【０００１】[0001]
【産業上の利用分野】本発明は、医薬、農薬等の製造中
間体として有用な３環性トリアゾロ誘導体の製造方法に
関する。TECHNICAL FIELD The present invention relates to a method for producing a tricyclic triazolo derivative which is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and the like.
【０００２】[0002]
【従来の技術】本発明者らは、抗ヒスタミン作用と抗Ｐ
ＡＦ作用を合せ持った薬剤の探索を行ってきた結果、そ
の一例としてＰＣＴ／ＪＰ９２／００５２３において、
下記一般式（ＩＶ）2. Description of the Related Art The present inventors have antihistamine action and anti-P
As a result of conducting a search for a drug that also has an AF action, as an example, in PCT / JP92 / 00523,
The following general formula (IV)
【化４】［式中、Ｒ4は水素、低級アルキル、または炭素数３〜
５のシクロアルキルを表し、Ｒ5、Ｒ6はそれぞれ水
素、低級アルキル、低級アルコキシまたはハロゲンを表
し、ＷはＣ＝Ｏ、ＣＲ7Ｒ8（Ｒ7、Ｒ8はそれぞれ水
素、低級アルキルを表す）を表し、Ａは、炭素数１〜５
の飽和もしくは不飽和アルキレンを表し、ヘテロ原子を
含んでも良い。ｌは０〜２を表し、ｎは１〜３を表し、
…は単結合もしくは二重結合を表し、ＹはＮまたはＣを
表し、ＺはＣ（Ｂ）Ａｒ1Ａｒ2（Ｂは水素、ヒドロキ
シ、もしくはメトキシを、Ａｒ1、Ａｒ2はそれぞれ、
水素、置換もしくは非置換のアリールを表す）、ＣＡｒ
1Ａｒ2（Ａｒ1、Ａｒ2は上記に同じ）、Ｏ−ＣＨＡ
ｒ1Ａｒ2（Ａｒ1、Ａｒ2は上記に同じ）、または縮
合芳香環を表す］で表される4,5-ジヒドロトリアゾロ
[4,3-a] キノキサリン誘導体が両作用を合せ持つ化合物
であることを報告しており、その合成中間体である下記
一般式（ＩＩＩ）[Chemical 4] [In the formula, R4 is hydrogen, lower alkyl, or C 3 -C 3
5 represents cycloalkyl, R5 and R6 each represent hydrogen, lower alkyl, lower alkoxy or halogen, W represents C═O, CR7 R8 (R7 , R8 represent hydrogen and lower alkyl, respectively) ), A is a carbon number of 1 to 5
Represents saturated or unsaturated alkylene and may contain a hetero atom. l represents 0 to 2, n represents 1 to 3,
... represents a single bond or a double bond, Y represents N or C, Z is C (B) Ar1 Ar2 (B is hydrogen, hydroxy, or methoxy, and Ar1 and Ar2 are respectively
Hydrogen, substituted or unsubstituted aryl), CAr
1 Ar2 (Ar1 and Ar2 are the same as above), O-CHA
r1 Ar2 (Ar1 and Ar2 are the same as above), or a condensed aromatic ring]], 4,5-dihydrotriazolo
It has been reported that a [4,3-a] quinoxaline derivative is a compound having both actions, and its synthetic intermediate shown by the following general formula (III)
【化５】（式中、Ｒ1、Ｒ2はそれぞれ水素、低級アルキル、低
級アルコキシ、またはハロゲンを表し、Ｒ3は水素、低
級アルキル、炭素数３〜５のシクロアルキル、または置
換もしくは非置換アリ−ルを表す）で表される３環性ト
リアゾロ誘導体の製造方法も例示されている。[Chemical 5] (In the formula, R1 and R2 each represent hydrogen, lower alkyl, lower alkoxy, or halogen, and R3 represents hydrogen, lower alkyl, cycloalkyl having 3 to 5 carbon atoms, or substituted or unsubstituted aryl. The method for producing the tricyclic triazolo derivative represented by
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、ＰＣＴ
／ＪＰ９２／００５２３に報告されている一般式（ＩＩ
Ｉ）の３環性トリアゾロ誘導体の製造方法は、毒性およ
び悪臭の強い硫黄化合物を使用しており特別の反応装置
が必要とされる等の理由から満足できるものではない。However, the PCT
/ JP92 / 00523 general formula (II
The method for producing a tricyclic triazolo derivative of I) is not satisfactory because it uses a sulfur compound having strong toxicity and bad odor and requires a special reaction device.
【０００４】[0004]
【課題を解決するための手段】これらの欠点を克服する
ため、本発明者らは鋭意研究を重ねた結果、一般式（Ｉ
ＩＩ）の３環性トリアゾロ誘導体の新規合成法を見出し
本発明を完成させた。すなわち、本発明は、塩基の存在
下、一般式（Ｉ）In order to overcome these drawbacks, the inventors of the present invention have conducted extensive studies and as a result have found that the compound of the general formula (I
The present invention has been completed by finding a new synthetic method of the tricyclic triazolo derivative of II). That is, the present invention provides a compound of general formula (I) in the presence of a base.
【化６】（式中、Ｒ1、Ｒ2はそれぞれ水素、低級アルキル、低
級アルコキシ、またはハロゲンを表す）で表されるオル
トフェニレンジアミン誘導体と、一般式（ＩＩ）[Chemical 6] (In the formula, R1 and R2 each represent hydrogen, lower alkyl, lower alkoxy, or halogen), and an orthophenylenediamine derivative represented by the general formula (II)
【化７】（式中、Ｒ3は水素、低級アルキル、炭素数３〜５のシ
クロアルキル、または置換もしくは非置換アリ−ルを表
す）で表される2-( クロロメチル)-1,3,4-オキサジアゾ
−ル誘導体とを反応させることにより下記一般式（ＩＩ
Ｉ）[Chemical 7] (In the formula, R3 represents hydrogen, lower alkyl, cycloalkyl having 3 to 5 carbon atoms, or substituted or unsubstituted aryl). 2- (chloromethyl) -1,3,4-oxadiazo The following general formula (II
I)
【化８】（式中、Ｒ1、Ｒ2、Ｒ3は前記と同義である）で表さ
れる３環性トリアゾロ誘導体を製造する方法を提供する
ものである。[Chemical 8] The present invention provides a method for producing a tricyclic triazolo derivative represented by the formula (wherein R1 , R2 and R3 are as defined above).
【０００５】本発明で使用するオルトフェニレンジアミ
ン誘導体（Ｉ）としては、例えば、オルトフェニレンジ
アミン、4,5-ジメチルオルトフェニレンジアミン、4、5-
ジメトキシオルトフェニレンジアミン、4、5-ジクロロオ
ルトフェニレンジアミンなどが挙げられる。Examples of the orthophenylenediamine derivative (I) used in the present invention include orthophenylenediamine, 4,5-dimethylorthophenylenediamine, 4,5- and 5-dimethylorthophenylenediamine.
Examples thereof include dimethoxy orthophenylenediamine and 4,5-dichloroorthophenylenediamine.
【０００６】本発明で使用する2-( クロロメチル)-1,3,
4-オキサジアゾ−ル誘導体（ＩＩ）としては例えば、2-
( クロロメチル)-5-メチル-1,3,4- オキサジアゾ−ル、
2-(クロロメチル)-5-エチル-1,3,4- オキサジアゾ−
ル、2-( クロロメチル)-5-プロピル-1,3,4- オキサジア
ゾ−ル、2-( クロロメチル)-5-イソプロピル-1,3,4- オ
キサジアゾ−ル、2-( クロロメチル)-5-ブチル-1,3,4-
オキサジアゾ−ル、2-(クロロメチル)-5-フェニル-1,3,
4- オキサジアゾ−ルなどが挙げられる。2- (chloromethyl) -1,3, used in the present invention
Examples of the 4-oxadiazol derivative (II) include 2-
(Chloromethyl) -5-methyl-1,3,4-oxadiazol,
2- (chloromethyl) -5-ethyl-1,3,4-oxadiazo-
2- (chloromethyl) -5-propyl-1,3,4-oxadiazol, 2- (chloromethyl) -5-isopropyl-1,3,4-oxadiazol, 2- (chloromethyl) -5-butyl-1,3,4-
Oxadiasol, 2- (chloromethyl) -5-phenyl-1,3,
4-oxadiazol and the like can be mentioned.
【０００７】本発明の目的物である３環性トリアゾロ誘
導体（ＩＩＩ）としては、4,5-ジヒドロ[1,2,4] トリア
ゾロ[4,3-a] キノキサリン、1-メチル-4,5- ジヒドロ
[1,2,4] トリアゾロ[4,3-a] キノキサリン、1,6,7-トリ
メチル-4,5- ジヒドロ[1,2,4]トリアゾロ[4,3-a] キノ
キサリン、1-メチル-6,7- ジクロロ-4,5- ジヒドロ[1,
2,4] トリアゾロ[4,3-a] キノキサリン、1-メチル-6,7-
ジメトキシ-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a]
キノキサリン、1-エチル-4,5- ジヒドロ[1,2,4]トリア
ゾロ[4,3-a] キノキサリン、1-プロピル-4,5- ジヒドロ
[1,2,4] トリアゾロ[4,3-a] キノキサリン、1-イソプロ
ピル-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a] キノキ
サリン、1-フェニル-4,5- ジヒドロ[1,2,4] トリアゾロ
[4,3-a] キノキサリン、1-(2- フリル）-4,5- ジヒドロ
[1,2,4] トリアゾロ[4,3-a] キノキサリン、1-(2- チエ
ニル）-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a] キノ
キサリンなどが挙げられる。The tricyclic triazolo derivative (III) which is the object of the present invention includes 4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline and 1-methyl-4,5. -Dihydro
[1,2,4] Triazolo [4,3-a] quinoxaline, 1,6,7-trimethyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-methyl -6,7-Dichloro-4,5-dihydro [1,
2,4] Triazolo [4,3-a] quinoxalines, 1-methyl-6,7-
Dimethoxy-4,5-dihydro [1,2,4] triazolo [4,3-a]
Quinoxaline, 1-ethyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-propyl-4,5-dihydro
[1,2,4] Triazolo [4,3-a] quinoxaline, 1-isopropyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-phenyl-4,5 -Dihydro [1,2,4] triazolo
[4,3-a] Quinoxaline, 1- (2-furyl) -4,5-dihydro
[1,2,4] triazolo [4,3-a] quinoxaline, 1- (2-thienyl) -4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, etc. .
【０００８】本発明で使用する塩基としては、炭酸カリ
ウム、炭酸ナトリウム、炭酸水素カリウム、炭酸水素ナ
トリウムなどが挙げられ、好ましくは炭酸カリウム、炭
酸ナトリウムである。Examples of the base used in the present invention include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like, with potassium carbonate and sodium carbonate being preferred.
【０００９】本発明で使用する反応溶媒としては、例え
ば、メタノ−ル、エタノ−ル、プロパノ−ル、ブタノ−
ル、ペンタノ−ル、ヘキサノ−ル、2-エトキシエタノ−
ル、などの低級アルコ−ル類、ジメチルホルムアミド、
ジメチルアセトアミドなどのアミド類などが挙げられ
る。The reaction solvent used in the present invention is, for example, methanol, ethanol, propanol or butanol.
, Pentanole, hexanole, 2-ethoxyethanol
Lower alcohols such as diol, dimethylformamide,
Examples thereof include amides such as dimethylacetamide.
【００１０】本発明において、オルトフェニレンジアミ
ン誘導体は2-( クロロメチル)-1,3,4-オキサジアゾ−ル
誘導体に対し、１〜４倍モル使用するのが好ましく、
１．５〜３倍モル使用するのが望ましい。また、使用す
る塩基の量は特に制限はないが2-( クロロメチル)-1,3,
4-オキサジアゾ−ル誘導体に対し１．１ないし２倍モル
使用するのが好ましい。In the present invention, the orthophenylenediamine derivative is preferably used in 1 to 4 times the molar amount of the 2- (chloromethyl) -1,3,4-oxadiazol derivative,
It is desirable to use 1.5 to 3 times the molar amount. The amount of base used is not particularly limited, but 2- (chloromethyl) -1,3,
It is preferable to use 1.1 to 2 times the molar amount of the 4-oxadiazol derivative.
【００１１】反応温度は０℃から溶媒の沸点、好ましく
は50℃から100 ℃の範囲で行われ、反応時間は用いる溶
媒、反応温度によって異なるが、１〜60時間の範囲で行
われる。The reaction temperature is 0 ° C to the boiling point of the solvent, preferably 50 ° C to 100 ° C, and the reaction time is 1 to 60 hours, depending on the solvent used and the reaction temperature.
【００１２】本発明で得られる３環性トリアゾロ誘導体
（ＩＩＩ）を用いることにより、ＰＣＴ／ＪＰ９２／０
０５２３に記載された方法に従い、抗ヒスタミン、抗Ｐ
ＡＦ作用を併せ持つ4,5-ジヒドロトリアゾロ[4,3-a] キ
ノキサリン誘導体（ＩＶ）を容易に製造することができ
る。By using the tricyclic triazolo derivative (III) obtained in the present invention, PCT / JP92 / 0
According to the method described in 0523, antihistamine, anti-P
A 4,5-dihydrotriazolo [4,3-a] quinoxaline derivative (IV) having an AF action can be easily produced.
【００１３】[0013]
【実施例】以下に実施例を挙げて本発明をさらに具体的
に説明するが、本発明はこの実施例によって限定される
ものではない。The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.
【００１４】参考例１ 1-アセチル-2- クロロアセチルヒドラジンReference Example 1 1-Acetyl-2-chloroacetylhydrazine
【化９】アセトヒドラジド99.97g(1.35mol) 、炭酸ナトリウム8
4.65g(0.799mol)を水に溶解し、０℃に冷却した。クロ
ロアセチルクロリド161.72g(1.43mol)を２時間かけて滴
下した後、室温で１時間攪拌した。析出結晶を瀘別、エ
タノ−ル- 水(2:1)500mlより再結晶し題記化合物を129.
25g 得た。[Chemical 9] Acetohydrazide 99.97g (1.35mol), sodium carbonate 8
4.65 g (0.799 mol) was dissolved in water and cooled to 0 ° C. 161.72 g (1.43 mol) of chloroacetyl chloride was added dropwise over 2 hours, and then the mixture was stirred at room temperature for 1 hour. The precipitated crystals were filtered off and recrystallized from 500 ml of ethanol-water (2: 1) to give the title compound as 129.
25 g was obtained.
【００１５】無色結晶 mp:154-157℃ IR(KBr)cm-1:3202,3058,3032,1640-1570,1504,1375,12
76,1241,1141,1004,930,785,723,632,565,4721 HNMR(CD3OD) δ:4.12(2H,s),2.00(3H,s)Colorless crystal mp: 154-157 ° C IR (KBr) cm-1 : 3202,3058,3032,1640-1570,1504,1375,12
76,1241,1141,1004,930,785,723,632,565,4721 HNMR (CD3OD) δ: 4.12 (2H, s), 2.00 (3H, s)
【００１６】参考例２ 2-( クロロメチル)-5-メチル-1,3,4- オキサジアゾ−ルReference Example 2 2- (Chloromethyl) -5-methyl-1,3,4-oxadiazol
【化１０】オキシ塩化リン58g(0.38mol)に1-アセチル-2- クロロア
セチルヒドラジン17.75g(0.118mol)を加え110 ℃で30分
攪拌した。微減圧下、過剰のオキシ塩化リンを留去した
後、1mmHg で減圧蒸留を行った。留分をエ−テルに溶解
し10% 炭酸ナトリウム水溶液、飽和食塩水で洗浄、硫酸
マグネシウムで乾燥した。エ−テルを留去後、減圧蒸留
を行い、題記化合物を6.93g 得た。[Chemical 10] To 75 g (0.38 mol) of phosphorus oxychloride, 17.75 g (0.118 mol) of 1-acetyl-2-chloroacetylhydrazine was added, and the mixture was stirred at 110 ° C for 30 minutes. After the excess phosphorus oxychloride was distilled off under slight vacuum, vacuum distillation was performed at 1 mmHg. The fraction was dissolved in ether, washed with 10% aqueous sodium carbonate solution and saturated brine, and dried over magnesium sulfate. After distilling off ether, distillation under reduced pressure was carried out to obtain 6.93 g of the title compound.
【００１７】無色液体 bp:63-64℃/0.3mmHg IR(Neat)cm-1:3028,1591,1572,1435,1396,1357,1272,12
28,1054,1000,980,959 768,752,677,6251 HNMR(CDCl3) δ:4.68(2H,s),2.57(3H,s)Colorless liquid bp: 63-64 ℃ / 0.3mmHg IR (Neat) cm-1 : 3028,1591,1572,1435,1396,1357,1272,12
28,1054,1000,980,959 768,752,677,6251 HNMR (CDCl3) δ: 4.68 (2H, s), 2.57 (3H, s)
【００１８】参考例３ 2-( クロロメチル)-5-エチル-1,3,4- オキサジアゾ−ルReference Example 3 2- (Chloromethyl) -5-ethyl-1,3,4-oxadiazol
【化１１】アセトヒドラジドの代わりにプロピオニルヒドラジンを
用いる以外は、参考例１と同様の反応を、次いで１−ア
セチル２−クロロアセトヒドラジンの代わりに１−プロ
ピオニル−２−クロロアセチルヒドラジンを用いる以外
は参考例２と同様の反応を行なうことにより題記化合物
を得た。[Chemical 11] A reaction similar to that of Reference Example 1 was performed except that propionylhydrazine was used instead of acetohydrazide, and then Reference Example 2 was used except that 1-propionyl-2-chloroacetylhydrazine was used instead of 1-acetyl2-chloroacetohydrazine. The same reaction was performed to obtain the title compound.
【００１９】無色液体 bp:58-59℃/0.02mmHg IR(neat)cm-1:2988,1589,1568,1460,1433,1388,1216,11
93,1027,1006,988,760,6631 HNMR(CDCl3) δ:4.68(2H,s),2.91(2H,q,J=7.5Hz),1.40
(3H,t,J=7.5Hz)Colorless liquid bp: 58-59 ° C / 0.02mmHg IR (neat) cm-1 : 2988,1589,1568,1460,1433,1388,1216,11
93,1027,1006,988,760,6631 HNMR (CDCl3) δ: 4.68 (2H, s), 2.91 (2H, q, J = 7.5Hz), 1.40
(3H, t, J = 7.5Hz)
【００２０】参考例４ 2-( クロロメチル)-5-プロピル-1,3,4- オキサジアゾ−
ルReference Example 4 2- (Chloromethyl) -5-propyl-1,3,4-oxadiazo-
Le
【化１２】アセトヒドラジドの代わりにブチリルヒドラジンを用い
る以外は、参考例１と同様の反応を、次いで１−アセチ
ル２−クロロアセトヒドラジンの代わりに１−ブチリル
−２−クロロアセチルヒドラジンを用いる以外は参考例
２と同様の反応を行なうことにより題記化合物を得た。[Chemical 12] A reaction similar to that of Reference Example 1 was performed except that butyrylhydrazine was used instead of acetohydrazide, and then 1-butyryl-2-chloroacetylhydrazine was used instead of 1-acetyl2-chloroacetohydrazine. The title compound was obtained by performing a similar reaction to.
【００２１】無色液体 bp:70-72℃/0.4mmHg IR(neat)cm-1:2972,2940,2880,1586,1568,1464,1433,13
81,1241,1189,1027,984,7541 HNMR(CDCl3) δ:4.68(2H,s),2.86(2H,t,J=7.5Hz),2.1-
1.6(1H,m),1.04(3H,t,J=7.5Hz)Colorless liquid bp: 70-72 ° C / 0.4mmHg IR (neat) cm-1 : 2972,2940,2880,1586,1568,1464,1433,13
81,1241,1189,1027,984,7541 HNMR (CDCl3) δ: 4.68 (2H, s), 2.86 (2H, t, J = 7.5Hz), 2.1-
1.6 (1H, m), 1.04 (3H, t, J = 7.5Hz)
【００２２】参考例５ 2-( クロロメチル)-5-イソプロピル-1,3,4- オキサジア
ゾ−ルReference Example 5 2- (Chloromethyl) -5-isopropyl-1,3,4-oxadiazol
【化１３】アセトヒドラジドの代わりにイソブチリルヒドラジンを
用いる以外は、参考例１と同様の反応を、次いで１−ア
セチル２−クロロアセトヒドラジンの代わりに１−イソ
ブチリル−２−クロロアセチルヒドラジンを用いる以外
は参考例２と同様の反応を行なうことにより題記化合物
を得た。[Chemical 13] A reaction similar to that of Reference Example 1 except that isobutyrylhydrazine was used instead of acetohydrazide, and then Reference Example except that 1-isobutyryl-2-chloroacetylhydrazine was used instead of 1-acetyl2-chloroacetohydrazine. The title compound was obtained by performing the same reaction as in 2.
【００２３】無色液体 bp:53-54℃/0.2mmHg IR(neat)cm-1:2980,1586,1564,1369,1152,1025,752,6591 HNMR(CDCl3) δ:4.68(2H,s),3.21(1H,quint,J=7Hz),1.
41(6H,d,J=7.0Hz)Colorless liquid bp: 53-54 ° C / 0.2mmHg IR (neat) cm-1 : 2980,1586,1564,1369,1152,1025,752,6591 HNMR (CDCl3) δ: 4.68 (2H, s), 3.21 (1H, quint, J = 7Hz), 1.
41 (6H, d, J = 7.0Hz)
【００２４】参考例６ 2-( クロロメチル)-5-フェニル-1,3,4- オキサジアゾ−
ルReference Example 6 2- (Chloromethyl) -5-phenyl-1,3,4-oxadiazo-
Le
【化１４】ベンゾイルヒドラジン8.87g(65.2mmol) 、エチルイミノ
クロロアセテ−ト塩酸塩11.34g(71.8mmol)をエタノ−ル
100ml 中に加え、４時間還流した。冷却後、水を加え、
析出結晶を瀘別し、題記化合物を9.96g 得た。[Chemical 14] Benzoyl hydrazine 8.87 g (65.2 mmol), ethyliminochloroacetate hydrochloride 11.34 g (71.8 mmol) in ethanol
It was added to 100 ml and refluxed for 4 hours. After cooling, add water,
The precipitated crystals were separated by filtration to obtain 9.96 g of the title compound.
【００２５】無色結晶 mp:118-120℃ IR(KBr)cm-1:3030,2974,1576,1553,1487,1452,1247,11
66,1071,781,760,745 7081 HNMR(CDCl3) δ:8.2-8.0(2H,m),7.6-7.4(3H,m),4.78(2
H,s)Colorless crystal mp: 118-120 ° C IR (KBr) cm-1 : 3030,2974,1576,1553,1487,1452,1247,11
66,1071,781,760,745 7081 HNMR (CDCl3) δ: 8.2-8.0 (2H, m), 7.6-7.4 (3H, m), 4.78 (2
H, s)
【００２６】実施例１ 1-メチル-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a] キ
ノキサリン (１)Example 1 1-Methyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline (1)
【化１５】O-フェニレンジアミン2.23g(20.6mmol) 、炭酸カリウム
2.43g(17.6mmol) をn-ブタノ−ル30mlに懸濁させた中
に、2-( クロロメチル)-5-メチル-1,3,4- オキサジアゾ
−ル1.55g(11.7mmol) を滴下した。46時間還流した後、
冷却、無機塩を瀘別した。溶媒を留去、アセトンより再
結晶を行い、題記化合物を0.94g 得た。[Chemical 15] 2.23 g (20.6 mmol) of O-phenylenediamine, potassium carbonate
In suspension of 2.43 g (17.6 mmol) in 30 ml of n-butanol, 1.55 g (11.7 mmol) of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol was added dropwise. . After refluxing for 46 hours,
After cooling, the inorganic salt was filtered off. The solvent was distilled off and recrystallized from acetone to obtain 0.94 g of the title compound.
【００２７】淡黄色結晶 mp:181-183℃ IR(KBr)cm-1:3230,1562,1510,1499,14311 HNMR(CDCl3) δ:7.50-6.82(4H,m),4.58(2H,d,J=1.8),
4.18(1H,brs),2.78(3H,s) MS(EI):186(M+,base peak),144,118Light yellow crystal mp: 181-183 ° C IR (KBr) cm-1 : 3230,1562,1510,1499,14311 H NMR (CDCl3) δ: 7.50-6.82 (4H, m), 4.58 (2H, d , J = 1.8),
4.18 (1H, brs), 2.78 (3H, s) MS (EI): 186 (M +, base peak), 144,118
【００２８】実施例２ 1-エチル-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a] キ
ノキサリン (２)Example 2 1-Ethyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline (2)
【化１６】2-( クロロメチル)-5-メチル-1,3,4- オキサジアゾ−ル
の代わりに2-( クロロメチル)-5-エチル-1,3,4- オキサ
ジアゾ−ルを用いる以外は実施例１と同様の反応を行な
うことにより題記化合物を得た。[Chemical 16] Example 1 except that 2- (chloromethyl) -5-ethyl-1,3,4-oxadiazol was used instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol. The title compound was obtained by performing a similar reaction to.
【００２９】淡黄色結晶 mp:147-151℃ IR(KBr)cm-1:3264,1562,1522,1499,1437,1315,745,420
cm-11 HNMR(CDCl3) δ:7.43(1H,m),7.3-6.8(3H,m),4.57(2H,
d,J=1.8),4.16(1H,brs),3.12(2H,q,J=7.5),1.51(3H,t,J
=7.3) MS(EI):200(M+,base peak),144,118Light yellow crystal mp: 147-151 ° C IR (KBr) cm-1 : 3264,1562,1522,1499,1437,1315,745,420
cm-11 H NMR (CDCl3) δ: 7.43 (1H, m), 7.3-6.8 (3H, m), 4.57 (2H,
d, J = 1.8), 4.16 (1H, brs), 3.12 (2H, q, J = 7.5), 1.51 (3H, t, J
= 7.3) MS (EI): 200 (M +, base peak), 144,118
【００３０】実施例３ 1-プロピル-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a]
キノキサリン (３)Example 3 1-Propyl-4,5-dihydro [1,2,4] triazolo [4,3-a]
Quinoxaline (3)
【化１７】2-( クロロメチル)-5-メチル-1,3,4- オキサジアゾ−ル
の代わりに2-( クロロメチル)-5-プロピル-1,3,4- オキ
サジアゾ−ルを用いる以外は実施例１と同様の反応を行
なうことにより題記化合物を得た。[Chemical 17] Example 1 except that 2- (chloromethyl) -5-propyl-1,3,4-oxadiazol is used instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol. The title compound was obtained by performing a similar reaction to.
【００３１】淡黄色結晶 mp:116-120℃ IR(KBr)cm-1:3242,2970,1615,1562,1524,1502,1460,14
31,1299,750,4201 HNMR(CDCl3) δ:7.42(1H,d,J=7.9),7.3-6.8(3H,m),4.5
7(2H,d,J=1.8),4.16(1H,brs),1.91(2H,t,J=7.4),2.2-1.
7(2H,m),1.10(3H,t,J=7.3) MS(EI):214(M+,base peak),144,118Pale yellow crystal mp: 116-120 ° C IR (KBr) cm-1 : 3242,2970,1615,1562,1524,1502,1460,14
31,1299,750,4201 HNMR (CDCl3) δ: 7.42 (1H, d, J = 7.9), 7.3-6.8 (3H, m), 4.5
7 (2H, d, J = 1.8), 4.16 (1H, brs), 1.91 (2H, t, J = 7.4), 2.2-1.
7 (2H, m), 1.10 (3H, t, J = 7.3) MS (EI): 214 (M +, base peak), 144,118
【００３２】実施例４ 1-イソプルピル-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3
-a] キノキサリン (４)Example 4 1-Isopropyl-4,5-dihydro [1,2,4] triazolo [4,3]
-a] quinoxaline (4)
【化１８】2-( クロロメチル)-5-メチル-1,3,4- オキサジアゾ−ル
の代わりに2-( クロロメチル)-5-イソプロピル-1,3,4-
オキサジアゾ−ルを用いる以外は実施例１と同様の反応
を行なうことにより題記化合物を得た。[Chemical 18] 2- (chloromethyl) -5-methyl-1,3,4-instead of oxadiazol 2- (chloromethyl) -5-isopropyl-1,3,4-
The title compound was obtained by the same reaction as in Example 1 except that oxadiazol was used.
【００３３】淡黄色結晶 mp:126-129℃ IR(KBr)cm-1:3254,2974,1562,1524,1508,1460,1431,13
25,1301,1278,7451 HNMR(CDCl3) δ:7.47(1H,d,J=7.5),7.3-6.8(3H,m),4.5
5(2H,d,J=1.8),4.32(1H,brs),3.7-3.2(1H,m),1.51(6H,
s) MS(EI):214(M+,base peak),144,118Pale yellow crystal mp: 126-129 ° C IR (KBr) cm-1 : 3254,2974,1562,1524,1508,1460,1431,13
25,1301,1278,7451 HNMR (CDCl3) δ: 7.47 (1H, d, J = 7.5), 7.3-6.8 (3H, m), 4.5
5 (2H, d, J = 1.8), 4.32 (1H, brs), 3.7-3.2 (1H, m), 1.51 (6H,
s) MS (EI): 214 (M +, base peak), 144,118
【００３４】実施例５ 1-フェニル-4,5- ジヒドロ[1,2,4] トリアゾロ[4,3-a]
キノキサリン (５)Example 5 1-Phenyl-4,5-dihydro [1,2,4] triazolo [4,3-a]
Quinoxaline (5)
【化１９】2-( クロロメチル)-5-メチル-1,3,4- オキサジアゾ−ル
の代わりに2-( クロロメチル)-5-フェニル-1,3,4- オキ
サジアゾ−ルを用いる以外は実施例１と同様の反応を行
なうことにより題記化合物を得た。[Chemical 19] Example 1 except that 2- (chloromethyl) -5-phenyl-1,3,4-oxadiazol is used instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol. The title compound was obtained by performing a similar reaction to.
【００３５】無色結晶 mp:136-141℃ IR(KBr)cm-1:1510,1468,1423,756,7021 HNMR(CDCl3) δ:7.7-7.4(5H,m),7.2-6.5(4H,m),4.64(2
H,s) MS:248(M+,base peak),144,118Colorless crystal mp: 136-141 ° C IR (KBr) cm-1 : 1510,1468,1423,756,7021 HNMR (CDCl3) δ: 7.7-7.4 (5H, m), 7.2-6.5 (4H, m) , 4.64 (2
H, s) MS: 248 (M +, base peak), 144,118
【００３６】[0036]
【発明の効果】本発明によれば、医薬、農薬等の製造中
間体として有用な３環性トリアゾロ誘導体（ＩＩＩ）
を、毒性および悪臭の強い硫黄化合物を使用することな
く、簡便にかつ効率良く製造することができる。INDUSTRIAL APPLICABILITY According to the present invention, a tricyclic triazolo derivative (III) useful as an intermediate for the production of pharmaceuticals, agricultural chemicals, etc.
Can be simply and efficiently produced without using a sulfur compound having strong toxicity and malodor.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28166092AJP3252483B2 (en) | 1992-10-20 | 1992-10-20 | Method for producing tricyclic triazolo derivative |
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28166092AJP3252483B2 (en) | 1992-10-20 | 1992-10-20 | Method for producing tricyclic triazolo derivative |
| Publication Number | Publication Date |
|---|---|
| JPH06128261Atrue JPH06128261A (en) | 1994-05-10 |
| JP3252483B2 JP3252483B2 (en) | 2002-02-04 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28166092AExpired - Fee RelatedJP3252483B2 (en) | 1992-10-20 | 1992-10-20 | Method for producing tricyclic triazolo derivative |
| Country | Link |
|---|---|
| JP (1) | JP3252483B2 (en) |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5723463A (en)* | 1995-03-24 | 1998-03-03 | Asta Medica Aktiengesellschaft | Pyrido 3,2-E!pyrazinones with anti-asthmatic action and processes for their manufacture |
| WO2004080958A3 (en)* | 2003-03-07 | 2004-12-23 | Merck & Co Inc | Process to tetrahydrotriazolopyrazines and intermediates |
| WO2013050424A1 (en) | 2011-10-03 | 2013-04-11 | Euroscreen S.A. | NOVEL CHIRAL N-ACYL-5,6,7,(8-SUBSTITUTED)-TETRAHYDRO-[1,2,4]TRIAZOLO[4,3-a]PYRAZINES AS SELECTIVE NK-3 RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITION, METHODS FOR USE IN NK-3 RECEPTOR MEDIATED DISORDERS AND CHIRAL SYNTHESIS THEREOF |
| US8871761B2 (en) | 2010-04-02 | 2014-10-28 | Euroscreen S.A. | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| US10065960B2 (en) | 2010-04-02 | 2018-09-04 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| US10787458B2 (en) | 2014-09-25 | 2020-09-29 | Ogeda Sa | Chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazines |
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5723463A (en)* | 1995-03-24 | 1998-03-03 | Asta Medica Aktiengesellschaft | Pyrido 3,2-E!pyrazinones with anti-asthmatic action and processes for their manufacture |
| WO2004080958A3 (en)* | 2003-03-07 | 2004-12-23 | Merck & Co Inc | Process to tetrahydrotriazolopyrazines and intermediates |
| US9926325B2 (en) | 2010-04-02 | 2018-03-27 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| US8871761B2 (en) | 2010-04-02 | 2014-10-28 | Euroscreen S.A. | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| US10065960B2 (en) | 2010-04-02 | 2018-09-04 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| US10544150B2 (en) | 2010-04-02 | 2020-01-28 | Ogeda Sa | NK-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in NK-3 receptors mediated disorders |
| EP3029042A1 (en) | 2011-10-03 | 2016-06-08 | Euroscreen S.A. | Novel chiral n-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective nk-3 receptor antagonists, pharmaceutical composition, methods for use in nk-3 receptor mediated disorders and chiral synthesis thereof |
| US9475814B2 (en) | 2011-10-03 | 2016-10-25 | Euroscreen S.A. | Chiral N-acyl-5,6,7(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof |
| WO2013050424A1 (en) | 2011-10-03 | 2013-04-11 | Euroscreen S.A. | NOVEL CHIRAL N-ACYL-5,6,7,(8-SUBSTITUTED)-TETRAHYDRO-[1,2,4]TRIAZOLO[4,3-a]PYRAZINES AS SELECTIVE NK-3 RECEPTOR ANTAGONISTS, PHARMACEUTICAL COMPOSITION, METHODS FOR USE IN NK-3 RECEPTOR MEDIATED DISORDERS AND CHIRAL SYNTHESIS THEREOF |
| US10065961B2 (en) | 2011-10-03 | 2018-09-04 | Ogeda Sa. | Chiral N-acyl-5,6,7,(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof |
| US10683295B2 (en) | 2011-10-03 | 2020-06-16 | Ogeda Sa | Chiral N-acyl-5,6,7(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-A]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof |
| US10941151B2 (en) | 2011-10-03 | 2021-03-09 | Ogeda Sa | Chiral N-acyl-5,6,7(8-substituted)-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazines as selective NK-3 receptor antagonists, pharmaceutical composition, methods for use in NK-3 receptor mediated disorders and chiral synthesis thereof |
| US10787458B2 (en) | 2014-09-25 | 2020-09-29 | Ogeda Sa | Chiral synthesis of N-acyl-(3-substituted)-(8-substituted)-5,6-dihydro-[1,2,4]triazolo[4,3-A]pyrazines |
| Publication number | Publication date |
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| JP3252483B2 (en) | 2002-02-04 |
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| LAPS | Cancellation because of no payment of annual fees |