JP2019514923A - インダゾールの合成 - Google Patents
インダゾールの合成 Download PDFInfo
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- JP2019514923A JP2019514923A JP2018556409A JP2018556409A JP2019514923A JP 2019514923 A JP2019514923 A JP 2019514923A JP 2018556409 A JP2018556409 A JP 2018556409A JP 2018556409 A JP2018556409 A JP 2018556409A JP 2019514923 A JP2019514923 A JP 2019514923A
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Abstract
Description
・製造方法のスケールアップ/スケーラビリティ
・N2−アルキル化反応における高い位置選択性
・クロマトグラフィー分離および精製ステップの回避
・結晶化を介した最終処理
・クラス3溶媒(FDAガイドラインによる)を使用した多形形態の最終調整
(式中、
R1は2−(メチルスルホニル)エチルであり;
R4はジフルオロメチル、トリフルオロメチルまたはメチルであり;
R5は水素またはフッ素であり;
好ましくはR4=トリフルオロメチルおよびR5=Hである):
・ジエチルエーテルの使用は、発火点が低く、爆発性が高いために、回避しなければならない。
・製造が容易であるより一般的なメチルマグネシウムクロリドの代わりに、比較的高価なメチルマグネシウムブロミドを使用した。
・クロマトグラフィー分離は、通常、有機溶媒の大規模な不経済な消費を必要とするため、技術的スケールでは回避すべきである。
・結晶化手順が記載されていない。研究所での慣用手段によると、式(V)の化合物を乾燥するまで蒸発させた。この操作は、技術的スケールでは実行不可能である。
・収率は不満足である:技術的な目的のために、少なくとも75%の収率が達成されるべきである。
スキーム2は、式(VIII)のアニリン様化合物からの式(I)の純粋な生成物の合成全体を示す。式(I)の生成物は、99面積%(HPLC)超の純度で得られる。各ステップで達成された最良の収率で計算すると、50%の全収率が得られる。これには、最終的な結晶形態の設置も含まれる。
1.アミドカップリング(式(VI)による化合物の調製):収率84%;
2.グリニャール反応、引き続いてクロマトグラフィー精製:収率45%;
3.文献で公知の方法と同様の2−ブロモエチルメチルスルホンによるアルキル化、引き続いてクロマトグラフィー精製:収率9.68%;
新規な方法の利点が非常に明確になる:
先行技術から公知の上記の方法では、最終結晶形態の設置を含めないで、わずか3.7%の全体収率しか達成することができなかった。
以下のステップ(A):
(式(V):
(式中、Rはアルキル基、例えばメチル、エチルまたはn−プロピル基、またはアリール基、例えばフェニル基を表す)
と、場合により芳香族炭化水素溶媒、例えばトルエンまたはキシレン中、好ましくは前記溶媒の還流温度で反応させ、
それによって、式(I)の前記化合物を得る)
を含む方法に関する。
(式(VI):
場合によりアルカリ金属ハライド、例えば塩化リチウムの存在下で反応させ、
それによって、式(V)の前記化合物を得る)
によって調製される、上記の式(I)の化合物を調製する方法に関する。
(式(VIII):
場合によりカップリング剤、例えば2,4,6−トリプロピル−1,3,5,2,4,6−トリオキサトリホスフィナン2,4,6−三酸化物(T3P)の存在下で反応させ、
それによって、式(VI)の前記化合物を得る)
によって調製される、上記の式(I)の化合物を調製する方法に関する。
式(IX’):
(式中、Rはアルキル基、例えばメチル、エチルまたはn−プロピル基、またはアリール基、例えばフェニル基を表す)
の使用に関する。
HPLC
方法A
装置:1290 Infinity Sampler&Agilent 1100シリーズを備えたAgilent Technologie 1260 Infinity
Zorbax SB−AQ、50*4,6mm、1,5μm
緩衝液:リン酸二水素アンモニウムpH:2.4
アセトニトリル
0分。5%緩衝液
8.3分。80%緩衝液
11分。80%緩衝液
210nm/4nm
1.2ml/分。
装置 1.Agilent Technologies、HPLC 1290 Infinity(DAD付き):超高速液体クロマトグラフサーモスタット制御カラムオーブン、UV検出器およびデータ評価システム
2.ステンレス鋼カラム
長さ:5cm
内径:2.1mm
充填:SB−Aq Rapid Resolution HD、1.8μm
試薬 1.アセトニトリル、HPLC用
2.テトラヒドロフラン、HPLC用
3.水、分析グレード
3.リン酸85%、分析グレード
試験溶液 式(I)の試料化合物を0.5mg/mlの濃度でテトラヒドロフランに溶解する。
(例えば、正確に秤量した式(I)の試料化合物約25mgを、アセトニトリル50mlに溶解する)
較正溶液 参照標準化合物*を、0.5mg/mlの濃度でアセトニトリルに溶解する(例えば、正確に秤量した参照標準物質約25mgを、アセトニトリル50mlに溶解する)
*参照標準化合物とは、高純度の化合物、すなわち97面積%HPLC超として分析されなければならない化合物を意味する
対照溶液 較正溶液と同一の対照溶液を調製する。さらに、対照溶液は少量の有機不純物を含有する。
検出感度溶液 0.76μg/mlの濃度に希釈した成分Solbrol P(CAS番号:94−13−3;プロピル4−ヒドロキシベンゾエート)(保持時間約2.80分)を含有する溶液を調製する。
HPLC条件 上記条件は、例えば以下である。最適な分離を達成するために、これらを、必要に応じて、クロマトグラフの技術的可能性およびそれぞれのカラムの特性に適合させるべきである。
溶離液 A.水:テトラヒドロフラン(v:v)9:1、次いで、0.1%リン酸85%
B.アセトニトリル:テトラヒドロフラン9:1
流量 0.8mL/分
カラムオーブンの温度 40℃
サンプルチャンバーの温度 室温
検出 測定波長:220 nm
帯域幅:6nm
注入体積 2.0μl
吸引速度 200μL/分
ニードル洗浄 フラッシュポート用溶媒:テトラヒドロフラン
Datenrate 10Hz
細胞寸法 10mm
平衡時間 10分(開始条件で)
勾配
アッセイ(含量)の計算 アッセイを、線形回帰を使用し、有効なクロマトグラフデータシステム(例えば、Empower)を用いて、参照標準の試料重量、アッセイおよび重量を考慮して計算する。
ヘッドスペースガスクロマトグラフィー(GC−HS)を介した残留溶媒分析
分割注入およびFID(カラム:Restek Rxi Sil MS;長さ:20m;内径:0.18mm;df=1μm)を用いるAgilent 6890ガスクロマトグラフ。インジェクター温度160℃、流量1.2ml/分(H2)分割比18、オーブン温度40℃(4.5分)−14℃/分−70℃−90℃/分−220℃(1.69分)。検出器:温度300℃、400ml/分(合成空気)、40ml/分(H2)、30ml/分(N2)、速度20Hz。
Perkin Elmer Turbomatrix 40ヘッドスペースサンプラー:オーブン80℃、ニードル150℃、移送ライン160℃、システム圧力140kPa、平衡時間32分、加圧4.0分、注入時間0.04分(サンプラー)0.05分(GC)。
試料濃度:DMF2ml中物質20mg
アノード材料 Cu
K−α1[Å] 1,54060
発生装置設定 40mA、40kV
一次ビームモノクロメータ 焦点を合わせるX線鏡
回転試料 はい
スキャン軸 gonio
開始位置[2θ°] 2.0066
終了位置[2θ°] 37.9906
以下の実施例が本発明を説明する。
実施例番号1
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)
メチル5−アミノ−1H−インダゾール−6−カルボキシレート2000g(10.46mol)、6−(トリフルオロメチル)ピリジン−2−カルボン酸1899g(9.94mol)およびN,N−ジイソプロピルエチルアミン2028g(15.69mol)をTHF14.2kg中で混合する。0〜5℃で、T3Pの酢酸エチル中溶液(50重量%)13.3kgを30分以内に滴加する。撹拌を同じ温度で2時間続ける。
反応混合物を周囲温度(20℃)に加温する。温度を20〜25℃に保ちながら水3000gを添加する。撹拌を10分間続ける。4N炭酸ナトリウム水溶液を用いて、pHを約7.4(7〜8)に調整する。撹拌を10分間続ける。必要であれば、4N炭酸ナトリウム水溶液を用いて、pHを再び7.4に調整する。
収量:
バッチ番号1:3476g(95%)
バッチ番号2:3449g(95%)
バッチ番号3:3476g(95%)
バッチ番号4:3494g(96%)
HPLC(方法A):Rt=6.5分。
1H NMR(300 MHz,DMSO−d6):δ[ppm]=3.97(s,3 H),8.13−8.27(m,2 H),8.30(s,1 H),8.33−8.45(m,1 H),8.45−8.51(m,1 H),9.15(s,1 H),12.57(s,1 H),13.44(br s,1 H).
N−[6−(2−ヒドロキシプロパン−2−イル)−1H−インダゾール−5−イル]−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(V)
以下の節で、反応手順および後処理の様々な変形を記載する。これらの手順は、それぞれの技術プラントの所定の条件で方向づけられる。
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)50g(137.255mmol)をTHF800mlに溶解した。常圧(1気圧)下、THF約300mlを70℃で留去した。次いで、溶液を0〜3℃に冷却した。
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)30g(82.4mmol)をTHF480mlに溶解した。常圧(1気圧)下、THF約180mlを70℃で留去した。次いで、混合物(わずかな懸濁液)を0〜3℃に冷却した。
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
メチル5−({[6−(トリフルオロメチル)ピリジン−2−イル]カルボニル}アミノ)−1H−インダゾール−6−カルボキシレート(VI)30g(82.4mmol)をTHF600mlに溶解した。常圧(1気圧)下、THF約150mlを70℃で留去した。次いで、混合物(わずかな懸濁液)を0〜3℃に冷却した。
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
この変形を、kgスケール(10kg超)の技術的バッチの製造に使用した(表4参照)。
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
イソプロパノール/水中での撹拌を介した精製
粗生成物の純度に応じて、好ましくは1:1のイソプロパノールと水との混合物中での撹拌を介した追加の精製ステップを行うことができる。粗生成物の純度に応じて、粗出発材料に対して2〜10容量の範囲で撹拌を行う。以下の実施例は、3容量のイソプロパノール/水中での撹拌を記載する:
8.17(d,1H),8.37(t,1H),8.46(d,1H),8.78(s,1H),12.33(s,1H),12.97(br s,1H).
N−{6−(2−ヒドロキシプロパン−2−イル)−2−[2−(メチルスルホニル)エチル]−2H−インダゾール−5−イル}−6−(トリフルオロメチル)ピリジン−2−カルボキサミド(I)
この変形を、kgスケールの技術的バッチの製造に使用し、これは国際公開第2016/083433号パンフレットに記載されるプロトコルに従う。
この変形を、kgスケールの技術的バッチの製造に使用した。
変形番号2として記載される手順に従って、出発材料(V)に関して3.396kgおよび1.699kgのスケールのバッチを製造した:
Claims (12)
- 前記芳香族炭化水素溶媒が、トルエンである、請求項1に記載の方法。
- 式(I)の前記化合物が、特に溶媒、例えばエタノールまたはイソプロパノールからの、結晶化によって精製される、請求項1から6のいずれか一項に記載の方法。
- 前記溶媒が、エタノールである、請求項7に記載の方法。
- 前記溶媒が、イソプロパノールである、請求項7に記載の方法。
- 式(IX’)の前記ビニル化合物が、メチルビニルスルホンである、請求項11に記載の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP16167652.3 | 2016-04-29 | ||
EP16167652 | 2016-04-29 | ||
PCT/EP2017/059744 WO2017186689A1 (en) | 2016-04-29 | 2017-04-25 | Synthesis of indazoles |
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