JP4403482B2 - 置換複素環尿素合成のための中間体およびその製造方法 - Google Patents

置換複素環尿素合成のための中間体およびその製造方法 Download PDF

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JP4403482B2
JP4403482B2 JP2000525102A JP2000525102A JP4403482B2 JP 4403482 B2 JP4403482 B2 JP 4403482B2 JP 2000525102 A JP2000525102 A JP 2000525102A JP 2000525102 A JP2000525102 A JP 2000525102A JP 4403482 B2 JP4403482 B2 JP 4403482B2
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preparation
intermediates
synthesis
methods
substituted heterocyclic
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JP2001526223A5 (ja
JP2001526223A (ja
Inventor
デュマ，ジャック
キール，ウデイ
ブルーノ ロウインガー，チモシー
パウルゼン，ホルガー
リードル，バーンド
ジェイ スコット，ウイリアム
エイ スミス，ロジャー
イー ウッド，ジル
ハトゥームーモクダッド，ホリア
ジョンソン，ジェフリー
リー，ウエンディ
レッドマン，アニコ
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Bayer Corp
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Bayer Corp
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Description

【技術分野】
【０００１】
本発明は、ｐ３８仲介プロセスによって生産および／または活性化される一以上のサイトカインまたはタンパク分解酵素によって仲介される疾病の処理に有用な置換複素環尿素合成のための中間体およびその製造方法に関する。
【発明の開示】
【０００２】
本発明は、下記式（Ｉ）を有する２−（Ｎ−メチルカルバモイル）−４−クロロピリジンに関する。
【０００３】
【化２】
Figure 0004403482
【０００４】
本発明はまた、４−クロロピリジンとＮ−メチルホルムアミドを反応させることよりなる式（Ｉ）の化合物の製造方法に関する。
【０００５】
式（Ｉ）の２−（Ｎ−メチルカルバモイル）−４−クロロピリジンから合成される置換複素環化合物の例は、
Ｎ−（１−メチル−３−フェニル−５−ピラゾリル）−Ｎ’−（３−（４−２−メチルカルバモイル）ピリジル）チオフェニル尿素；
Ｎ−（５−ｔ−ブチル−３−イソオキサゾリル）−Ｎ’−（４−（４−（２−メチルカルバモイル）ピリジル）オキシフェニル尿素；および
Ｎ−（５−ｔ−ブチル−３−イソオキサゾリル−Ｎ’−（３−（４−（２−メチルカルバモイル）ピリジル）オキシフェニル尿素を含む。
【０００６】
式（Ｉ）の化合物は、ハロゲンピリジンを用いる求核芳香族置換によって対応する置換アニリンに誘導し、次いで以下に述べる反応に従って最終生成物である尿素へ導くことができる。
【０００７】
スキームIVに示すように、尿素生成はヘテロアリールイソシアネート（１７）とアリールアミン（１６）の反応を含む。ヘテロアリールシアネートはヘテロアリールアミンからホスゲンまたはトリクロロメチルクロロホルメート（ジホスゲン）、ビス（トリクロロメチル）カーボネート（トリホスゲン）またはＮ，Ｎ−カルボニルジイミダゾール（ＣＤＩ）のようなホスゲン均等物との処理によって合成し得る。イソシアネートはエステル、酸ハライドまたは無水物のような複素環酸誘導体からクルチウスタイプ転位によって誘導することができる。このように酸誘導体（２１）のアジドソースとの反応、続いて転位はイソシアネートを与える。対応するカルボン酸（２２）はジフェニルフォスフォリルアジド（ＤＰＰＡ）または同様な試薬を使用してクルチウスタイプの転位へかけることができる。尿素はアリールイソシアネート（２０）と複素環アミンとの反応から生成することができる。
【０００８】
スキームIV 尿素生成の選択された方法（Ｈｅｔ＝複素環）
【０００９】
【化３】
Figure 0004403482
【実施例】
【００１０】
すべての反応は乾燥アルゴンまたは乾燥窒素の陽圧のもとで炎乾燥またはオーブン乾燥されたガラス器具内で実施され、そして特記しない限り磁気的に攪拌された。敏感な液体および溶液はシリンジまたはカニューレにより移され、そしてゴム栓を通って反応容器へ導入された。特記しない限り、「減圧下の濃縮」の用語は約１５ｍｍＨｇにおけるＢｕｃｈｉロータリエバポレーターの使用を指す。
【００１１】
すべての温度は未補正の摂氏（℃）で報告される。特記しない限り、すべての部およびパーセントは重量による。
【００１２】
市販グレードの試薬および溶剤がさらに精製することなく使用された。薄層クロマトグラフィー（ＴＬＣ）はＷｈａｔｍａｎプレコートガラスバックシリカゲル６０Ａ Ｆ−２５４の２５０μｍプレートを使用して実施した。プレートの可視化は次の技術の一以上によって実施された。（ａ）紫外線照射、（ｂ）ヨウ素ガスへ曝露、（ｃ）エタノール中リンモリブデン酸１０％溶液中プレートの浸漬および続いて加熱、（ｄ）硫酸セリウム溶液中プレートの浸漬および続いて加熱、（ｅ）２，４−ジニトロフェニルヒドラジンの酸性エタノール溶液中プレートの浸漬および続いて加熱。カラムクロマトグラフィー（フラッシュクロマトグラフィー）は２３０−４００メッシュＥＭサイエンスシリカゲルを使用して実施された。
【００１３】
融点（ｍｐ）は、Ｔｈｏｍａｓ−Ｈｏｏｖｅｒ融点装置またはＭｅｔｔｌｅｒ
ＦＰ６６自動融点装置を使用して決定され、補正しなかった。フーリエ変換赤外スペクトルはＭａｔｔｓｏｎ ４０２０ Ｇａｌａｘｙシリーズ分光光度計を使用して得られた。プロトン（ 1Ｈ）核磁気共鳴（ＮＭＲ）スペクトルは、Ｇｅｎｅｒａｌ Ｅｌｅｃｔｒｉｃ ＧＮ−オメガ３００（３００ＭＨｚ）スペクトロメータにより、標準としてＭｅ4 Ｓｉ（ｄ０．００）またはプロトン化溶媒（ＣＨＣｌ3 δ７．２６；ＭｅＯＨ δ３．３０；ＤＭＳＯ δ２．４９）で測定された。炭素（13Ｃ）ＮＭＲスペクトルはＧｅｎｅｒａｌ Ｅｌｅｃｔｒｉｃ ＧＮ−オメガ３００（７５ＭＨｚ）スペクトロメータと、標準として溶媒（ＣＤＣｌ3 δ７７．０；ＭｅＯＤ−ｄ3 ；δ４９．０；ＤＭＳＯ−ｄ6 δ３９．５）で測定された。低解像質量スペクトルは、電子インパクト（ＥＩ）質量スペクトルとして、または高速原子衝撃（ＦＡＢ）質量スペクトルとして得られた。電子インパクト質量スペクトル（ＥＩ−ＭＳ）はサンプル導入のためＶａｃｕｍｅｔｒｉｃ脱着化学的イオン化プローブを備えたヒューレット−パッカード５９８９Ａ質量スペクトル計で得られた。イオン源は２５０℃に維持された。電子インパクトイオン化は電子エネルギー７０ｅＶおよびトラップ電流３００μＡで実施された。液体セリウム二次イオン質量スペクトル（ＦＡＢ−ＭＳ）すなわち高速原子衝撃の最新型はＫｒａｔｏｓ Ｃｏｎｃｅｐｔ １−Ｈスペクトル計を用いて得られた。化学的イオン化質量スペクトル（ＣＩ−ＭＳ）は試薬ガスとして（１×１０-4トルないし２．５×１０-4トル）メタンまたはアンモニアを使用し、ヒューレット−パッカードＭＳ−エンジン（５９８９Ａ）を使用して得られた。直接挿入脱着化学的イオン化（ＤＣＩ）プローブ（Ｖａｃｕｍｅｔｒｉｃｓ，Ｉｎｃ．）は１０秒で０〜１５Ａから立ち上げられ、サンプルの痕跡すべてが消失するまで（〜１〜２分）１０Ａに保たれた。スペクトルは２秒／走査において５０〜８００ａｍｕから走査された。ＨＰＬＣエレクトロスプレー質量スペクトル（ＨＰＬＣ ＥＳ−ＭＳ）は、四級ポンプ、可変波長検出器、Ｃ−１８カラム、およびエレクトロスプレーイオン化を有するＦｉｎｎｉｇａｎ ＬＣＱイオントラップ質量スペクトル計を備えたヒューレット−パッカード１１００ＨＰＬＣを使用して得られた。スペクトルはソースのイオンの数に従って可変イオン時間を使用して１２０〜８００ａｍｕから走査された。ガラスクロマトグラフィー／イオン選択性質量スペクトル（ＧＣ−ＭＳ）は、ＨＰ−１メチルシリコーンカラム（０．３３ｍＭコーティング；２５ｍ×０．２ｍｍ）を備えたヒューレット−パッカード５８９０ガスクロマトグラフ、およびヒューレット−パッカード５９７１質量選択性検出器（イオン化エネルギー７０ｅＶ）で得られた。元素分析はＲｏｂｅｒｔｓｏｎ Ｍｉｃｒｏｌｉｔ Ｌａｂｓ．Ｍａｄｉｓｏｎ ＮＪによって実施された。
【００１４】
すべての化合物は、帰属された構造と一致するＮＭＲスペクトル、ＬＲＭＳおよび元素分析もしくはＨＲＭＳをディスプレーした。
【００１５】
Ｂ１０．メニスシ反応による２−（Ｎ−メチルカルバモイル）ピリジンの生成
アルゴン下のＮ−メチルホルムアミド（２５０ｍＬ）中の４−クロロピリジン（１０．０ｇ）の溶液へ環境温度において濃Ｈ2 ＳＯ4 （３．５５ｍＬ）を加えた（発熱）。これへＨ2 Ｏ2 （１７ｍＬ，３０％水溶液）と、次いでＦｅＳＯ4 ・７Ｈ2 Ｏ（０．５５ｇ）を加えた。再び発熱した。反応液を暗所で環境温度において１時間攪拌し、次に４時間を要して４５℃へゆっくり加熱した。発泡がおさまった時、反応液を６０℃において１６時間加熱した。不透明な褐色溶液をＨ2 Ｏ（７００ｍＬ）、次いで１０％ＮａＯＨ溶液（２５０ｍＬ）で希釈した。水性混合物をＥｔＯＡｃ（３×５００ｍＬ）で抽出し、有機層を飽和ＮａＣｌ溶液（３×１５０ｍＬ）で別々に洗った。合併した有機層をシリカゲルのパッドを通して濾過し、ＥｔＯＡｃで溶出した。減圧下溶媒を除去し、褐色の残渣をシリカゲルクロマトグラフィー（５０％ＥｔＯＡｃ／５０％ヘキサンから８０％ＥｔＯＡｃ／２０％へキサンまでの勾配）によって精製した。得られた黄色オイルを０℃において７２時間にわたって結晶化させ、２−（Ｎ−メチルカルバモイル）−４−クロロピリジン（０．６１ｇ，５．３％）を得た。ＴＬＣ（５０％ＥｔＯＡｃ／５０％ヘキサン）Ｒｆ０．５０； 1Ｈ−ＮＭＲ（ＣＤＣｌ3 ）δ８．４４（ｄ，Ｊ＝５．１Ｈｚ，ＣＨＮ），８．２１（ｓ，１Ｈ，ＣＨＣＣＯ），７．９６（ｂｓ，１Ｈ，ＮＨ），７．４３（ｄｄ，１Ｈ，Ｊ＝２．４，５．４Ｈｚ，ＣｌＣＨＣＮ），３．０４（ｄ，３Ｈ，Ｊ＝５．１Ｈｚ，メチル）；ＣＩ−ＭＳｍ／ｚ１７１（（Ｍ＋Ｈ）+ ）

Claims (2)

  1. 下記式（Ｉ）を有する、２−（Ｎ−メチルカルバモイル）−４−クロロピリジン：
    Figure 0004403482
  2. ４−クロロピリジンとＮ−メチルホルムアミドを反応させることよりなる請求項１の式（Ｉ）を有する化合物の製造方法。
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