JPS63275582A - Production of 1-aminoimidazo(4,5-b)pyridine derivative - Google Patents
Production of 1-aminoimidazo(4,5-b)pyridine derivativeInfo
- Publication number
- JPS63275582A JPS63275582A JP10942787A JP10942787A JPS63275582A JP S63275582 A JPS63275582 A JP S63275582A JP 10942787 A JP10942787 A JP 10942787A JP 10942787 A JP10942787 A JP 10942787A JP S63275582 A JPS63275582 A JP S63275582A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- pyridine derivative
- pyridine
- tables
- aminoimidazo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- IPGDWOOCQTVPAY-UHFFFAOYSA-N imidazo[4,5-b]pyridin-1-amine Chemical class NN1C=NC2=NC=CC=C21 IPGDWOOCQTVPAY-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 150000003222 pyridines Chemical class 0.000 claims abstract description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 4
- PGDIPOWQYRAOSK-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical class C1=CN=C2NC(=O)NC2=C1 PGDIPOWQYRAOSK-UHFFFAOYSA-N 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- KXQPVJRJUJJWQJ-UHFFFAOYSA-N 1h-imidazo[4,5-b]pyridin-2-amine Chemical class C1=CN=C2NC(N)=NC2=C1 KXQPVJRJUJJWQJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 5
- 239000004202 carbamide Substances 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical class NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002140 halogenating effect Effects 0.000 abstract description 3
- 230000035772 mutation Effects 0.000 abstract description 3
- 230000001939 inductive effect Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract 3
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000004020 conductor Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- ZZARKLLLBRWNNV-UHFFFAOYSA-N 3-n-methyl-5-phenylpyridine-2,3-diamine Chemical compound N1=C(N)C(NC)=CC(C=2C=CC=CC=2)=C1 ZZARKLLLBRWNNV-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PDYMCBRGMDRAPX-UHFFFAOYSA-N 1-methyl-6-phenyl-3h-imidazo[4,5-b]pyridin-2-one Chemical compound C=1N=C2NC(=O)N(C)C2=CC=1C1=CC=CC=C1 PDYMCBRGMDRAPX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004305 biphenyl Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000002587 enol group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- JXXWJMUPNZDILL-UHFFFAOYSA-N imidazo[4,5-b]pyridin-2-one Chemical compound C1=CC=NC2=NC(=O)N=C21 JXXWJMUPNZDILL-UHFFFAOYSA-N 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007886 mutagenicity Effects 0.000 description 1
- 231100000299 mutagenicity Toxicity 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Abstract
Description
［産業上の利用分野］
本発明は２−アミノイミダゾ［４，５−ｂｌピリジン誘
導体を高収率で得ることのできる製造方法に関するもの
である。
［従来の技術］
従来、突然変異話起剤として知られている２−アミノイ
ミダゾ［４，５−ｂ］ピリジン誘導体を得る方法として
は天然のフライドビーフから抽出する方法があり、また
合成方法としては下記反応式で示すように
２−アミノ−３−メチルアミノ−５−フェニルピリジン
にシアン化臭素を作用させて、２−アミ、ノー１−メチ
ル−６−フェニルイミダゾ［４，５−ｂｌピリジンを合
成する方法［Ｃａｒｃｉｎｏｇｅｎｅｃｉｅｓ ７１
ｏａｌ−１ｏｓａ （１９８６） ］が知られているの
みである。
［発明が解決しようとする問題点］
前述のように天然物から抽出する方法では大量に入手す
ることが困難であり、また合成法で得るにしても、精製
段階でカラムクロマトグラフィーを必要とし、収率が５
〜８％に過ぎなかった。また前述したように２位にアミ
ノ基を有する２−アミノ−１−メチル−６−フェニルイ
ミダゾ［４，５−ｂｌピリジンを得る方法が知られてい
るのみであり、他の誘導体については適切な合成法が知
られていなかった。
そこで本発明においては、工程は増えるが収率のよい２
−アミノイミダゾ［４，５−ｂ ］ピリジン話導体の製
造方法について検討した。
［問題点を解決するための手段］
上記問題点を解決することのできた本発明とは下記一般
式［Ｉ］
［１］
但しＲ’ ：鎮状または環状の炭化水素残基Ｒ２＝水
素または低級アルキル基
Ｒ３，水素または低級アルキル基であり、Ｒ” 、Ｒ’
はいずれか一方が水素
で示される２、３−ジアミノピリジン誘導体を尿素と反
応させることによって下記一般式［１１，］または［Ｉ
Ｉｌｂｌ
［ＩＩ −１［ＩＩ １１］
但しｖｔｓ 、 Ｒ２、Ｒ３、何れも前記と同じ意味で
示される２−ヒドロキシイミダゾ［４，５−ｂｌピリジ
ン誘導体を得、次いでこれをハロゲン化して下記一般式
口Ｉ！、］または［ＩＩｌ ｂｌ［１１１、〕［１１１
１１ｂｌ
但しＲ１、Ｒ２、Ｒ３、何れも前記と同じ意味Ｘ：ハロ
ゲン
で示される２−へロイミダゾ［４，５−ｂｌピリジン話
導体を得、更にこれにアンモニアを反応させて下記一般
式［■、］または［ＩＶ ｂｌ但しＲ１、Ｒ２、Ｒ３、
何れも前記と同じで示される２−アミノイミダゾ［４，
５−ｂｌピリジン説導体を得ることを構成要旨としてい
る。
［作用］
本発明においてＲ１は鎖状または環状の炭化水素残基で
あり、プロピル、イソプロピル、第３級ブチル、ペンチ
ル、ヘキシル、シクロペンチル。
シクロヘキシル等のＣｎ Ｈ２ｎ＋１基で表わされるア
ルキル基あるいはシクロアルキル基の他、フェニル、ト
リル、キシリル、ビフェニル、ナフチル。
アントリル、フェナントリル等のアリール基（低級アル
キル基やアリール基等の置換分を有していても良い）、
フェニルメチル、フェニルエチル。
フェニルプロピル等アラルキル基等が例示される。
Ｒ２、Ｒ３は水素、メチル、エチル、プロピル、イソプ
ロピル、ブチル、イソブチル、第３級ブチル、ペンチル
、イソペンチル、ネオペンチル、ヘキシル等の炭素１〜
６個を有する低級アルキル基である。
ＸはＦ、Ｃ１，Ｂｒ、１等のハロゲンである。
次に本発明を反応の段階を追フて説明する。
■
［１］
［ｎ、］ ［Ｉｌｂ］２．３−
ジアミノピリジン誘導体に尿素を作用させて脱アンモニ
ア反応により２−ヒドロキシイミダゾ［４，５−ｂｌピ
リジン誘導体［１１，］または［ＩＩ ｂｌを得る。
反応は２．３−ジアミノピリジン誘導体［Ｉ］と尿素を
ナフタリン、テトラリン等の溶媒の存在下あるいは無溶
媒下で１６０〜１７０℃に加熱することによって行なわ
れる。
得られた２−ヒドロキシイミダゾ［４，５−ｂｌピリジ
ン誘導体［ＩＩ ｍｌまたは ［Ｉｌｂ］はエノール形
であ［ｎ、］ ［ｎ、］’＊ ｈ ′
ｔ 。
［１１ｂ］ ［ｎｂ］’ケト形
の２−オキソイミダゾ［４，５−ｂ］ピノジン誂導体［
１１ａｌ’ 、［１１ｂｌ’ と共存して存在するので
この２−オキソイミダゾ［４，５−ｂ］ピリジン話導体
［１１−１’ 、 ［ｌＩｂ１’も本発明工程段階の
範嗅に入る０次いで未精製のままあるいは常法により未
反応物を除去および分離精製して次の反応を行なう。
［１１，１［ｎｔ、］
［１１ｂ］ ＣＩＩＩｂｌ前
記■で得られた２−ヒドロキシイミダゾ［４，５−ｂ］
ピリジン銹導体［１１，］または［Ｉｌ ｂ］にハロゲ
ン化剤を作用させて２−ハロイミダゾ［４，５−ｂｌピ
リジン誘導体［１１１，３または［１１１ｂｌを得る。
ハロゲン化剤としてはオキシ塩化燐等が挙げられ、ハロ
ゲン化反応は適当な溶媒の存在下あるいは無溶媒下で加
熱することにより行なわれ、２−ハロイミダゾ［４，５
−ｂｌピリジン誘導体［１１１，］または［ＩＩＩ ｂ
ｌを得る。次いで未精製のまま或は常法に従って未反応
物を除去および分離精製して次の反応を行なう。
［ｍ、１ ［ＩＶａｌまたは
［ｍ、］ ［ＩＶａｌ前記■で得
られた２−ハロイミダゾ［４，５−ｂｌ ピリジン誘導
体［１１１，１または［ｌｌＩｂ１にアンモニア（アン
モニア水を含む）を水、メタノール、エタノール等の溶
媒の存在下あるいは無溶媒下で、１２０〜１５０℃、１
〜３０ａｔｍの加圧・加熱下でそれぞれ作用させ、ハロ
ゲンのアミノ置換により２−アミノイミダゾ［４，５−
ｂ］ ピリジン誘導体［ＩＶ、］または［■５１を得る
。常法に従って未反応物を除去および分離精製して目的
とするそれぞれの２−アミノイミダゾ［４，５−ｂ］ピ
リジン話厚導体得る０次に本発明の実施例を示す。
［実施例］
■
２−アミノ−３−メチルアミノ−５−フェニルピリジン
５０ ｇ （０，２５モル）と尿素１８ ｇ （０，３
０モル）とを１００℃で１６時間溶融反応させた後、エ
タノール１６０ｍ１を加え１時間還流後、冷却し、生じ
た結晶を濾別した。さらにエタノール３１で再結晶化し
て４４ｇ（収率７８．２％）の２−ヒドロキシ−１−メ
チル−６−フェニルイミダゾ［４，５−ｂ］ ピリジン
を得た。
■
前記■で得られた２−ヒドロキシ−１−メチル−６−フ
ェニルイミダゾ［４，５−ｂｌピリジン４４ｇ（０，１
９８モ）１／）をオキシ塩化燐（ＰＯＣｌｓ−蒸留品）
９３０１１に懸濁し、塩酸ガスを通じなから還流し、２
４時間後溶液が透明になり反応が終了したらＰＯＣＪ２
ｓを減圧除去し、残漬を氷水５００ｍｆ中に注入し、５
０℃で加熱溶解後、１０％ＮａＯＨ水溶液にてアルカリ
性にすると白色結晶が析出した。結晶を濾別し、水洗後
乾燥し、９０％エタノール水溶液Ｉｆｌで再結晶化して
、２−クロロ−１−メチル−６−フェニルイミダゾ（４
，５−ｂｌピリジン３６．７ｇ（収率７６．９％）を得
た。
■
前記■で得られた２−クロロ−１−メチル−６−フェニ
ルイミダゾ[Industrial Field of Application] The present invention relates to a manufacturing method capable of obtaining a 2-aminoimidazo[4,5-bl pyridine derivative in high yield. [Prior Art] Conventionally, there is a method for obtaining a 2-aminoimidazo[4,5-b]pyridine derivative, which is known as a mutation promoter, by extracting it from natural fried beef, and a method for synthesizing it is As shown in the reaction formula below, 2-amino-3-methylamino-5-phenylpyridine is reacted with bromine cyanide to form 2-amino-1-methyl-6-phenylimidazo[4,5-blpyridine]. [Carcinogenecies 71
oal-1osa (1986)] is known. [Problems to be solved by the invention] As mentioned above, it is difficult to obtain large quantities by extraction from natural products, and even if it is obtained by synthesis, column chromatography is required in the purification step. Yield is 5
It was only ~8%. Furthermore, as mentioned above, only a method for obtaining 2-amino-1-methyl-6-phenylimidazo[4,5-bl pyridine having an amino group at the 2-position is known, and other derivatives may be obtained using appropriate methods. There was no known synthesis method. Therefore, in the present invention, the number of steps is increased but the yield is good.
A method for manufacturing a -aminoimidazo[4,5-b]pyridine conductor was investigated. [Means for Solving the Problems] The present invention that can solve the above problems is represented by the following general formula [I] [1] where R' is a cyclic or cyclic hydrocarbon residue R2=hydrogen or lower Alkyl group R3, hydrogen or lower alkyl group, R'', R'
is prepared by the following general formula [11,] or [I
Ilbl [II-1 [II 11] However, vts, R2, R3, all of which have the same meaning as above, obtain a 2-hydroxyimidazo[4,5-bl pyridine derivative, which is then halogenated to form the following general formula. I! ,] or [IIl bl[111,][111
11bl However, R1, R2, and R3 all have the same meanings as above. ] or [IV bl except R1, R2, R3,
2-aminoimidazo[4,
The gist of the structure is to obtain a 5-bl pyridine conductor. [Function] In the present invention, R1 is a chain or cyclic hydrocarbon residue, such as propyl, isopropyl, tertiary butyl, pentyl, hexyl, or cyclopentyl. In addition to alkyl groups or cycloalkyl groups represented by Cn H2n+1 groups such as cyclohexyl, phenyl, tolyl, xylyl, biphenyl, and naphthyl. Aryl groups such as anthryl and phenanthryl (which may have substituents such as lower alkyl groups and aryl groups),
Phenylmethyl, phenylethyl. Examples include aralkyl groups such as phenylpropyl. R2 and R3 are hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
It is a lower alkyl group having 6 alkyl groups. X is a halogen such as F, C1, Br, 1, etc. Next, the present invention will be explained by following the reaction steps. ■ [1] [n,] [Ilb]2.3-
A 2-hydroxyimidazo[4,5-bl pyridine derivative [11,] or [II bl] is obtained by a deammonia reaction by allowing urea to act on the diamino pyridine derivative. The reaction is carried out by heating the 2,3-diaminopyridine derivative [I] and urea to 160 to 170°C in the presence of a solvent such as naphthalene or tetralin or in the absence of a solvent. The resulting 2-hydroxyimidazo[4,5-bl pyridine derivative [II ml or [Ilb] is in the enol form [n,] [n,]'*h'
t. [11b] [nb]' Keto form of 2-oxoimidazo[4,5-b]pinodine conductor [
Since these 2-oxoimidazo[4,5-b]pyridine conductors [11-1' and [lIb1'] coexist with 11al' and [11bl', the The next reaction is carried out as purified or after removal of unreacted substances and separation and purification by a conventional method. [11,1 [nt,] [11b] CIIIbl 2-hydroxyimidazo[4,5-b] obtained in the above (■)
A 2-haloimidazo[4,5-bl pyridine derivative [111,3 or [111bl] is obtained by reacting the pyridine rust conductor [11,] or [Ilb] with a halogenating agent. Examples of the halogenating agent include phosphorus oxychloride, and the halogenation reaction is carried out by heating in the presence of a suitable solvent or in the absence of a solvent.
-bl pyridine derivative [111,] or [III b
get l. Next, the next reaction is carried out either unpurified or by removing unreacted substances and separating and purifying it according to a conventional method. [m, 1 [IVal or [m,] [IVal] 2-haloimidazo[4,5-bl pyridine derivative obtained in the above ① In the presence of a solvent such as ethanol or without a solvent, at 120 to 150°C, 1
2-Aminoimidazo[4,5-
b] Pyridine derivative [IV, ] or [■51 is obtained. The desired 2-aminoimidazo[4,5-b]pyridine thick conductors were obtained by removing unreacted substances and separating and purifying them according to conventional methods.Examples of the present invention will now be described. [Example] ■ 50 g (0.25 mol) of 2-amino-3-methylamino-5-phenylpyridine and 18 g (0.3 mol) of urea
After a melt reaction of 0 mol) at 100° C. for 16 hours, 160 ml of ethanol was added and the mixture was refluxed for 1 hour, cooled, and the resulting crystals were filtered off. Further, it was recrystallized from ethanol 31 to obtain 44 g (yield 78.2%) of 2-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine. ■ 44 g (0,1
98 mo) 1/) as phosphorus oxychloride (POCls-distilled product)
93011, reflux through passing hydrochloric acid gas, and
After 4 hours, when the solution becomes clear and the reaction is complete, POCJ2
s was removed under reduced pressure, and the residue was poured into 500 mf of ice water.
After heating and dissolving at 0°C, the mixture was made alkaline with a 10% NaOH aqueous solution to precipitate white crystals. The crystals were filtered, washed with water, dried, and recrystallized from 90% ethanol aqueous solution Ifl to give 2-chloro-1-methyl-6-phenylimidazo (4
, 36.7 g (yield 76.9%) of 5-bl pyridine were obtained. ■ 2-chloro-1-methyl-6-phenylimidazo obtained in the above ■
【４．５−ｂ】 ピリジン３６．７ｇ（０，
１４８ｍｏ１）と２８％７ンー１−−−７水７００ｉ＋
ｆＬをオートクレーブに入れ１５０℃で８時間反応させ
、濃縮してアンモニアを除去し、結晶を濾別洗浄して、
４．８１のメタノールで再結晶化すると白色結晶の２−
アミノ−１−メチル−６−フェニルイミダゾ［４，５−
ｂ］ピリジン２１ｇ（収率６３．３％）を得ることがで
きた。
ＵＶ （ＣＨｓ ＯＨ） ： ２２５ 、２７３ 、
３１６Ｉ Ｒ（Ｋ Ｂ ｒ ）ｃｌｌ： ３０９１，１
６６８，１５９５゜１５５１． １４７２． １４３９
゜
１４２３、 １４０８． １２８９． ７６０ＨＮＭＲ
（２００ＭＨｚ、ＤＭＳＯ−ｄｓ ）：８．３１ （
５−Ｈ、ｄ 、 Ｊ ＝２．ＩＨｚ）７．７１ （
７−Ｈ、ｄ 、 ｊ ＝２．１Ｈｚ ）７．７２
（２’ 、６’ −Ｈ，ｄ 、 ｊ ＝
７．３Ｈｚ）７．４８ （３’ 、５’ −）１．
ｔ 、 Ｊ −７，３Ｈ２）７．３５ （４’
−Ｈ、ｔ 、 Ｊ ＝７．３Ｈｚ）７．０
（Ｎ）１２ 、 ｂｒｏａｄ Ｓ ）３．６
０ （Ｉ ＣＨｓ、Ｓ ）ＭＳ ：ｍ ／ｚ
： ２２４ ．１０６８ＣＩ３Ｈ１２Ｎ４，２２
４ 、１０８２融点：３００℃以上
Ｓａｌｍｏｎｅｌｌａ ｍｕｔａｇｅｎｉｃｉｔｙ ４
３１ ｒｅｖｅｒｔａｎｔｓ／ｎｍｏｌｅ（Ｓｔｒａｉ
ｎ １５３８）
［発明の効果］
本発明は以上のように構成されているので、２−アミノ
イミダゾ［４，５−ｂ］ピリジン誘導体を高収率で得る
ことができる。また該２−アミノイミダゾ［４，５−ｂ
］ピリジン話導体は突然変異屈起剤としての効能も良い
ものである。[4.5-b] Pyridine 36.7g (0,
148mo1) and 28%7-1---7 water 700i+
fL was placed in an autoclave and reacted at 150°C for 8 hours, concentrated to remove ammonia, and the crystals were filtered and washed.
Recrystallization with 4.81 methanol gives white crystals of 2-
Amino-1-methyl-6-phenylimidazo[4,5-
b] 21 g (yield 63.3%) of pyridine could be obtained. UV (CHs OH): 225, 273,
316I R (K B r ) cll: 3091,1
668,1595°1551. 1472. 1439
゜1423, 1408. 1289. 760HNMR
(200MHz, DMSO-ds): 8.31 (
5-H, d, J = 2. IHz) 7.71 (
7-H, d, j = 2.1Hz) 7.72
(2', 6'-H, d, j =
7.3Hz) 7.48 (3', 5'-)1.
t, J-7,3H2) 7.35 (4'
-H, t, J = 7.3Hz) 7.0
(N)12, broad S)3.6
0 (I CHs, S ) MS: m /z
: 224. 1068CI3H12N4,22
4, 1082 Melting point: 300°C or higher Salmonella mutagenicity 4
31 revertants/nmole (Strai
n 1538) [Effects of the Invention] Since the present invention is configured as described above, a 2-aminoimidazo[4,5-b]pyridine derivative can be obtained in high yield. Also, the 2-aminoimidazo[4,5-b
] The pyridine conductor is also effective as a mutation-inducing agent.
Claims (1)
素または低級アルキル基 Ｒ＾３：水素または低級アルキル基であり、Ｒ＾２、Ｒ
＾３はいずれか一方が水素 で示される２，３−ジアミノピリジン誘導体を尿素と反
応させることによって下記一般式［II＿ａ］または［I
I＿ｂ］ ▲数式、化学式、表等があります▼［II＿ａ］または▲
数式、化学式、表等があります▼［II＿ｂ］ 但しＲ＾１、Ｒ＾２、Ｒ＾３：何れも前記と同じ意味で
示される２−ヒドロキシイミダゾ［４，５−ｂ］ピリジ
ン誘導体を得、次いでこれをハロゲン化して下記一般式
［III＿ａ］または［III＿ｂ］ ▲数式、化学式、表等があります▼［III＿ａ］または
▲数式、化学式、表等があります▼［III＿ｂ］ 但しＲ＾１、Ｒ＾２、Ｒ＾３：何れも前記と同じ意味Ｘ
：ハロゲン で示される２−ハロイミダゾ［４，５−ｂ］ピリジン誘
導体を得、更にこれにアンモニアを反応させることを特
徴とする下記一般式［IV＿ａ］または［IV＿ｂ］▲数式
、化学式、表等があります▼［IV＿ａ］または▲数式、
化学式、表等があります▼［IV＿ｂ］ 但しＲ＾１、Ｒ＾２、Ｒ＾３：何れも前記と同じで示さ
れる２−アミノイミダゾ［４，５−ｂ］ピリジン誘導体
の製造方法。[Claims] The following general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] However, R^1: Chain or cyclic hydrocarbon residue R^2: Hydrogen or lower alkyl group R^ 3: Hydrogen or lower alkyl group, R^2, R
^3 is prepared by the following general formula [II_a] or [I
I_b] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II_a] or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ [II_b] However, R^1, R^2, R^3: Obtain a 2-hydroxyimidazo[4,5-b]pyridine derivative, all of which have the same meaning as above, This is then halogenated to form the following general formula [III_a] or [III_b] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III_a] or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III_b] However, R^1, R^ 2. R^3: Same meaning as above
: The following general formula [IV_a] or [IV_b] is characterized by obtaining a 2-haloimidazo[4,5-b]pyridine derivative represented by halogen and further reacting it with ammonia. Yes ▼ [IV_a] or ▲ Formula,
There are chemical formulas, tables, etc. ▼ [IV_b] However, R^1, R^2, R^3: A method for producing a 2-aminoimidazo[4,5-b]pyridine derivative, all of which are shown as above.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10942787A JPS63275582A (en) | 1987-05-02 | 1987-05-02 | Production of 1-aminoimidazo(4,5-b)pyridine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10942787A JPS63275582A (en) | 1987-05-02 | 1987-05-02 | Production of 1-aminoimidazo(4,5-b)pyridine derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63275582A true JPS63275582A (en) | 1988-11-14 |
Family
ID=14509969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10942787A Pending JPS63275582A (en) | 1987-05-02 | 1987-05-02 | Production of 1-aminoimidazo(4,5-b)pyridine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63275582A (en) |
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| US11096940B2 (en) | 2017-06-22 | 2021-08-24 | Celgene Corporation | Treatment of hepatocellular carcinoma characterized by hepatitis B virus infection |
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