JPS604824B2 - Indazole derivative - Google Patents
Indazole derivativeInfo
- Publication number
- JPS604824B2 JPS604824B2 JP51036100A JP3610076A JPS604824B2 JP S604824 B2 JPS604824 B2 JP S604824B2 JP 51036100 A JP51036100 A JP 51036100A JP 3610076 A JP3610076 A JP 3610076A JP S604824 B2 JPS604824 B2 JP S604824B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- phenyl
- parts
- concentrated
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は一般式
(式中、Rはアルデヒド基またはカルボキシル基、nは
2〜3の整数を示す。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R is an aldehyde group or a carboxyl group, and n is an integer of 2 to 3).
)で表わされるィンダゾール譲導体に係る。式1の化合
物は新規化合物であって、それ自体抗しセルピン作用を
有すると共に医薬品の合成中間体としても用いられる。). The compound of formula 1 is a new compound, which itself has an anti-serpin effect and is also used as a synthetic intermediate for pharmaceuticals.
式1の化合物は、一般式 (式中、Rは前記と同一の意味を有する。The compound of formula 1 has the general formula (In the formula, R has the same meaning as above.
)で表わされる化合物に、一般式(式中、×はハロゲン
原子、nは前記と同一の意味を有する。) to a compound represented by the general formula (wherein x is a halogen atom and n has the same meaning as above).
)で表わされる化合物を反応させることにより得られる
。なお、式1でRがカルボキシル基である化合物は、R
がアルデヒド基である式1の化合物を常法により酸化す
ることによっても得られる。) can be obtained by reacting a compound represented by In addition, the compound in which R is a carboxyl group in Formula 1, R
It can also be obtained by oxidizing a compound of formula 1 in which is an aldehyde group by a conventional method.
式ロの原料化合物は、例えば次式 で表わされるような方法で製造される。The raw material compound of formula (B) is, for example, the following formula It is manufactured by the method shown below.
式1の化合物を製造するに際しては、式ロの化合物と式
mの化合物との反応は、適宜な有機溶媒、例えばジメチ
ルホルムアミド、トルェン、メタノール、エタノール等
の中で行なわれる。In preparing the compound of formula 1, the reaction of the compound of formula (b) and the compound of formula (m) is carried out in a suitable organic solvent such as dimethylformamide, toluene, methanol, ethanol, etc.
反応は室温ないしそれ以上の温度で通常10〜90分、
好ましくは30〜75ooで75分以内で行なわれる。
式mの化合物は式0の化合物に対し過剰モル量使用する
ことが好ましい。また反応を円滑に行ない、かつ収率を
増すために、縮合剤、例えば当モル量または過剰モル量
の水素化ナトリウム、ナトリウムアルコラート、ナトリ
ウムアミド等を用いることが好ましい。式mの化合物と
して、その塩酸塩を用いる場合には、水酸化ナトリウム
等の塩基を用いて遊離アミンとし、これをトルェン等の
溶媒に溶解して使用することができる。反応混合物より
目的物(1)を単離するには、好ましくは反応混合物を
氷水に注ぎ、有機溶媒、例えばベンゼン、クロロホルム
等で抽出したのち水洗、乾燥し濃縮して得る。The reaction is usually carried out at room temperature or higher for 10 to 90 minutes.
Preferably, it is carried out within 75 minutes at 30 to 75 oo.
The compound of formula m is preferably used in molar excess relative to the compound of formula 0. Further, in order to carry out the reaction smoothly and increase the yield, it is preferable to use a condensing agent such as an equimolar amount or an excess molar amount of sodium hydride, sodium alcoholate, sodium amide, or the like. When using its hydrochloride as the compound of formula m, it can be used by converting it into a free amine using a base such as sodium hydroxide, and dissolving this in a solvent such as toluene. To isolate the desired product (1) from the reaction mixture, the reaction mixture is preferably poured into ice water, extracted with an organic solvent such as benzene, chloroform, etc., washed with water, dried, and concentrated.
なお、式1でRがカルボキシル基である化合物は、Rが
アルデヒド基である化合物を酸化剤例えば酸化銀、過マ
ンガン酸カリウム、無水クロム酸、二酸化マンガン等を
用いて酸化反応を行なう。In addition, for the compound in which R is a carboxyl group in Formula 1, the compound in which R is an aldehyde group is subjected to an oxidation reaction using an oxidizing agent such as silver oxide, potassium permanganate, chromic anhydride, manganese dioxide, etc.
次いで不落液を炉適し、炉液を濃縮し残溝をカラムクロ
マトグラフィーで処理し得る。得られた式1の化合物は
、常法により塩酸塩、硫酸塩等の無機酸塩またはシュウ
酸塩、コハク酸塩、マロン酸塩等の有機酸塩また、式1
の化合物のRがカルボキシル基の場合は、ナトリウム塩
、カリウム塩等のアルカリ金属塩とすることもできる。Next, the unfallen liquid can be passed through a furnace, the furnace liquid can be concentrated, and the remaining groove can be treated with column chromatography. The obtained compound of formula 1 can be converted into inorganic acid salts such as hydrochloride, sulfate, etc. or organic acid salts such as oxalate, succinate, malonate, etc. by a conventional method.
When R in the compound is a carboxyl group, it can also be an alkali metal salt such as a sodium salt or a potassium salt.
実施例 1
(原料化合物である式ロの化合物の製法)3ーフエニル
ー5ーメチルインダゾール100夕をピリジン100の
‘にとかし、無水酢酸100肌を加え室温で1時間蝿拝
する。Example 1 (Production method of the compound of formula 2, which is a raw material compound) 100 parts of 3-phenyl-5-methylindazole is dissolved in 100 parts of pyridine, 100 parts of acetic anhydride is added thereto, and the mixture is stirred at room temperature for 1 hour.
次いで水1そを加え析出した結晶を炉取すると1−アセ
チルー3ーフエニルー5ーメチルィンダゾール120夕
が得られる。これをァセトンーヘキサン混合溶媒より再
結晶すると融点99〜100マ○を示す。元素分析値:
C,6日,4N20として
C 日 N
計算値燐 76.78 5.64 11.19実
測 値燐 76.92 5‐55 11.23
得られた1ーアセチルー3ーフェニルー5−メチルィン
ダゾール502を四塩化炭素400舷にとかし、Nーブ
ロムコハク酸ィミド72夕を加え蝿梓下光(300Wフ
オトランプ)を4時間照射する。Next, 1 drop of water was added and the precipitated crystals were collected in a furnace to obtain 120 parts of 1-acetyl-3-phenyl-5-methylindazole. When this is recrystallized from an acetone-hexane mixed solvent, it exhibits a melting point of 99-100 mm. Elemental analysis value:
C, 6th, 4N20 as C day N Calculated value Phosphorus 76.78 5.64 11.19 Actual
Measured phosphorus 76.92 5-55 11.23
The resulting 1-acetyl-3-phenyl-5-methylindazole 502 was dissolved over 400 carbon tetrachloride, added with 72 m of N-bromosuccinimide, and irradiated with a 300W photolamp for 4 hours.
次いで不漆物を炉去し、炉液を濃縮すると1−アセチル
−3−フエニル−5−ジブロムメチルインダゾール65
夕を得る。これをアセトンより再結晶すると融点140
〜14が0を示す。元素分析値:C,6日,2N20B
r2としてC 日 N計算値燐 47.09
2.96 6.86実 測値■ 47.13
2.88 6.90得られた1ーアセチルー3−
フェニル−5−ジブロムメチルインダゾール54夕にエ
タノール400の‘、水80柵、ギ酸ナトリウム22夕
を加え加熱還流を1時間行なう。Then, the unlacquered material was removed in a furnace and the furnace liquid was concentrated to yield 1-acetyl-3-phenyl-5-dibromomethylindazole 65
Get the evening. When this is recrystallized from acetone, the melting point is 140.
~14 indicates 0. Elemental analysis value: C, 6 days, 2N20B
As r2, C day N calculated value Phosphorus 47.09
2.96 6.86 Actual measurement value ■ 47.13
2.88 6.90 Obtained 1-acetyl-3-
400 parts of ethanol, 80 parts of water, and 22 parts of sodium formate were added to 54 parts of phenyl-5-dibromomethylindazole, and heated under reflux for 1 hour.
得られた溶液を1/5まで濃縮しクロロホルムで抽出し
、水洗し、乾燥後濃縮すると1−アセチル−3−フエニ
ル−5一ホルミルインダゾール29夕を得る。これをメ
タノールより再結晶すると融点128〜13000を示
す。元素分析値:C,6日.2N202としてC 日
N計 算 値燭 72.72 4.58 1
0.60実 測 値鰍 72.65 4.53
1一0.55得られた1ーアセチル−3ーフェニルー
5一ホルミルィンダゾール29のこ氷酢酸180の‘、
濃塩酸90泌を加え加熱還流を30分行なう。The resulting solution was concentrated to 1/5, extracted with chloroform, washed with water, dried, and concentrated to obtain 1-acetyl-3-phenyl-5-formyl indazole 29 times. When this is recrystallized from methanol, it shows a melting point of 128-13,000. Elemental analysis value: C, 6 days. 2N202 as C day N calculation value candle 72.72 4.58 1
0.60 Actual measurement value 72.65 4.53
1-0.55 of the obtained 1-acetyl-3-phenyl-5-formylindazole 29 of glacial acetic acid 180',
Add 90ml of concentrated hydrochloric acid and heat under reflux for 30 minutes.
得られた溶液を水1そに注ぎ析出する結晶を炉取すると
、3−フェニル−5一ホルミルィンダゾール112を得
る。The obtained solution is poured into a glass of water and the precipitated crystals are collected in a furnace to obtain 3-phenyl-5-formylindazole 112.
これをクロロホルムーヘキサン混合溶媒より再結晶する
と融点140〜141℃を示す。元素分析値:C,4日
,州20として
C 日 N
計算 値燐 75.66 4.54 12.6
0実 測 値燐 75.71 4.49 12
.53実施例 2実施例1で得られた3−フェニル−5
−ホルミルインダゾール16夕をジメチルホルムアミド
150の‘にとかし、50%含有水素化ナトリウム3.
45夕を加え室温で1扮ご間鷹拝する。When this is recrystallized from a chloroform-hexane mixed solvent, it exhibits a melting point of 140-141°C. Elemental analysis value: C, 4th, state 20 C day N Calculation value Phosphorus 75.66 4.54 12.6
0 Actual measurement value Phosphorus 75.71 4.49 12
.. 53 Example 2 3-phenyl-5 obtained in Example 1
- Dissolve 16 parts of formyl indazole in 150 parts of dimethylformamide and 3 parts of 50% sodium hydride.
Add 45 minutes of cooking time and let it sit at room temperature for one hour.
次いでジメチルァミノプロピルクロラィド塩酸塩15夕
を含む水溶液に水酸化ナトリウム水溶液を加え塩基性と
し、トルェン50の【で抽出し苧硝で乾燥後これをジメ
チルホルムアミド溶液に加え7000で1時間鷹拝する
。得られた生成物をベンゼンで抽出し、水洗し、乾燥後
濃縮すると1ージメチルアミノプロピル−3ーフェニル
ー5一ホルミルィンダゾールを19タ得る。これをエー
テル−塩酸にて塩酸塩とすると1ージメチルアミノブロ
ピルー3ーフエニルー5一ホルミルィンダゾール塩酸塩
が得られ、これをエタノールーェーテル混合溶媒より再
結晶すると融点152〜154qoを示す。Next, an aqueous solution of sodium hydroxide was added to the aqueous solution containing 15% of dimethylaminopropyl chloride hydrochloride to make it basic, and the mixture was extracted with 50% of toluene, dried with sulfur, and then added to a dimethylformamide solution and heated at 7,000 °C for 1 hour. worship The obtained product was extracted with benzene, washed with water, dried and concentrated to obtain 19 t of 1-dimethylaminopropyl-3-phenyl-5-formylindazole. When this is converted into a hydrochloride with ether-hydrochloric acid, 1-dimethylaminobropy-3-phenyl-5-formylindazole hydrochloride is obtained, and when this is recrystallized from an ethanol-ether mixed solvent, it has a melting point of 152 to 154 qo. show.
元素分析値:C,幻22N30CIとしてC 日 N
計算値燐 66.37 6.45 12.22実
測 値燐 66.15 6.49 12.2
3実施例 3硝酸銀18のこエタノール150の【、水
150叫を加え、さらに8夕の水酸化ナトリウムを加え
酸化銀を作り、これに実施例2で得た1ージメチルアミ
ノプロピルー3ーフエニル−5一ホルミルインダゾール
17夕を含むエタノール50の上溶液を加え加熱還流を
30分間行なう。Elemental analysis value: C, as phantom 22N30 CI
3 Example 3 Add 150 parts of silver nitrate to 150 parts of ethanol, 150 parts of water, and further add 8 parts of sodium hydroxide to make silver oxide. To this, 1-dimethylaminopropyl-3-phenyl- obtained in Example 2 was added. A supernatant solution of 50% of ethanol containing 17% of formylindazole was added and heated under reflux for 30 minutes.
得られた不溶物を炉過し、炉液を濃縮し、残澄を塩酸で
中和したのちテトラヒドロフランで抽出し、有機層を濃
縮しカラムクロマトグラフイーで処理すると1−ジメチ
ルアミノプロピルー3ーフエニル−5ーカルボキシイン
ダゾールを8.0タ得る。これを水から再結晶すると融
点118〜119午0を示す。The resulting insoluble matter was filtered, the filtrate was concentrated, the residue was neutralized with hydrochloric acid, extracted with tetrahydrofuran, and the organic layer was concentrated and treated with column chromatography to yield 1-dimethylaminopropyl-3-phenyl. -8.0 ta of 5-carboxyindazole is obtained. When this is recrystallized from water, it shows a melting point of 118-119°C.
元素分析値:C,虹2,N302・比○としてC 日
N計算値燐 66.84 6.80 12.
31実 測 値燐 67.12 6.91 12
.36実施例 4実施例1で得た3−フェニル−5−ホ
ルミルィンダゾール11夕、50%含有水素化ナトリウ
ム2.37夕およびジメチルアミノェチルクロラィド塩
酸塩11夕を実施例2と同様に処理すると、油状物とし
て1−ジメチルアミノエチル一3ーフエニルー5−ホル
ミルィンダゾールを11#得る。Elemental analysis value: C, Rainbow 2, N302/C day
N calculated value Phosphorus 66.84 6.80 12.
31 Actual measurement value Phosphorus 67.12 6.91 12
.. 36 Example 4 11 parts of 3-phenyl-5-formylindazole obtained in Example 1, 2.37 parts of 50% sodium hydride and 11 parts of dimethylaminoethyl chloride hydrochloride were mixed with Example 2. A similar treatment yields 11# of 1-dimethylaminoethyl-3-phenyl-5-formylindazole as an oil.
これをエーテル−塩酸で塩酸塩とし、エタノールーェー
テル混合溶媒より再結晶すると融点177〜17900
を示す。元素分析値:C,8日2ぶ30CIとしてC
日 N
計算 値燐 65.55 6.11 12.74
実 測 値燐 65.11 6.32 12.3
2実施例 5硝酸銀9.6夕、水酸化ナトリウム4.1
夕および1−ジメチルアミノエチル一3ーフエニルー5
一ホルミルィンダゾール9夕を実施例3と同様に処理す
ると1ージメチルアミノェチルー3ーフェニル−5−力
ルボキシィンダゾールを4.5タ得る。When this is converted into a hydrochloride with ether-hydrochloric acid and recrystallized from an ethanol-ether mixed solvent, the melting point is 177-17900.
shows. Elemental analysis value: C, C as 8 days 2bu 30CI
Day N Calculation Value Phosphorus 65.55 6.11 12.74
Actual measurement value phosphorus 65.11 6.32 12.3
2 Example 5 Silver nitrate 9.6%, Sodium hydroxide 4.1%
and 1-dimethylaminoethyl-3-phenyl-5
When nine units of mono-formylindazole were treated in the same manner as in Example 3, 4.5 units of 1-dimethylaminoethyl-3-phenyl-5-ruboxindazole were obtained.
これを水より再結晶すると融点128〜130qoを示
す。元素分析値:C,8日,ぶ302として
C 日 NWhen this is recrystallized from water, it shows a melting point of 128 to 130 qo. Elemental analysis value: C, 8 days, C as 302 days N
Claims (1)
は2〜3の整数を示す。 )で表わされるインダゾール誘導体。[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is an aldehyde group or a carboxyl group, n
represents an integer between 2 and 3. ) An indazole derivative represented by
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP51036100A JPS604824B2 (en) | 1976-04-02 | 1976-04-02 | Indazole derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP51036100A JPS604824B2 (en) | 1976-04-02 | 1976-04-02 | Indazole derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS52122366A JPS52122366A (en) | 1977-10-14 |
JPS604824B2 true JPS604824B2 (en) | 1985-02-06 |
Family
ID=12460336
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP51036100A Expired JPS604824B2 (en) | 1976-04-02 | 1976-04-02 | Indazole derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS604824B2 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4535680B2 (en) * | 2001-04-16 | 2010-09-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | New 1H-indazole compounds |
-
1976
- 1976-04-02 JP JP51036100A patent/JPS604824B2/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
JPS52122366A (en) | 1977-10-14 |
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