JP2016190864A - ケモカイン受容体モジュレーターとしてのn−(6−((2r,3s)−3,4−ジヒドロキシブタン−2−イルオキシ)−2−(4−フルオロベンジルチオ)ピリミジン−4−イル)−3−メチルアゼチジン−1−スルホンアミド - Google Patents
ケモカイン受容体モジュレーターとしてのn−(6−((2r,3s)−3,4−ジヒドロキシブタン−2−イルオキシ)−2−(4−フルオロベンジルチオ)ピリミジン−4−イル)−3−メチルアゼチジン−1−スルホンアミド Download PDFInfo
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Abstract
Description
本発明はある種のヘテロ環式化合物、その製造に使用する方法および中間体、それらを含む医薬組成物および治療におけるその使用に関する。
ケモカイン類は、喘息およびアレルギー性疾患を含む種々の疾患および障害における免疫および炎症性応答、ならびに自己免疫性病態、例えばリウマチ性関節炎およびアテローム性動脈硬化症において重要な役割を有する。これらの分泌性小分子は、保存されたシステインモチーフにより特徴付けされる8〜14kDaタンパク質の増大しつつあるスーパーファミリーである。現時点で、ケモカインスーパーファミリーは、特徴的構造モチーフを示す三群、C−X−C、C−CおよびC−X3−Cファミリーに分類される。C−X−CおよびC−Cファミリーは配列類似性を有し、互いに、システイン残基のNH−近位対の間における1アミノ酸挿入に基づいて区別される。C−X3−Cファミリーは他の2つのファミリーと、システイン残基のNH−近位対の間に3アミノ酸挿入を有することに基づき区別される。
本発明は、(a)式(I)
本発明において、本発明の化合物は互変異性現象を示し、本明細書中の式は、可能な互変異性形態の1個のみを描記していることが理解されるべきである。本発明はあらゆる互変異性形態およびそれらの混合物を包含し、式で描記した1個の互変異性形態にのみ限定されないことが理解されるべきである。
本発明の化合物は、式(I)の化合物のインビボで加水分解されるエステルとして存在し得る。
他の面において、形態Aは、実質的に図2に示す特徴的示差熱量測定曲線を有する。
(ii) オキシ塩化リン、塩化ベンジルトリエチルアンモニウム、ジメトキシエタン;
(iii) 水素化ナトリウム、テトラヒドロフラン;
(iv) 炭酸セシウム、ジシクロヘキシル(2’,4’,6’−トリイソプロピルビフェニル−2−イル)ホスフィン、トリス(ジベンジリデンアセトン)ジパラジウム(0)、ジオキサン;
(v) トリフルオロ酢酸、ジクロロメタン。
(1) 呼吸器 − 慢性閉塞性肺疾患(COPD)を含む閉塞性気道疾患;喘息、例えば気管支、アレルギー性、内因性、外因性および塵埃喘息、特に慢性または難治性喘息(例えば遅発性喘息および気道過剰応答);気管支炎;乾酪性鼻炎、肥厚性鼻炎、化膿性鼻炎、乾燥性鼻炎および薬物性鼻炎を含む急性、アレルギー性、萎縮性鼻炎および慢性鼻炎;クループ性、線維素性および偽膜性鼻炎および腺病性鼻炎を含む膜性鼻炎;神経性鼻炎(枯草熱)を含む季節性鼻炎および血管運動神経性鼻炎;サルコイドーシス、農夫肺および関連疾患、類繊維肺および特発性間質性肺炎;
(i)腫瘍内科学において使用される抗増殖性/抗新生物剤およびその組み合わせ、例えばアルキル化剤(例えばシスプラチン、カルボプラチン、シクロホスファミド、窒素マスタード、メルファラン、クロラムブシル、ブスルファンおよびニトロソウレア類);代謝拮抗剤(例えば抗葉酸剤、例えばフルオロピリミジン類、例えば5−フルオロウラシルおよびテガフール、ラルチトレキセド、メトトレキサート、シトシンアラビノシド、ヒドロキシウレア、ゲムシタビンおよびパクリタキセル(タキソール(登録商標));抗腫瘍抗生物質(例えばアントラサイクリン類、例えばアドリアマイシン、ブレオマイシン、ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、マイトマイシン−C、ダクチノマイシンおよびミトラマイシン);有糸分裂阻害剤(例えばビンカアルカロイド、例えばビンクリスチン、ビンブラスチン、ビンデシンおよびビノレルビンおよびタキソイド類、例えばタキソールおよびタキソテール);およびトポイソメラーゼ阻害剤(例えばエピポドフィロトキシン、例えばエトポシドおよびテニポシド、アムサクリン、トポテカンおよびカンプトテシン);
下記表1は測定した本発明の化合物のインビトロ効力および測定したイヌのインビボでの半減期を示す。
効力(pIC 50 ) − リガンド結合アッセイ
American Type Culture Collectionからのヒト胚腎臓293細胞(HEK293細胞)を、予め真核発現ベクターpIRES-Neo2(Clontech)にクローン化したヒトCXCR2 cDNA(RefSeqNM_001557)でトランスフェクトした。ジェネテシン(Invitrogen)耐性細胞集団をCXCR2の安定発現について選択し、クローンを、96ウェル組織培養プレートにおける希釈クローニング(0.3細胞/ウェル)により産生した。
上記プロトコルを使用して、本発明の化合物のpIC50値が8.4であることを見出した。
次に、雄ビーグル犬におけるインビボ薬物動態パラメータを得るために使用した方法を記載する。これはあらゆる化合物を用いて使用するために応用できるが、デフォルト製剤、投与量レベルまたはサンプリング間隔が不適であるとき、溶解度、アッセイ感受性、予測されるクリアランスおよび半減期のようなパラメータに基づき修飾する必要がある可能性がある。ここに記載する方法は標準的手法を示し、そこから正当化され記録された修飾をすることができる。
1mgmL−1の標準投与溶液を調製した。推奨投与媒体(化合物が等張食塩水に十分可溶性ではないとき)は、pHを1M HClまたはNaOHで調節した10%DMSO:90%滅菌水または食塩水であった。化合物の必要量を、水添加前にDMSOに溶解した。投与溶液中の化合物濃度を、一定量をある名目上の濃度に一定量を希釈し(三連で)、10μlのこれを50μlブランク血漿に添加し、試験サンプルと共に分析することによりアッセイした。
化合物を、2尾のビーグル犬(11〜15kg)の尾静脈に30分間静注することにより投与した(約1mLkg−1)。送達された投与量を体重減少により概算した。
血液サンプル(〜1ml)をEDTA処理サンプリングチューブに採り、サンプル採取直後に血漿を遠心分離により調製した(3分間、13000rpm)。サンプルを24時間(例えば0分、5分、15分、30分、35分、45分、60分、90分、120分、180分、240分、300分、360分、420分、720分、1440分)の予定された時間に採った。被分析物の血漿中濃度をマススペクトロメトリーにより定量的に決定した。適切であれば、標準曲線範囲内にあることを確認するために試験サンプルをブランク血漿で希釈した。
標準および品質管理貯蔵液を、メタノール中1mg/mlで調製した化合物を別に秤量し、さらに100μg/mlに希釈することにより調製した。標準およびQC貯蔵液をメタノールで手動で希釈し、次の表により血漿に添加した。
試験サンプル、投与試験、標準およびQCの各々に、100μL(投与試験、標準およびQCについては90μl)のメタノール、100μlの内部標準を添加した。サンプルに蓋し、反復倒置により混合し、3500rpmで20分間遠心分離した。一定量(120μL)の各サンプルを、HPLC/MS−MSでの分析の準備ができたマイクロタイタープレートに移した。
HP1100 HPLCシステムと共にTSQ700またはTSQまたはSSQ7000マススペクトロメーターを使用した。使用した起源はAPCIまたはESIであった。試験サンプルにおいて見られた濃度の範囲を変換した標準およびQCサンプルは、名目上の濃度25%以内であることが予測された。
薬物動態データ分析および作表を、非コンパートメント解析ツールおよびExcelを使用して達成した。要約すれば、血漿濃度の自然対数を時間に対してプロットして、濃度−時間プロファイルを示した。初期分布相が過ぎた後濃度が半減するのに必要な時間として定義される消失半減期(疑似定常状態)を、最小4データ点を使用して各動物について個々に決定した。関係する曲線下面積(AUC)が>50%であることを確認し、治療関与半減期が算定できることを確認にした。PKプロファイルが疑われる腸肝再循環のため三相であるとき、最終相を、半減期を含むPKパラメータの計算のためのプロファイルから除いた。引用された半減期値は最低2尾のビーグル犬の平均を表す。
上記プロトコルを使用して、本発明の化合物は、イヌにおける半減期が3.7時間であることが判明した。
大多数の薬物にとって、血漿クリアランスの大きな構成要素は肝代謝である。固有クリアランス(CLint)は、化合物が代謝を受ける可能性の指標であり、血漿タンパク質結合および肝血流を考慮して、インビボでの肝クリアランスに関し得る。それ故に、CLintを、ヒトにおける化合物の半減期の予測においてキー・パラメータとして使用し得る。
HSA(ヒト血清アルブミン)を含まず、pH7.4の生理学的状態を維持する懸濁液緩衝液を使用した、ヒト肝細胞インキュベーションから固有クリアランス(CLint)を概算する方法を次に記載する。
凍結保存されたヒト肝細胞(複数ドナー)をCellzdirect(Carlsbad, U.S.)から購入し、液体窒素中に保存した。細胞を、無タンパク質肝細胞懸濁液緩衝液(レシピ:Milli-Q水で1Lにし、1M HClを用いてpH7.4にした2.34g Na HEPES、0.4g D−フルクトース、DMEM(1L粉末当量、Sigma;1g.l−1 グルコース含有、Na ピルベート含有、NaHCO3不含、フェノールレッド不含))に再懸濁した。凍結保存された細胞を融解して、次のとおり使用した。細胞の各バイアルを37℃の水浴に浸し、全ての氷が溶けるまで約2分間穏やかに振盪させた。融解した細胞懸濁液を、次いで、丸底遠心管中の予め温めた15ml肝細胞懸濁液緩衝液に仕込み、遠心管を倒置することにより穏やかに混合した。細胞懸濁液を600rpmで環境温度(〜26℃)で5分間遠心分離し、上清を吸引し、廃棄した。ペレットを肝細胞緩衝液(1.5ml/細胞バイアル)に穏やかに再懸濁させて、均質細胞懸濁液を得た。
インキュベートすべき試験化合物を、DMSO(1%v/v最終溶媒濃度)中0.1mMの濃縮貯蔵液から、適切なバイアル中の適当な体積(0.3ml)の無タンパク質懸濁液緩衝液に添加した。2×106細胞・ml−1濃度(最終インキュベーション細胞濃度の2倍、トリパンブルー排除により生存能>85%)の適当な体積の細胞(>0.3ml)を別のバイアルに入れ、両バイアルを37℃の水浴でプレインキュベートした。
溶媒:A:0.1%ギ酸のメタノール溶液およびB:0.1%ギ酸の水溶液(v/v)
カラム:Waters Xterra C18 20×3.9mm、3.5μm
流速:1.5ml.分−1
勾配:0%Bを0.3分間、0%〜100%Bを0.7分間かけて、100%Bに0.2分間維持、100%〜0%Bを0.01分間かけて。
インキュベートした化合物の得られたピーク面積をExcel表計算ソフトに入力し、ln[残存濃度]対時間のプロットを作成し、残存スロープから、t1/2を概算した。データ処理は一区画、薬物動態モデルと同種であり、消失速度定数(k)=ln(2)/t1/2を使用し、t1/2の観点でCLintを表す方程式を次の方程式に示すとおりに導くことができ、ここで、体積をml.106細胞−1で表す。
上記プロトコルを使用して、本発明の化合物は、2.9(±0.94)μL/分/106細胞のヒト肝細胞固有クリアランスを有することが判明した。
薬物が血漿タンパク質に結合する程度は、インビボでの効力および薬物動態の測定における重要因子である。血漿タンパク質結合の程度を決定するために使用する方法は、化合物の37℃での血漿と緩衝液の間の平衡透析である。血漿および緩衝液中の化合物濃度を、高速液体クロマトグラフィー(HPLC)と質量分析(MS)検出を使用して決定する。透析方法は、同時に10化合物までの混合物の使用を含む。アッセイで使用する濃度で、化合物を単独でまたは混合物で流したときの結果に有意な差はない。
膜(分子量カットオフ5000)を、最初に透析緩衝液に最低1時間浸漬することにより調製した。透析膜を次いで透析セルにマウントした。
凍結血漿(EDTA抗凝固剤)を通常ヒト血漿結合実験に使用した。血漿のpHを使用直前に1M HClを使用して7.4に調節した。
クロマトグラムを、混合物中の各化合物の較正曲線を自動的に計算し、緩衝液および血漿サンプルの濃度を内挿するMassLynxソフトウェアを使用して処理した。これらの濃度はまだ血漿の希釈についての補正が必要である。結合パーセントを、次の方程式を使用してMassLynxデータから計算した。
上記プロトコルを使用して、本発明の化合物は、0.11(±0.05)のヒト血漿タンパク質結合(%遊離)であることが判明した。
目的の化合物(1mg)を個々の1mLポリプロピレンバイアルに分配し、96ウェルプレートに1−オクタノール(700μL)と共に維持し、0.02M リン酸緩衝液(pH7.4)で予め飽和させた。プレートを一夜振盪し、遠心分離(800gで15分間)して、不溶性固体を沈殿させた。10化合物(またはそれ未満)の24個までの混合物を、1−オクタノール溶液(100μL)を12mL ガラスサンプルチューブのプレートに貯めることにより調製した。溶液の貯留を、各混合物中の化合物のいずれも、互いに2ダルトン以内のモノアイソトピック質量を有さず、MS定量中の混合物の要素の容易な分割を可能とするように、特注型アルゴリズムを使用して行った。化合物の貯留を自動で行い、ロボット制御で作成された特中型ワークリストを使用して制御した。混合物が10個未満の化合物を含むならば、1−オクタノール(0.02M リン酸緩衝液[pH7.4]で予め飽和)を添加して、1−オクタノール相の総体積を1mLとした。1−オクタノール飽和リン酸緩衝液(0.02M、pH7.4、2mL)を各混合物に添加し、振盪(450rpmで30分間)および遠心分離(800gで15分間)した。各分配混合物の最終1−オクタノールおよび水相をロボット制御で分配した。最初の工程は、1−オクタノール液体クラスを使用したLC分析のための一定量の1−オクタノール相(20μL)の採取であった。第二工程は、水相に曝すための過剰の1−オクタノール相の除去であった。これは、1−オクタノールをサンプルチューブの種々の位置から繰り返し吸引することにより行った。分離の最終工程は、一定量の水相(50μL)の採取であった。1−オクタノールおよび水相の一定量をDMSOを使用して連続的に希釈して、LC/MS分析用最終サンプルを得た。各最終1−オクタノール相で、濃度で10000倍範囲に変換される5連続希釈を行った。これらの溶液のMSピーク面積を使用して、対数(相対濃度)検量線に対する対数(ピーク面積)を作成した。100倍濃度範囲に変換される最終水相の3連続希釈も調製し、LC/MSピーク面積を、相対濃度の内挿を可能にする検量線の範囲内で最良に適合するこれらの希釈の一つを選択した。持ち越し汚染の程度を最小化するために、LC/MS分析の順番は1−オクタノールの最も濃縮されていない希釈物から開始し、その後、より濃縮された希釈物が続き、2回ブランク注入し、次いで水相希釈物の濃度を増加させていった。LogD7.4を1−オクタノールおよび水溶液の両者の希釈の程度について補正後、1−オクタノール相対濃度の一つ対内挿水性相対濃度の比から計算した。
上記プロトコルを使用して、本発明の化合物は1.9のLogD7.4を有することが判明した。
本発明を次の非限定的実施例により説明し、添付する図面を参照する。
次の略語を使用し得る。
水分析をカールフィッシャー滴定法で行った。
N−(6−((2R,3S)−3,4−ジヒドロキシブタン−2−イルオキシ)−2−(4−フルオロベンジルチオ)ピリミジン−4−イル)−3−メチルアゼチジン−1−スルホンアミド
酢酸ナトリウム(113g)を2−メルカプトピリミジン−4,6−ジオール(80g)の水(900mL)懸濁液に室温で添加した。1−(ブロモメチル)−4−フルオロベンゼン(105g)のアセトニトリル(90mL)溶液を2時間にわたり滴下した。反応物を20時間撹拌し、懸濁液を濾過し、水(3×)およびイソヘキサン(3×)で洗浄した。固体を真空で2時間乾燥し、トルエン(3×)と共沸蒸留して、副題生成物(125g)を白色固体として得た。
1H NMR (500 MHz, d6-DMSO) δ 11.62 (s, 2H), 7.57 - 7.36 (m, 2H), 7.14 (dd, J = 6.0, 14.8 Hz, 2H), 5.18 (s, 1H), 4.37 (d, J = 6.5 Hz, 2H)
オキシ塩化リン(92mL)を、工程(i)の副題生成物(100g)および塩化ベンジルトリエチルアンモニウム(9g)のジメトキシエタン(500mL)懸濁液に添加し、10時間加熱還流した。反応物を氷−水に注意深く注ぎ、水(400mL)および酢酸エチル(400mL)に分配し、有機相を取り、硫酸マグネシウムで乾燥し、濾過し、蒸発させた。粗製の生成物をシリカフラッシュクロマトグラフィーで、溶出勾配1〜40%ジクロロメタンのイソヘキサン溶液で溶出して精製した。精製フラクションを蒸発乾固して、副題生成物(86g)を赤色油状物として得た。
1H NMR (500 MHz, CDCl3) δ 7.46 - 7.34 (m, 2H), 7.08 - 6.94 (m, 3H), 4.34 (s, 2H)
工程(ii)の副題生成物(85.7g)および60%水素化ナトリウム(14.2g)をテトラヒドロフラン(1000mL)に懸濁し、氷/水で30分間冷却した。(R)−1−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)エタノール(中間体A)の2−メチルテトラヒドロフラン(53%w/v)(104mL)溶液を20分間かけて滴下し、反応物を0℃〜室温で20時間撹拌した。反応物を水(500mL)および酢酸エチル(500mL)に分配した。水相を酢酸エチル(2×500mL)で再抽出し、合わせた有機相を乾燥し、真空で蒸発させた。粗製の物質をIsolera LSを使用して勾配溶出0〜30%酢酸エチルのイソヘキサン溶液を用いるシリカフラッシュクロマトグラフィーで精製した。精製フラクションを蒸発乾固して、副題生成物(94g)を黄色油状物として得た。
1H NMR (500 MHz, CDCl3) δ 7.43 - 7.35 (m, 2H), 7.04 - 6.95 (m, 2H), 6.41 (d, J = 5.3 Hz, 1H), 5.27 - 5.17 (m, 1H), 4.33 (s, 2H), 4.20 - 4.15 (m, 1H), 4.07 - 4.02 (m, 1H), 3.83 - 3.76 (m, 1H), 1.39 (dd, J = 6.9, 27.4 Hz,6H), 1.31 (d, J = 6.3 Hz, 3H)
ジオキサン(700mL)に溶解した工程(iii)の副題生成物(94g)を3−メチルアゼチジン−1−スルホンアミド(中間体B)(42.5g)、炭酸カリウム(65.1g)、ジシクロヘキシル(2’,4’,6’−トリイソプロピルビフェニル−2−イル)ホスフィン(11.2g)およびトリス(ジベンジリデンアセトン)ジパラジウム(0)(10.8g)で窒素下処理した。得られた混合物を100℃で60分間撹拌した。反応混合物を水(500mL)で希釈し、酢酸エチル(500mL)で抽出した。有機相を硫酸マグネシウムで乾燥し、濾過し、真空で蒸発させて、粗製の生成物を得た。粗製の生成物をシリカフラッシュクロマトグラフィーで30%酢酸エチルのイソヘキサン溶液で溶出して精製した。精製フラクションを蒸発乾固して、副題生成物(98g)を赤色油状物として得た。
m/z [M+H]+ = 513 (calc=512)(APCI)
工程(v)の副題生成物(98g)をジクロロメタン(200mL)中、0℃で撹拌し、トリフルオロ酢酸(200mL)を添加した。反応物を室温に温め、さらに18時間撹拌した(アルコールのTFAエステル形成)。揮発物を真空で除去し、残渣をメタノール(20mL)で希釈し、7Mアンモニアのメタノール溶液(100mL)で処理した。溶液を20分間撹拌し、蒸発乾固して、粗製の生成物を得た。粗製の生成物をシリカフラッシュクロマトグラフィーで勾配溶出50%〜100%酢酸エチルのイソヘキサン溶液で精製した。精製フラクションを蒸発させて、表題生成物を白色固体として得て、それをアセトニトリルから結晶化させて、白色結晶固体(46.8g)を得た。
m/z [M+H]+ = 473 (calc=472)(APCI)
1H NMR (500 MHz, d6-DMSO) δ 11.06 (s, 1H), 7.49 (dd, 2H), 7.13 (t, 2H), 6.09 (s, 1H), 5.28 - 5.18 (m, 1H), 4.93 (d, 1H), 4.65 (t, 1H), 4.37 (q, 2H), 3.97 (t, 2H), 3.70 - 3.60 (m, 1H), 3.58 - 3.49 (m, 2H), 3.37 (t, 2H), 2.59 (td, 1H), 1.20 (d, 3H), 1.09 (d, 3H)
vs=極めて強い;s=強い;m=中程度;w=弱い
(R)−1−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)エタノール
L−アスコルビン酸(65kg、369mol)、アセトン(283kg)および2,2−ジメトキシプロパン(46kg、443mol)の混合物にp−トルエンスルホン酸(1.1kg、5.5mol)を添加した。温度を25±5℃に調節した。スラリーを2時間撹拌し、その間窒素を、物質が反応器の底に沈降するのを防ぐために、底のバルブから頻繁に流した。NMR分析(溶媒:D2O)は98.5%変換を示した。
ヘプタン(222kg)を添加し、温度を5±5℃に調節した。反応混合物を少なくとも30分間撹拌し、濾過した。反応器中のアセトニド生成物の残りを母液を使用してフィルターケーキ上に濯ぎ入れた。フィルターケーキをヘプタン(111kg)で洗浄し、50℃で乾燥して、5,6−O−イソプロピリデン−L−アスコルビン酸(73kg、336mol)をほとんど白色の粉末として得た。収率:91%。
1H NMR (400 MHz, d6-DMSO, マレイン酸およびTFAと) δ 4.71 (d, J = 3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J = 7.0, 8.4 Hz, 1H), 3.90 (dd, J = 6.3, 8.4 Hz, 1H), 1.27 (s, 6H)
5,6−O−イソプロピリデン−L−アスコルビン酸(58.8kg、272mol)を水(294kg)で希釈した水酸化ナトリウム溶液(27.5kg、50%、340mol)に添加し、温度を30±5℃に調節した。重炭酸ナトリウム(57kg、680mol)を添加し、混合物を15分間撹拌し、温度を40±5℃に上げた。35%過酸化水素(55kg、562mol)を混合物に35〜60℃で60分間をかけて添加した。反応混合物を2時間撹拌し、NMR分析(溶媒:D2O)は<1%残存出発物質を示した。
亜硫酸ナトリウム(4.2kg、33mol)を反応器に添加し、30分間撹拌後、過酸化物の試験は陰性であった。
さらに重炭酸ナトリウム(34kg、408mol)添加後、混合物を70±5℃に加熱し、少なくとも1時間撹拌し、NMR分析(溶媒:D2O)は次の中間体である(2R)−[(4S)−2,2−ジメチル−1,3−ジオキソラン−4−イル](ヒドロキシ)エタン酸への98.5%変換を示した。
約150Lの水を減圧下除去し、塩類を濾過して除去した。フィルターケーキを水(30L)で洗浄した。
NMP(330kg)を合わせた母液/洗浄液に添加し、温度を30±5℃に調節した。ヨウ化メチル(83kg、585mol)を添加し、反応器を閉じた。温度を55±5℃に調節し、反応混合物を少なくとも120分間反応させて、NMR分析(溶媒:D2O)は6%の残存ヒドロキシエタン酸中間体を示した。
水(147kg)に溶解した亜硫酸ナトリウム(56kg、446mol)を添加し、混合物を30分間撹拌した。溶液を、総量406kgのトルエンを使用して、10分間、30±10℃で4回抽出した。合わせた有機相の残存量が約350Lとなるまで、溶媒を減圧下、最高温度70℃で除去することにより濃縮した。溶液を30℃以下に冷却し、Milliporeフィルターでスチールバレルに移して、(R)−メチル2−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)−2−ヒドロキシアセテートのトルエン溶液(359kg、9.4%、177mol)を得た。収率:65%。
1H NMRは、副題生成物の市販サンプルと一致した。
(R)−メチル2−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)−2−ヒドロキシアセテートのトルエン溶液(359kg、9.4%、177mol)から、トルエンを凝縮が止むまで減圧下、最高温度70℃で留去した。
アセトニトリル(153kg)を添加し、温度を25±5℃に調節した。トリエチルアミン(41kg、405mol)、4−(ジメチルアミノ)ピリジン(1.12kg、9.2mol)および約30分間、p−トルエンスルホニルクロライド(52.5kg、276mol)のアセトニトリル(146kg)溶液を25±5℃で添加した。反応混合物をさらに3時間撹拌後、NMR分析(溶媒:d6−DMSO)は満足すべき変換を示した(94%)。
MTBE(235kg)および水(326kg)を添加し、二相系を約3時間撹拌し、その後HPLC分析は、p−トルエンスルホニルクロライドのレベルは、総ピーク面積の<0.1%であることを示した。温度を25±5℃に調節し、15分間分離させた。水相を取り、さらにMTBE(156kg)で抽出して、廃棄した。2個の有機相を合併し、水(326kg)で洗浄した。有機相を塩化ナトリウム(各回16kg)の水溶液(各回140kg)で4回、各々5〜10分間、25±5℃で洗浄した。有機相を水(各回185kg)で2回、各々5〜10分間、25±5℃で洗浄した。NMR分析(溶媒:d6−DMSO)は、スルホン酸エステル中間体に対するmoleで<2%NMP(出発溶液からの残存)であることを示した。
活性炭(6.0kg)を添加し、スラリーを15分間、25±5℃で撹拌し、炭素を2個のパラレル・バッグ・フィルターで濾去した。0.6μmのカートリッジフィルターをバッグフィルター後に使用した。フィルターおよびパイプをMTBE(27kg)で濯いだ。
母液および洗液を合わせ、凝縮が止むまで、溶媒を減圧下および最高温度50℃で除去することにより体積を減らした。ヘプタン(106kg)を添加し、溶液を再び凝縮が止むまで、溶媒を減圧下に、最高温度50℃で除去することにより減らし、約60Lの溶液を反応器に残した。MTBE(185kg)を添加し、温度を25±5℃に調節後、ヘプタン(75kg)を添加した。溶液を30分間以上かけて0〜5℃に冷却し、ヘプタン(150kg)をさらに20分間かけて添加した。スラリーを1時間、0〜5℃で撹拌し、濾過した。フィルターケーキをMTBE(16kg)とヘプタン(30kg)の混合物で洗浄した。湿生成物をバキュームトレイドライヤーに載せ、35℃(100mbar未満)で乾燥して、(R)−メチル2−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)−2−(トシルオキシ)アセテート(51.3kg、154mol)を明褐色粉末として得た。収率:87%。
1H NMR (400 MHz, CDCL3) δ 7.83 (m, 2H), 7.35 (m, 2H), 4.84 (d, J = 4.8 Hz, 1H), 4.46 (m, 1H), 4.04 (dd, J = 6.6, 9.1 Hz, 1H), 3.97 (dd, J = 5.2, 9.1 Hz, 1H), 3.70 (s, 3H), 2.45 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H)
(R)−メチル2−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)−2−(トシルオキシ)アセテート(76.1kg、221mol)をメタノール(57kg)およびジクロロメタン(208kg)に溶解した。
メタノール(14kg)、ジクロロメタン(53kg)および出発物質溶液の1/3(74mol)を反応器に仕込んだ。溶液を10〜15℃に調節した。水素化ホウ素ナトリウム(6.3kg、169mol)を、18回に分けて8〜15℃に温度を維持した反応器に添加した。添加完了後、混合物を0.5時間撹拌した。さらに上記と同じ方法を使用して出発物質溶液の1/3(74mol)およびさらに水素化ホウ素ナトリウム(6.3kg、169mol)を添加し、0.5時間撹拌した。この方法を、出発物質溶液の最後の1/3(74mol)およびさらなる水素化ホウ素ナトリウム(6.3kg、169mol)で再度繰り返した。HPLC分析は、中間体(S)−1−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)−2−ヒドロキシエチル4−メチルベンゼンスルホネートへの>99.9%変換を示した。
ジクロロメタン(200kg)を反応混合物に加えた。ナトリウムメトキシドのメタノール溶液(43kg、30%、239mol)を20〜25℃で60分間添加した。約0.5時間後、HPLC分析は中間体アルコールの99.7%消費を示した。
酢酸ナトリウム(25kg)の水(230L)溶液を反応混合物に添加した。混合物を10〜15分間、20〜25℃で撹拌した。15分間の分離後、下部有機相を除いた。上部水相をジクロロメタン(376kg)で抽出した。下部有機相を取り、最初の有機相と合わせ、水相を廃棄した。
水(359L)を合併した有機相に添加した。10〜15分間、20〜25℃で撹拌し、15分間分離させた後、下部有機相を硫酸ナトリウム(63kg)を含む反応器に移した。
混合物の体積を溶媒を除去することにより310Lまで減少させ、硫酸ナトリウムを濾別した。フィルターケーキをジクロロメタン(94kg)で洗浄した。合併した液相を激しく混合し、ポリプロピレンバッグフィルターを介してスチールドラムに注いで、(S)−2,2−ジメチル−4−((R)−オキシラン−2−イル)−1,3−ジオキソランのDCM溶液(467.5kg、6.2%、203mol)を透明黄色液体として得た。収率:91%。
溶媒を除去した少量のサンプルを溶媒の蒸発と真空下の蒸留により得る。
1H NMR (単離サンプル, 400 MHz, d6-DMSO) δ 4.01 (dd, J = 6.6, 8.2 Hz, 1H), 3.92 (m, 1H), 3.72 (dd, J = 5.8, 8.2 Hz, 1H), 3.03 (ddd, J = 2.6, 4.1, 5.2 Hz, 1H), 2.77 (dd, J = 4.1, 5.0 Hz, 1H), 2.58 (dd, J = 2.6, 5.0 Hz, 1H), 1.34 (s, 3H), 1.27 (s, 3H)
(S)−2,2−ジメチル−4−((R)−オキシラン−2−イル)−1,3−ジオキソランのジクロロメタン溶液(465kg、6.2%、200mol)から、ジクロロメタンを41〜42℃で蒸留し、THF(129kg)に置き換えた。反応器内で設定した体積(235L)に到達するまで蒸留を60℃で続けた。リチウムアルミニウムハイドライド(LAH)のTHF(26.4kg、10%、70mol)溶液を反応器に22℃で添加し、25℃で約1時間撹拌後に、GC分析は出発物質の>99.9%消費を示した。
水を少しずつ温度および泡立ちを制御するよう調節した速度で添加漏斗を介して添加した。計2.6Lの水(1L/kgLAH)を添加した。水酸化ナトリウム溶液(2.6kg、15%、1L/kgLAH)を上記水の場合と同じ方法で添加した。水(7.9L、3L/kgLAH)を前記と同じ方法を使用してもう1度添加漏斗を介して添加した。
スラリーを濾過し、フィルターケーキをTHF(36kg)で洗浄した。濾液を、最高温度85℃で、凝縮が止むまでTHFを除去することにより濃縮した。2−MeTHF(129kg)を反応器に添加し、約120Lの液量となるまで溶媒を留去した。KF分析は<0.1%水を示した。溶液をカートリッジフィルターを通してPE裏打ちドラムに注いで、(R)−1−((S)−2,2−ジメチル−1,3−ジオキソラン−4−イル)エタノール溶液(103kg、27%、187mol)を透明、明黄色液体として得た。収率:94%。
溶媒を除いた少量サンプルを溶媒の蒸発と真空下の蒸留により得る。
1H NMR (単離サンプル, 400 MHz, d6-DMSO) δ ppm 4.77 (d, J = 5.1 Hz, 1H), 3.95 (dd, J = 8.0, 6.2 Hz, 1H), 3.76 (dd, 8.0, 6.0 Hz, 1H), 3.70 (m, 1H), 3.46 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.07 (d, J = 6.2 Hz, 3H)
方法A:
40gの(1R)−1−[(4S)−2,2−ジメチル−1,3−ジオキソラン−4−イル]エチル]−3,4,5−トリメトキシベンゾエート(117.5mmol)を7倍相対体積(280mL)のメタノールに溶解した。この溶液に20gの47%w/w水酸化ナトリウム水溶液(2当量、235mmol)を添加し、溶液を50℃に加熱した。典型的に1〜2時間以内に反応は完了し、減圧下蒸発させた。2−メチル−テトラヒドロフラン(160mL、4倍相対体積)を添加し、混合物を再び減圧下蒸発させて、痕跡量のメタノールを除去した。さらに2−メチル−テトラヒドロフラン(200mL、5相対体積)を添加し、得られた懸濁液を環境温度で30分間撹拌し、濾過した。フィルターケーキを72mL(1.8体積)の2−メチルテトラヒドロフランで洗浄した。透明濾液を再び減圧下で濃縮して、アルコールを無色油状物として得た。
収率:13.4g(78%)
20gの(1R)−1−[(4S)−2,2−ジメチル−1,3−ジオキソラン−4−イル]エチル]−3,4,5−トリメトキシベンゾエート(58.76mmol)を10倍相対体積(200mL)の2−メチルテトラヒドロフランに溶解した。透明溶液に4.24mLのメチル−トリブチル塩化アンモニウム(75%水溶液、11.75mmol)、9.89g(58.76mmol)の50%水酸化カリウム水溶液を添加した。得られた混合物を再び50℃で撹拌し、典型的に20時間以内に完了した(<1%残存出発物質)。懸濁液を濾過し、透明濾液を約100mL体積まで蒸留することによりさらに乾燥した。混合物を濾過し、100mLの2−メチルテトラヒドロフランを層積し、再び20mL総体積まで濃縮した。得られた透明溶液を、容器の濯ぎに先に使用した30mLの2−メチルテトラヒドロフランで希釈した。
収率:2−メチルテトラヒドロフラン中の50mL溶液は7.9g(理論値の92%)(R)−1−[(S)−2,2−ジメチル−1,3−ジオキソラン−4−イル]エタノール含有する。
溶媒を除いた少量のサンプルを溶媒の蒸発と真空下の蒸留により得る。
1H NMR (単離サンプル, 400 MHz, d6-DMSO) δ ppm 4.77 (d, J = 5.1 Hz, 1H), 3.95 (dd, J = 8.0, 6.2 Hz, 1H), 3.76 (dd, 8.0, 6.0 Hz, 1H), 3.70 (m, 1H), 3.46 (m, 1H), 1.29 (s, 3H), 1.25 (s, 3H), 1.07 (d, J = 6.2 Hz, 3H)
[(1R,2S)−2,3,−ジヒドロキシ−1−メチル−プロピル]3,4,5−トリメトキシベンゾエート
E−クロチルアルコール(100%w/wで20kg、277mol)を、約20℃で3Åモレキュラー・シーブペレット(8kg)を含むカートリッジを一定速度で約80分間かけて通し、乾燥回収容器に入れた。約32分間の維持後、カートリッジは褐色となり、約31分間加圧窒素を使用して浄化した。投入E−クロチルアルコールの約85%を乾燥E−クロチルアルコールとして回収した。
乾燥E−クロチルアルコール(100%w/wで20kg、277mol)の溶液に、酒石酸L−(+)−ジイソプロピル(11.7kg、50mol)およびトルエン(167kg)を約−8℃でオルトチタン酸テトライソプロピル(11.8kg、42mol)およびトルエン(33kg)と共に添加した。バッチを約30分間撹拌し、クメンヒドロペルオキシド(87%w/w、58.2kg、333mol)およびトルエン(78kg)を少なくとも4時間かけて添加した。バッチを約2時間撹拌し、3,4,5−トリメトキシ安息香酸(2.9kg、13.9mol)を添加した。バッチを、約1時間かけてオルトチタン酸テトライソプロピル(7.9kg、28mol)、3,4,5−トリメトキシ安息香酸(47.1kg、222mol)およびトルエン(152kg)のスラリーに約30℃で添加し、トルエン(17kg)でラインを洗浄した。オルトチタン酸テトライソプロピル(23.7kg、83mol)およびトルエン(40kg)を約2時間かけて添加し、バッチを約3時間撹拌した。バッチを冷却し、亜リン酸トリメチル(17.2kg、139mol)およびトルエン(35kg)を添加した。バッチを約30℃に温め、塩酸水溶液(10%w/w、84kg、次いで63kg)で2回洗浄し、水(3×60kg)で3回洗浄した。合わせた水相を2−メチルテトラヒドロフラン(344kg)で洗浄した。有機相を合わせ、水(60kg)で洗浄し、真空下で約260±40Lのバッチ体積まで蒸留した。
温度を約35℃に調節し、ヘキサン(65kg)を少なくとも30分間かけて添加した。バッチに種晶を添加し、少なくとも1時間撹拌し、約0℃で少なくとも3時間かけて冷却した。[種晶は、溶液の一部を別の容器に採取し、これを過飽和温度またはそれ以下まで冷却することにより得られる。沈殿した固体を濾過し、直接メインバッチに戻し、その後の制御された結晶化において種結晶として機能させ得る。]
さらなるヘキサン(325kg)を少なくとも2時間かけて添加し、スラリーを少なくともさらに1時間熟成させ、固体を濾過により単離した。固体をヘキサン(2×130kg)で洗浄し、一定重量となるまで乾燥した。収率:100%w/wで57%。強度=93%w/w[3,4,5−トリメトキシ安息香酸(TMBA)も含有]。
1H NMR [500 MHz, CDCl3, 内部標準としての2,3,5,6-テトラクロロニトロベンゼン(TCNB)と共に];δ 7.71 (s, TCNB), 7.33 (s, 残存TMBA), 7.26 (s, 2H), 7.24 (s, CDCl3), 5.13 (m, 1H), 3.89 (m, 9H), 3.73 (m, 2H), 3.63 (1H, m), 1.44 (d, J = 6.6 Hz, 2H)
エナンチオマー過剰:典型的に97%
1H NMR [400 MHz, CDCl3, with 2,3,5,6-テトラクロロニトロベンゼン(TCNB)];δ 7.71 (s, TCNB), 7.28 (s, 2H), 7.24 (s, CDCl3), 5.15 (m, 1H), 4.20 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.88 (s, 9H), 1.36 (m, 9H)
エナンチオマー過剰:典型的に>99%ee(単離温度を、出発[(1R,2S)−2,3,−ジヒドロキシ−1−メチル−プロピル]−3,4,5−トリメトキシベンゾエートのエナンチオ過剰および所望の単離(1R)−1−[(4S)−2,2−ジメチル−1,3−ジオキソラン−4−イル]エチル−3,4,5−トリメトキシベンゾエートのエナンチオ過剰によって調節し得る)
3−メチルアゼチジン−1−スルホンアミド
酢酸イソプロピル(300mL)を1000mlの3口フラスコに添加し、−10〜−5℃に冷却した。イソシアン酸クロロスルホニル(44.5mL)を−5〜10℃で添加し、フェニルメタノール(50.5mL)の酢酸イソプロピル(60mL)溶液を−5〜10℃で60分間かけて添加した。混合物を−5〜10℃で反応させ、ベンジルアルコール含量が<2%となるまでHPLCモニターした(1時間、0℃の後)。アセトニトリル(300mL)、3−メチルアゼチジンヒドロクロライド(50g)(中間体C、市販品または下記のとおり製造)およびトリエチルアミン(162mL)の混合物を2000mLの3口フラスコで撹拌し、これに中間体ベンジルクロロスルホニルカルバメートの酢酸イソプロピル(360mL)溶液を<−5℃で90分間かけて滴下した。混合物をRTに一夜温めた。酢酸で反応停止させ、pHを4〜5に調節した。混合物を分離し、水相を酢酸イソプロピル(500ml)で洗浄し、分離した。有機相を合わせ、10%塩水(2×120ml)で洗浄し、無水硫酸マグネシウムで乾燥し、濾過し、フィルターケーキを酢酸イソプロピル(30ml)で洗浄し、濾過して、副題生成物(145g)を赤色油状物として得た。
1H NMR (500 MHz, CDCl3) δ 11.43 (s, 1H), 7.57 (m, 5H), 5.18 (s, 2H), 4.08 - 3.96 (m, 2H), 3.60 - 3.50 (m, 2H), 2.67 - 2.54 (m, 1H), 1.22 - 1.11 (d, 3H)
2個の反応器に分けた工程(i)の副題生成物(132g)を撹拌中の10%Pd/C(4.94g)のエタノール(1000mL)溶液に添加した。混合物を3.00barで16時間水素化した。溶媒を蒸発させて、粗製の生成物を得た。粗製の生成物を30%酢酸エチルのジクロロメタンで溶出するシリカフラッシュクロマトグラフィーで精製した(KMnO4で染色)。純粋フラクションを蒸発乾固して、表題生成物(60.3g)を白色固体として得た。
1H NMR (500 MHz, CDCl3) δ 6.82 (s, 2H), 3.75 (t, J = 8.0 Hz, 2H), 3.36 - 3.24 (m, 2H), 2.59 - 2.46 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H)
3−メチルアゼチジン塩酸塩
THF(170mL)および水(85mL)に溶解したアゼチジン−3−オール(14.7g)の溶液を炭酸カリウム(37.1g)で窒素下に処理した。混合物をRTで30分間撹拌し、0℃に冷却し、クロロギ酸ベンジル(20.0mL)を30分間かけて、0℃で滴下した。得られた混合物を20℃で60時間撹拌した。反応混合物を水(150mL)で希釈し、酢酸エチル(200mL)で抽出した。有機相を硫酸マグネシウムで乾燥し、濾過し、蒸発させて、粗製の生成物を無色油状物として得た。粗製の生成物を50%酢酸エチルのイソヘキサン溶液〜100%酢酸エチルで溶出するシリカフラッシュクロマトグラフィーで精製した。純粋フラクションを蒸発乾固して、副題生成物(19.40g、69.8%)を無色油状物として得た。
1H NMR (500 MHz, CDCL3) δ 7.41 - 7.28 (m, 5H), 5.09 (s, 2H), 4.70 - 4.54 (m, 1H), 4.23 (dd, J = 6.7, 9.9 Hz, 2H), 3.89 (dd, J = 4.4, 10.0 Hz, 2H), 2.34 (d, J = 6.1 Hz, 1H)
工程(i)の副題生成物(17.9g)のDMSO(100mL)溶液を、15分間かけて、ピリジン・三酸化硫黄(44.7g)およびトリエチルアミン(39.3mL)のDMSO(200ml)溶液に0℃で添加した(5℃までわずかに発熱)。混合物を5分後RTに温め、16時間撹拌した。混合物を氷/水に注ぎ、酢酸エチルで2回抽出した。合わせた有機相を塩水で洗浄し、硫酸ナトリウムで乾燥し、真空で濃縮して、粗製の生成物を得た。粗製の生成物を100%ジクロロメタンで溶出するシリカフラッシュクロマトグラフィーで精製した。純粋フラクションを蒸発乾固して、副題生成物(17.9g)を淡黄色油状物として得た。
1H NMR (500 MHz, CDCL3) δ 7.40 - 7.31 (m, 5H), 5.17 (s, 2H), 4.78 (s, 4H)
メチルトリフェニルホスホニウムブロマイド(93g)およびカリウムtert−ブトキシド(29.3g)のジエチルエーテル(700mL)懸濁液をRTで20分間撹拌し、35℃で1時間、窒素下に加熱した。輝黄色混合物を工程(ii)の副題生成物(17.9g)のジエチルエーテル(200mL)溶液を1時間、35℃で滴下することにより処理した(橙色懸濁液形成)。得られた混合物を35℃で12時間撹拌した。混合物を冷却し、セライトパッドで濾過し、ジエチルエーテルで洗浄した。濾液を水(300mL)で洗浄し、硫酸マグネシウムで乾燥し、濾過し、蒸発させて、粗製の生成物を得た。粗製の生成物を10%酢酸エチルのイソヘキサン溶液〜50%酢酸エチルのイソヘキサン溶液で溶出するシリカフラッシュクロマトグラフィーで精製した(KMnO4で染色)。精製フラクションを蒸発乾固して、副題生成物(14.1)を無色油状物として得た。
1H NMR (400 MHz, CDCL3) δ 7.39 - 7.28 (m, 5H), 5.12 (s, 2H), 5.01 (m, 2H), 4.57 (t, 4H)
エタノール(100mL)に溶解した工程(iii)の副題生成物(14.1g)溶液を10%Pd/C(JM型87L)(1.48g)で水素下に処理した。得られた混合物を20℃で40時間、4.50bar圧の水素ガス中で撹拌した。Cbz保護基がなお結合していたため、水酸化パラジウム/炭素(2g)のエタノール(100mL)溶液に変えた。混合物をさらに24時間、4.50barで水素化した。混合物をセライトパットで濾過し、濾液を氷浴で0℃に冷却した。4M HClのジオキサン溶液(26.0mL)を滴下し、溶液を蒸発乾固して、表題生成物(7.46g)を明褐色油状物として得た。
1H NMR (400 MHz, CDCL3) δ 9.24 (s, 2H), 3.95 (ddd, J = 7.4, 9.8, 11.4 Hz, 2H), 3.55 - 3.45 (m, 2H), 2.85 (dt, J = 6.7, 14.2 Hz, 1H), 1.16 (d, 3H)
Claims (4)
- 式(VI)
の化合物からの製造方法。 - 式(XII)の化合物が式(XI)
の化合物から製造される、請求項1に記載の方法。 - 式(XI’)
の化合物またはその塩。 - 式(XII’)
の化合物またはその塩。
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