 ％次亜塩素酸ナトリウム水溶液(6 ml)を徐々に加え、加え終わったら室温に戻し塩化メチレンで抽出し水洗した。有機層を硫酸ナトリウムで脱水、溶媒をエバポレート後、得られた粗結晶をメタノール/水から再結晶し黄色針状晶を得た。収量78 mｇ(86 ％). mp,95-97 ℃.
Synthesis of 5,6-Diethylbenzofuroxan (1)
Add 50% aqueous sodium hydroxide solution (2 ml) to 3,4-Diethyl-6-nitroaniline (90 mg) / methanol solution (10 ml) and cool at 0 ° C with 4% aqueous sodium hypochlorite solution (6 ml). ) Was gradually added, and when the addition was completed, the temperature was returned to room temperature, extracted with methylene chloride, and washed with water. The organic layer was dehydrated with sodium sulfate and the solvent was evaporated. The obtained crude crystals were recrystallized from methanol / water to obtain yellow needle crystals. Yield 78 mg (86%). Mp, 95-97 ° C.
5-Ethylbenzofuroxan(2)の合成
3-Ethyl-6-nitroaniline (90 mg)/メタノール溶液(10 ml)に50 ％水酸化ナトリウム水溶液(2 ml)を加え、0 ℃で冷却しながら4 ％次亜塩素酸ナトリウム水溶液(6 ml)を徐々に加え、加え終わったら室温に戻し、ジクロロメタンで抽出し水洗した。有機層を硫酸ナトリウムで脱水、溶媒をエバポレート後、得られた粗結晶をメタノール/水から再結晶し黄色不定形晶を得た。収量72mg(80%). mp,39-41 ℃.
Synthesis of 5-Ethylbenzofuroxan (2)
Add 50% aqueous sodium hydroxide solution (2 ml) to 3-Ethyl-6-nitroaniline (90 mg) / methanol solution (10 ml) and cool at 0 ° C with 4% aqueous sodium hypochlorite solution (6 ml) Was gradually added, and when the addition was completed, the temperature was returned to room temperature, extracted with dichloromethane and washed with water. The organic layer was dehydrated with sodium sulfate and the solvent was evaporated. The obtained crude crystals were recrystallized from methanol / water to obtain yellow amorphous crystals. Yield 72 mg (80%). Mp, 39-41 ° C.
2-Ethyl-6-nitrophenylazide(3N)の合成
2-Ethyl-6-nitroaniline(165 mg,1 mmol)に20 ％塩酸6 mlを加え、0-5 ℃に冷却しながら亜硝酸ナトリウム(69 mg,1 mmol)水溶液(1 ml)をゆっくり加えた。その生成したジアゾニウムイオン溶液に0-5 ℃に冷却しながらアジ化ナトリウム(65 mg, 1 mmol)水溶液(1 ml)を徐々に加えた。そのまま室温で３０分間攪拌し続けた。反応後、ジクロロメタンで抽出し水洗した。有機層を硫酸ナトリウムで脱水、溶媒をエバポレートし、カラムクロマトグラフィー（n-ヘキサン：ジクロロメタン＝60：40）により精製し、得られた溶液をエバポレートした。油状物質として得られた。収量160 mg (86 ％). decomp 56-57 ℃.。
Synthesis of 2-Ethyl-6-nitrophenylazide (3N)
2-Ethyl-6-nitroaniline (165 mg, 1 mmol) was added with 6 ml of 20% hydrochloric acid, and sodium nitrite (69 mg, 1 mmol) aqueous solution (1 ml) was slowly added while cooling to 0-5 ° C. . Sodium azide (65 mg, 1 mmol) aqueous solution (1 ml) was gradually added to the resulting diazonium ion solution while cooling to 0-5 ° C. The stirring was continued for 30 minutes at room temperature. After the reaction, it was extracted with dichloromethane and washed with water. The organic layer was dehydrated with sodium sulfate, the solvent was evaporated and purified by column chromatography (n-hexane: dichloromethane = 60: 40), and the resulting solution was evaporated. Obtained as an oil. Yield 160 mg (86%). Decomp 56-57 ° C.
4-Ethylbenzofuroxan(3)の合成
2-Ethyl-6-nitrophenylazide (195 mg 1 mmol)のアセトニトリル（10 ml）溶液を、メリーゴーラウンド型光照射装置、高圧水銀ランプ400W、パイレックス（登録商標）（登録商標）フィルターを使用し2時間、室温で光分解反応した。反応後、溶媒をエバポレートし、プレパラティブTLC(Merck, Silica gel plate 60 F254 Art. 105717)（ヘキサン：ジクロロメタン＝50：50）により精製した。収量77 mg (46 ％)。パイレックス（登録商標）（登録商標）フィルターとは、パイレックス（登録商標）（アメリカのコーニング社の耐熱ガラス）で作った管状フィルターである。
Synthesis of 4-Ethylbenzofuroxan (3)
2-Ethyl-6-nitrophenylazide (195 mg 1 mmol) in acetonitrile (10 ml) using a merry-go-round light irradiation device, high-pressure mercury lamp 400W, Pyrex (registered trademark) filter for 2 hours, Photolytic reaction at room temperature. After the reaction, the solvent was evaporated, purified by preparative TLC (Merck, Silica gel plate 60 F 254 Art 105717.) ( Hexane: dichloromethane = 50: 50) was purified by. Yield 77 mg (46%). The Pyrex (registered trademark) filter is a tubular filter made of Pyrex (registered trademark) (heat-resistant glass manufactured by Corning, USA).
2-Bromo-6-nitro-4-trifluoromethyl-phenylazide(4N)の合成
水浴上で15℃に保ちながらBromo-6-nitro-4-trifluoromethyl-phenylamine (2.8510g,10mmol)に酢酸(100mL)を加え硫酸水素ニトロシル(10mL)を撹拌しながら加える。滴下終了10分後、温度を10℃に下げさらに10分後アジ化ナトリウム(1.5g/H2O1.5mL)を加え、滴下終了後1時間45分撹拌する。その後氷水(800mL)を加え、冷却しながら1時間30分撹拌する。その後、分液ロートを用い、ジクロロメタンを加えてジクロロメタン層を分取して、精製水で洗浄し、硫化ナトリウムを加え一晩放置する。溶媒を飛ばした後、カラムクロマトグラフィーで分離精製し(n-ヘキサン：ジクロロメタン＝９５：５)減圧乾燥した。2.8948g(93%)の結晶が得られた。
Synthesis of 2-Bromo-6-nitro-4-trifluoromethyl-phenylazide (4N)
Acetic acid (100 mL) is added to Bromo-6-nitro-4-trifluoromethyl-phenylamine (2.8510 g, 10 mmol) while maintaining at 15 ° C. on a water bath, and nitrosyl hydrogen sulfate (10 mL) is added with stirring. Ten minutes after the completion of the dropwise addition, the temperature is lowered to 10 ° C., and further 10 minutes later, sodium azide (1.5 g / H 2 O 1.5 mL) is added. Ice water (800 mL) is then added and stirred for 1 hour 30 minutes while cooling. Thereafter, using a separatory funnel, dichloromethane is added to separate the dichloromethane layer, washed with purified water, and sodium sulfide is added and left overnight. After removing the solvent, the residue was separated and purified by column chromatography (n-hexane: dichloromethane = 95: 5) and dried under reduced pressure. 2.8948 g (93%) of crystals were obtained.
4-Bromo-6-trifluoromethylbenzofuroxan (4)の合成
2- Bromo-6-nitro-4-trifluoromethyl-phenylazide(0.31102g,1mmol)にジエチレングリコール(4ml)を加え、150℃油浴上で還流冷却器を付け、3時間加熱し反応させた。これを水100mlに入れ、その後ジクロロメタンで抽出し精製水で洗浄した後、硫酸ナトリウムを加え一晩放置する。溶媒を飛ばした後、カラムクロマトグラフィーで分離精製し(n-ヘキサン：ジクロロメタン=95:5)、減圧乾燥した。0.2228g(79%)の結晶が得られた。
Synthesis of 4-Bromo-6-trifluoromethylbenzofuroxan (4)
Diethylene glycol (4 ml) was added to 2-Bromo-6-nitro-4-trifluoromethyl-phenylazide (0.31102 g, 1 mmol), and the mixture was heated and reacted for 3 hours with a reflux condenser on a 150 ° C. oil bath. This is put into 100 ml of water, then extracted with dichloromethane, washed with purified water, added with sodium sulfate and left overnight. After removing the solvent, the residue was separated and purified by column chromatography (n-hexane: dichloromethane = 95: 5) and dried under reduced pressure. 0.2228 g (79%) of crystals were obtained.
次にこのようにして合成された化合部のＩＲ分析などを行い、構造を確認した。その結果を以下に示す。
5,6-diethybenzofuroxan (1).
黄色針状晶、mp,95-97 ℃. IR (KBr) cm-1: ・・1623, 1591, 1478, 1376; 1H-NMR
(DMSO-d6): ・・1.23(brt, 6H, J = 7.2 Hz), 2.69(brq, 4H, J = 7.2 Hz), 7.39(brs, 2H),; HRMS (EI) m/z: 192.0898. Calcd for C10H12N2O2 : M,192.0899. Anal. Calcd for C10H12N2O2 : C, 62.49; H, 6.29; N, 14.57. Found: C,62.40; H,6.27; N,14.44。
5-ethybenzofuroxan (2).
Next, IR analysis etc. of the compound part synthesize | combined in this way were performed, and the structure was confirmed. The results are shown below.
5,6-diethybenzofuroxan (1).
Yellow needles, mp, 95-97 ° C. IR (KBr) cm-1: ・ ・ 1623, 1591, 1478, 1376; 1 H-NMR
(DMSO-d6): ・ ・ 1.23 (brt, 6H, J = 7.2 Hz), 2.69 (brq, 4H, J = 7.2 Hz), 7.39 (brs, 2H) ,; HRMS (EI) m / z: 192.0898. Calcd for C10H12N2O2: M, 192.0899. Anal. Calcd for C10H12N2O2: C, 62.49; H, 6.29; N, 14.57. Found: C, 62.40; H, 6.27; N, 14.44.
5-ethybenzofuroxan (2).
黄色不定形晶、mp,39-41 ℃. IR (KBr) cm-1: ・・1617, 1585, 1483, 1380; 1H-NM
R (CDCl3): ・・ 1.21 (t, 3H, J = 7.5 Hz), 2.69(q, 2H, J = 7.5 Hz), 7.11(brs-like, 1H), 7.30 (brs-like, 1H), 7.48 (brs-like, 1H); HRMS (EI) m/z: 164.0586. Calcd for C8H8N2O2 : M,164.0586. Anal. Calcd for C8H8N2O2 : C, 58.53; H, 4.91; N, 17.06. Found: C,58.36; H,4.99; N,16.84.
2-ethyl-6-nitrophenylazide (3N).
Yellow amorphous crystals, mp, 39-41 ° C. IR (KBr) cm-1: ・ ・ 1617, 1585, 1483, 1380; 1 H-NM
R (CDCl3): ・ ・ 1.21 (t, 3H, J = 7.5 Hz), 2.69 (q, 2H, J = 7.5 Hz), 7.11 (brs-like, 1H), 7.30 (brs-like, 1H), 7.48 (brs-like, 1H); HRMS (EI) m / z: 164.0586.Calcd for C8H8N2O2: M, 164.0586. Anal.Calcd for C8H8N2O2: C, 58.53; H, 4.91; N, 17.06. Found: C, 58.36; H, 4.99; N, 16.84.
2-ethyl-6-nitrophenylazide (3N).
油状物質。decomp 56-57 ℃. IR (KBr) cm-1:・・2124, 1530, 1445, 1348; 1H-NMR
(CDCl3): ・・1.26 (t, 3H, J = 7.4 Hz), 2.80(q, 2H, J = 7.4 Hz）, 7.25(t, 1H, J = 8.0 Hz), 7.47(dd, 1H, J = 1.5, 8.0 Hz), 7.81(dd, 1H, J = 1.5, 8.0 Hz); HRMS (EI) m/z: 192.0648. Calcd for C8H8N4O2 : M,192.0647.
4-ethylbenzofuroxan (3).
Oily substance. decomp 56-57 ℃. IR (KBr) cm-1: ・ ・ 2124, 1530, 1445, 1348; 1H-NMR
(CDCl3): ・ ・ 1.26 (t, 3H, J = 7.4 Hz), 2.80 (q, 2H, J = 7.4 Hz), 7.25 (t, 1H, J = 8.0 Hz), 7.47 (dd, 1H, J = 1.5, 8.0 Hz), 7.81 (dd, 1H, J = 1.5, 8.0 Hz); HRMS (EI) m / z: 192.0648.Calcd for C8H8N4O2: M, 192.0647.
4-ethylbenzofuroxan (3).
mp 61-62 ℃. 黄色針状晶 IR (KBr) cm-1: ・・1615, 1576, 1482, 1381; 1H- NMR (DMSO-d6): at 23.8 oC, ・・ 1.19(t, 0.75H, J = 7.3 Hz), 1.31(t, 2.25H, J = 7.3 Hz), 2.90(q, 2H, J = 7.3 Hz) , 7.1-7.6 (m, 3H); HRMS (EI) m/z:164.0591. Calcd for C8H8N2O2 : M,164.0586. Anal. Calcd for C8H8N2O2: C, 58.53; H, 4.91; N, 17.06. Found: C,58.47; H,4.98; N,17.08。 mp 61-62 ° C. Yellow needle IR (KBr) cm-1: ・ ・ 1615, 1576, 1482, 1381; 1H-NMR (DMSO-d6): at 23.8 o C, ・ ・ 1.19 (t, 0.75H , J = 7.3 Hz), 1.31 (t, 2.25H, J = 7.3 Hz), 2.90 (q, 2H, J = 7.3 Hz), 7.1-7.6 (m, 3H); HRMS (EI) m / z: 164.0591 Calcd for C8H8N2O2: M, 164.0586. Anal. Calcd for C8H8N2O2: C, 58.53; H, 4.91; N, 17.06. Found: C, 58.47; H, 4.98; N, 17.08.
2-Bromo-4-trifluoromethyl-6-nitrophenylazide (4N).
mp 23-24o ; 白色結晶 IR (KBr) cm-1: ν 2132, 1541, 1338; 1H-NMR (DMSO-d6): δ 8.45 (d, 1H, J = 1.5 Hz), 8.49 (d, 1H, J = 1.5 Hz); HRMS (EI) m/z: 309.9309. Calcd for C7H2N4O2F3Br : M, 309.9313. Anal. Calcd for C7H2N4O2F3Br : C, 27.03; H, 0.65; N, 18.01. Found: C, 26.97; H, 0.84; N, 17.95.
4-Bromo-6-trifluoromethylbenzofuroxan (4).
2-Bromo-4-trifluoromethyl-6-nitrophenylazide (4N).
mp 23-24 o ; white crystal IR (KBr) cm-1: ν 2132, 1541, 1338; 1H-NMR (DMSO-d 6 ): δ 8.45 (d, 1H, J = 1.5 Hz), 8.49 (d, HRMS (EI) m / z: 309.9309.Calcd for C7H2N4O2F3Br: M, 309.9313. Anal.Calcd for C7H2N4O2F3Br: C, 27.03; H, 0.65; N, 18.01. Found: C, 26.97; H, 0.84; N, 17.95.
4-Bromo-6-trifluoromethylbenzofuroxan (4).
黄色針状晶、mp 49-50o ; IR (KBr) cm-1: ν 1604, 1534, 1487, 1382, 1304; 1H-NMR (DMSO-d6): δ 7.93 (s, 0.06H), 8.21 (s, 0.94H), 8.30 (s, 0.94H), 8.54 (s, 0.06H); HRMS (EI) m/z: 281.9248. Calcd for C7H2N2O2F3Br : M, 281.9251. Anal. Calcd C7H2N2O2F3Br : C, 29.71; H, 0.71; N, 9.90. Found: C, 29.79; H, 0.96; N, 9.84. Yellow needles, mp 49-50 o ; IR (KBr) cm-1: ν 1604, 1534, 1487, 1382, 1304; 1H-NMR (DMSO-d 6 ): δ 7.93 (s, 0.06H), 8.21 (s, 0.94H), 8.30 (s, 0.94H), 8.54 (s, 0.06H); HRMS (EI) m / z: 281.9248.Calcd for C7H2N2O2F3Br: M, 281.9251. Anal. H, 0.71; N, 9.90. Found: C, 29.79; H, 0.96; N, 9.84.
本発明においては、ベンゾフロキサン誘導体から、下記のキノキサリン・フェナジン・ベンゾフラザンの各誘導体を合成している。 In the present invention, the following quinoxaline, phenazine, and benzofurazan derivatives are synthesized from benzofuroxane derivatives.
ベンゾフロキサン誘導体からキノキサリン誘導体の合成は、シリカゲルやモレキュラシーブにベンゾフロキサン類及び活性メチレン化合物（β−ジケトン化合物）を吸着させ、固相状態で加熱して得られる方法である。その反応過程は次のように示される。 The synthesis of a quinoxaline derivative from a benzofuroxane derivative is a method obtained by adsorbing a benzofuroxane and an active methylene compound (β-diketone compound) on silica gel or molecular sieve and heating in a solid phase. The reaction process is shown as follows.
2-Benzoyl-3-methyl-6,7-diethylquinoxaline 1,4-dioxide(6d)の合成
5,6-Diethylbenzofuroxan (19 mg, 0.1 mmol)及びBenzoylacetone(16 mg, 0.1 mmol)をジクロロメタン(10 ml)に溶かし、シリカゲルを2 g加えた。溶媒をエバポレート後、油浴上で110 ℃, 2 時間加熱を行い、反応後、プレパラティブTLC (ジクロロメタン：メタノール=98:2)により精製した。メタノールから再結晶し黄色不定形晶を得た。その機器分析結果は、次の通りであった。
Synthesis of 2-Benzoyl-3-methyl-6,7-diethylquinoxaline 1,4-dioxide (6d)
5,6-Diethylbenzofuroxan (19 mg, 0.1 mmol) and Benzoylacetone (16 mg, 0.1 mmol) were dissolved in dichloromethane (10 ml), and 2 g of silica gel was added. The solvent was evaporated and heated on an oil bath at 110 ° C. for 2 hours. After the reaction, purification was performed by preparative TLC (dichloromethane: methanol = 98: 2). Recrystallization from methanol gave yellow amorphous crystals. The instrumental analysis results were as follows.
Yield 25 mg (74 %). 黄色粉末（メタノールより再結晶）. mp 198-200 oC; IR (KBr): n1721 cm-1; 1H-NMR (DMSO-d6): d 1.28 (t, 3H, J = 7.5 Hz), 1.31 (t, 3H, J = 7.5 Hz), 2.29(s, 3H), 2.89(q, 2H, J = 7.5 Hz), 2.92(q, 2H, J = 7.5 Hz) ,7.57(t-like, 2H, J = 7.7Hz), 7.76(t-like, 1H, J = 7.7Hz), 8.03(d, 2H, J = 7.2 Hz), 8.15(s, 1H), 8.32(s, 1H); HRMS (EI) m/z: Found:336.1473. Calcd for C20H20N2O3 (M):336.1473; Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71. 70; H, 6.27; N, 8.26. Yield 25 mg (74%). Yellow powder (recrystallized from methanol). Mp 198-200 o C; IR (KBr): n1721 cm -1 ; 1 H-NMR (DMSO-d6): d 1.28 (t, 3H , J = 7.5 Hz), 1.31 (t, 3H, J = 7.5 Hz), 2.29 (s, 3H), 2.89 (q, 2H, J = 7.5 Hz), 2.92 (q, 2H, J = 7.5 Hz), 7.57 (t-like, 2H, J = 7.7Hz), 7.76 (t-like, 1H, J = 7.7Hz), 8.03 (d, 2H, J = 7.2 Hz), 8.15 (s, 1H), 8.32 (s HRMS (EI) m / z: Found: 336.1473.Calcd for C20H20N2O3 (M): 336.1473; Anal.Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.70 ; H, 6.27; N, 8.26.
この反応に於ける利点は、次の通りである。無溶媒である。皮膚等に付着しても浸透性が少ない。弱い固体酸で刺激性が少ない。シリカゲル自身が分離精製用の担体で反応後すぐ処理が可能である。シリカゲルではBenzofuroxan類あるいはキノキサリン誘導体を単体で吸着させた場合反応しない。シリカゲル、モレキュラシーブの再生は比較的容易。 The advantages in this reaction are as follows. Solvent-free. Even if it adheres to the skin etc., the permeability is low. It is a weak solid acid and less irritating. Silica gel itself can be processed immediately after the reaction with a carrier for separation and purification. Silica gel does not react when Benzofuroxan or a quinoxaline derivative is adsorbed alone. Regeneration of silica gel and molecular sieve is relatively easy.
ここで説明した、quinoxaline 1,4-dioxide誘導体には、低酸素状態で選択的に細胞毒性が認められている。この誘導体は、低酸素状態において生体内還元を受けて反応性(細胞に障害性）の高いラジカル性化合物へと変換されるので、低酸素状態において特に強い細胞毒性を発揮する。癌細胞組織においては、異常な増殖により毛細血管が破壊され、他の組織から孤立し、十分に酸素や栄養分が届かず低酸素状態になっている。 The quinoxaline 1,4-dioxide derivatives described here are selectively cytotoxic in hypoxia. This derivative undergoes in vivo reduction in a hypoxic state and is converted into a radical compound having high reactivity (damage to cells), and thus exhibits particularly strong cytotoxicity in a hypoxic state. In cancer cell tissues, capillaries are destroyed by abnormal growth, isolated from other tissues, and oxygen and nutrients do not reach sufficiently and are in a low oxygen state.
そこで、2位にBenzoyl基を持つquinoxaline 1,4-dioxide誘導体ではヒトの肝癌細胞であるHepg2細胞に適用したところ、低酸素細胞毒性が確認された。
また、2-Benzoyl-3-methyl-6,7-diethylquinoxaline 1,4-dioxideには抗菌性が認められた。
Therefore, quinoxaline 1,4-dioxide derivatives with a Benzoyl group at the 2nd position were confirmed to be hypoxic cytotoxic when applied to Hepg2 cells, which are human liver cancer cells.
In addition, antibacterial activity was observed in 2-Benzoyl-3-methyl-6,7-diethylquinoxaline 1,4-dioxide.
2-Hydroxy-3-methoxyphenazine 5,10-dioxide（７）
Benzofuroxan ０．２５mmol及び2-Methoxybenzene-1,4-diol ０．２７５mmolをメタノール（５mL）に溶かし、そこにモレキュラシーブ４Ａを１ｇ入れ、溶媒をエバポレート後、２時間室温下に置く。カラムクロマトグラフィー (ジクロロメタン：メタノール=95:5)及びプレパラティブTLC (ジクロロメタン：メタノール=95:5)により精製し、赤色粉末を得た。収率９１％。機器分析結果は、次のとおりである。
2-Hydroxy-3-methoxyphenazine 5,10-dioxide (7)
0.25 mmol of Benzofuroxan and 0.275 mmol of 2-Methoxybenzene-1,4-diol are dissolved in methanol (5 mL), 1 g of molecular sieve 4A is added thereto, and the solvent is evaporated. Purification by column chromatography (dichloromethane: methanol = 95: 5) and preparative TLC (dichloromethane: methanol = 95: 5) gave a red powder. Yield 91%. The instrumental analysis results are as follows.
mp 248-250 oC; IR (KBr): n1620, 1524, 1470, 1347, 1223, 1185, 1082, 852, cm-1; 1H-NMR (DMSO-d6): d 4.06(s, 3H, OCH3), 7.80 (s, 1H), 7.81(s, 3H), 7.84-7.89(m, 2H), 8.52-8.57(m, 2H) ,11.47(brs, 1H, deuterium oxide-exchangeable); HRMS (EI) m/z: Found:258.0639. Calcd for C13H10N2O4 (M):258.0639; Anal. Calcd for C13H10N2O4: C, 60.47; H, 3.90; N, 10.85. Found: C, 60.42; H, 4.01; N, 10.80.
2-Hydroxy-3-methoxyphenazine 5,10-dioxideは抗菌性が確認された。
mp 248-250 o C; IR (KBr): n1620, 1524, 1470, 1347, 1223, 1185, 1082, 852, cm -1 ; 1 H-NMR (DMSO-d6): d 4.06 (s, 3H, OCH3 ), 7.80 (s, 1H), 7.81 (s, 3H), 7.84-7.89 (m, 2H), 8.52-8.57 (m, 2H), 11.47 (brs, 1H, deuterium oxide-exchangeable); HRMS (EI) m / z: Found: 258.0639.Calcd for C13H10N2O4 (M): 258.0639; Anal.Calcd for C13H10N2O4: C, 60.47; H, 3.90; N, 10.85. Found: C, 60.42; H, 4.01; N, 10.80.
2-Hydroxy-3-methoxyphenazine 5,10-dioxide was confirmed to be antibacterial.
さらに、ベンゾフラザン誘導体の合成例について説明する。 Further, synthesis examples of benzofurazan derivatives will be described.
4-Ethylbenzofurazan(3Z)の合成
4-Ethylbenzofuroxan (164 mg,1 mmol)に亜リン酸トリメチル(2 ml)を加え、30分間加熱還流した。反応後、溶媒を減圧蒸留により留去し、プレパラティブＴＬＣ（ヘキサン：ジクロロメタン＝50：50）により精製した。白色針状晶
収量111 mg(75 ％). 機器分析結果は次のとおりである。
Synthesis of 4-Ethylbenzofurazan (3Z)
Trimethyl phosphite (2 ml) was added to 4-Ethylbenzofuroxan (164 mg, 1 mmol), and the mixture was heated to reflux for 30 minutes. After the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by preparative TLC (hexane: dichloromethane = 50: 50). White needle crystal yield 111 mg (75%). The instrumental analysis results are as follows.
mp 30-31 oC; IR (KBr): n1619, 1531, 1400, 1354 cm-1; 1H-NMR (CDCl3): d 1.35 (t, 3H, J = 7.6 Hz), 3.00(q, 2H, J = 7.6 Hz), 7.36(d, 1H, J = 6.6 Hz) , 7.54(dd, 1H, J = 8.9, 6.6 Hz) , 7.85(d, 1H, J = 8.9 Hz); HRMS (EI) m/z: Found:148.0634. Calcd for C8H8N2O (M):148.0637; Anal. Calcd for C8H8N2O: C,64.85; H, 5.44; N, 18.91. Found: C,64.64; H,5.53; N,18.73. mp 30-31 o C; IR (KBr): n1619, 1531, 1400, 1354 cm -1 ; 1 H-NMR (CDCl3): d 1.35 (t, 3H, J = 7.6 Hz), 3.00 (q, 2H, J = 7.6 Hz), 7.36 (d, 1H, J = 6.6 Hz), 7.54 (dd, 1H, J = 8.9, 6.6 Hz), 7.85 (d, 1H, J = 8.9 Hz); HRMS (EI) m / z: Found: 148.0634.Calcd for C8H8N2O (M): 148.0637; Anal.Calcd for C8H8N2O: C, 64.85; H, 5.44; N, 18.91. Found: C, 64.64; H, 5.53; N, 18.73.
Claims (13)
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、Ｒ４は、Ｈである。 A novel benzofuroxan derivative having the structural formula shown below.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。 A process for producing a benzofurazane derivative represented by the following chemical formula 9, wherein the benzofuroxane derivative of the chemical formula 4 according to claim 3 is reacted with a reducing agent.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、
Ｒ４はＨ、及び
Ｒ５は、メチル基、Ｒ６は、メチル基、メトキシ基、又はフェニル基である。 A novel quinoxaline 1,4-dioxide derivative represented by the following chemical formula 10.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 ,
R4 is H, R5 is a methyl group, and R6 is a methyl group, a methoxy group, or a phenyl group.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、
Ｒ４はＨ、
Ｒ５は、Ｈ、アルデヒド基、カルボン酸、アセチル基またはCOC2H5基、及び、
Ｒ６は、ＯＨ、メチル基、メトキシ基、
Ｒ７は、Ｈ、ＯＨ A novel phenazine derivative represented by the following chemical formula 10.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 ,
R4 is H,
R5 is H, an aldehyde group, a carboxylic acid, an acetyl group or a COC 2 H 5 group, and
R6 is OH, methyl group, methoxy group,
R7 is H, OH
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。 A novel benzofurazane derivative represented by the following chemical formula 11.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。 A method for producing a novel benzofuroxane derivative represented by the following chemical formula 13 by reacting a nitroaminobenzene derivative represented by the following chemical formula 12 with a hypochlorous acid compound.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。 A method for producing a novel benzofuroxane derivative represented by the following chemical formula 16 by azidating a nitroaminobenzene derivative represented by the following chemical formula 14 to obtain a compound represented by the following chemical formula 15 and thermally decomposing it.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
Ｒ２，Ｒ３は、Ｈ、又はエチル基、
Ｒ３は、Ｈ、エチル基又は−ＣＦ3、及び、
Ｒ４は、Ｈである。 The following azido nitrobenzene derivative represented by Chemical formula 15 according to claim 11.
R2 and R3 are H or an ethyl group,
R3 is H, an ethyl group or —CF 3 , and
R4 is H.
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| JP2001502717A (en) * | 1996-10-28 | 2001-02-27 | ノバルティス アクチエンゲゼルシャフト | Naphthyridine derivative |
| WO2001047485A1 (en) * | 1999-12-24 | 2001-07-05 | Henkel Kommanditgesellschaft Auf Aktien | Agent for colouring fibres containing keratin |
| WO2004087684A1 (en) * | 2003-04-04 | 2004-10-14 | Novartis Ag | Benzo[1,2,5]oxadiazoles and benzo [1,2,5]thiadiazoles useful as histopathological staining agents, imaging agents and biomarkers |
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