JP2017524742A - テトラヒドロキノリン誘導体の調製のための合成中間体の調製方法 - Google Patents
テトラヒドロキノリン誘導体の調製のための合成中間体の調製方法 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
Description
本明細書に使用される用語「薬学的に許容可能な」は、その従来の意味を有し、過度の毒性、炎症、アレルギー反応なしで、かつ合理的な利益/リスク比に相応する他の問題を複雑化することなく、哺乳動物、特にヒトの組織との接触に適した正しい医学的判断の範囲内にある化合物、材料、組成物、及び/または投与形態を指す。
式I:
反応器Aに、プロピオンアルデヒド(90g、5当量(eq))及びアセトニトリル(50ml)を添加し、反応器Bにp−トルエンスルホン酸(1.77g、3mol%)、4−トリフルオロメチルアニリン(50g、1当量)及びアセトニトリル(100mL)を添加し、反応器Cに、N−ビニルホルムアミド(26.5g、1.2当量)及びアセトニトリル(100mL、2容量(vols))を添加した。
4−アミノベンゾトリフルオリド(100g、78mL、0.62mol)を室温でCH2Cl2(200mL)に溶解した。プロピオンアルデヒド(44.7mL、0.62mol)、次いでCH2Cl2(200mL)を添加した。その透明な溶液を室温で1時間撹拌し、イミンの淡黄色溶液を得た。反応混合物をさらにCH2Cl2(300mL)で希釈し、氷上で冷却した。N−ビニルホルムアミド(86.8mL、1.24mol、2.0当量)を上述のように、インサイチュ調製イミン溶液に一度に添加した。TsOH(2.36g、12.4mmol、2mol%)を反応混合物に添加し、この反応混合物を氷上で0℃〜室温にて一晩撹拌した。ヘプタン(700mL)をその懸濁液に添加した。5分後、スラリーをガラスフィルタで吸引濾過した。オフホワイトの結晶を、フィルタ上にてヘプタン(2×200mL)で吸引洗浄した。得られた固体を、ロータリーエバポレータを用いて減圧下50℃で乾燥し、生成物(99g、収率59%)をオフホワイトの固体として得た。液体クロマトグラフィ−質量分析(LCMS)及び1H−核磁気共鳴(NMR)により、生成物を確認した。次に、粗固体を高温アセトンから再結晶した。溶解しなかった固体は、濾過により高温アセトン溶液から除去した。得られた透明溶液を5℃で一晩保存した。得られた濃いスラッシュをガラスフィルタで濾過し、ヘプタン(2×200mL)で洗浄した。これにより、52.5gの白色固体が得られた(収率32%)。母液を蒸発させ、イソプロパノール(IPA)(±100mL)から再結晶させ、13.5gの白色固体を得た。両方のバッチを合わせ、66gの収量が得られた(収率39%)。1H NMR (300MHz, CDCl3) δ 8.40 (s, 1 H), 7.34 (t, 1 H), 7.26 (d, J = 7.7 Hz, 1 H), 6.52 (d, J = 8.4 Hz, 1 H), 5.88 − 5.54 (m, J = 26.6 Hz, 1H), 5.52 − 5.36 (m, 1H), 4.85 − 4.67 (m, J = 16.3, 10.8 Hz, 1 H), 4.14 (s, 1 H), 3.58 − 3.31 (m, 1 H), 2.45 − 2.30 (m, 1 H), 1.80 − 1.36(m, 4H), 1.03 (t, 3 H)。
実施例2a)ラセミ2−エチル−6−(トリフルオロメチル)−1,2,3,4−テトラヒドロキノリン−4−アミン(ラセミ−化合物B)
ポヴァロフ生成物(20g、73.5mmmol)と、濃HCl(22.3mL)と、エタノール(60mL)との混合物を50℃で5時間加熱した。30〜40℃に冷却した後、混合物を蒸発させて総容量を60mLとした。その後、混合物を冷却し、ジクロロメタン(160mL)を添加し、次いで6MのNaOH(60mL)で塩基性化しpH12〜13とした。層を分離し、液相をジクロロメタン(40mL)で抽出した。有機層を合わせて水(40mL)で洗浄し、硫酸ナトリウムで乾燥し、蒸発乾固させ、17.6gのラセミ化合物Bを得た(収率95%)。
4−アミノベンゾトリフルオリド(6.3mL、50.0mmol)をCH3CN(40mL)に室温(RT)で溶解した。プロピオンアルデヒド(4.3mL、60mmol、1.2当量、4℃で保存)を一度に添加した。温度を25℃に上昇させた。その透明溶液を室温(冷却するため水浴内で)5分間撹拌し、イミンの淡黄色溶液を得た。N−ビニルホルムアミド(4.4mL、63mmol、1.25当量、4℃で保存)をインサイチュ調製イミン溶液に一度で添加し、次いでTsOH(160mg、0.017当量)を添加した。温度を27℃に上昇させた。5分後、沈殿が生成した。混合物を窒素雰囲気下室温で一晩撹拌した。NMR分析により、成分がポヴァロフ生成物に完全に転化されたことを示した。混合物に水(140mL)を添加し、次いでH2SO4(14mL)を添加し、その混合物を60℃に温めた。0.5時間後、NMRにより、ポヴァロフ生成物がラセミ化合物Bに完全に転化されたことを明らかにした。混合物をトルエン(50mL)で抽出した。水層は、濃NaOH水溶液でpH10に塩基性化された。塩基性の水層をトルエン(200mL)で抽出し、トルエン層を乾燥し(Na2SO4)、濃縮して、7.3g(60%)の粗2−エチル−6−(トリフルオロメチル)−1,2,3,4−テトラヒドロキノリン−4−アミン(ラセミ化合物B)をNMRによる80〜90%の純度の褐色固体として得た。1H NMR (300MHz, CDCl3) δ 7.62 (s, 1H), 7.28 (d, 1 H), 6.45 (d, J = 8.4 Hz, 1 H), 4.03 (s, 2 H), 4.00 (s, 1 H), 3.48 − 3.28 (m, J = 2.8 Hz, 1 H), 2.27 − 2.08 (m, 1 H), 1.67 − 1.32 (m, 6 H), 1.00 (t, 3H )。
ジ−p−トルオイル−L−酒石酸1水和物(134.7g、0.33mol、0.75当量)を粗ラセミ化合物B(108.4g)のメタノール(1L、9V)溶液に添加し、結晶が形成するまで撹拌した。得られたスラッシュを加熱還流し、室温まで冷却させ、その後氷上で冷却した。結晶が生成し、これを濾過により採取し、乾燥させた(99.9g固体)。この材料をメタノール(750mL、7V)から再び結晶化させ、メチルtert−ブチルエーテル(TBME)(200mL、2V)で洗浄し、99.5%鏡像体過剰率を有する、81.6gの化合物Bジトルオイル酒石酸(B−DTTA)塩(収率27%)を得た。
10gの化合物B−DTTA塩(94%鏡像体過剰率)に、トルエン(100mL)及び2NのNaOH(100mL)を添加した。混合物を10分間撹拌し、その後層を分離した。水相をトルエン(2×100mL)で抽出した。次に、合わせたトルエン層を塩水で洗浄し、Na2SO4で乾燥させ、蒸発乾固して乾燥した。これにより褐色油を得、これに3Vのイソプロパノールを添加した。メタンスルホン酸(MsOH)(1mL)を得られた懸濁液に滴下した。まず懸濁液が透明混合液になった。数分後、固体を形成し始めた。これらの固体を採取し、TBME(2×)で洗浄し、乾燥させた。これにより4g(化合物B−TA塩から75%の収率)の化合物BMsOH塩を98.6%の鏡像体過剰率で得た。
化合物Bメタンスルホン酸塩を化合物Aに転化するために、WO2007/116922に記載のものと類似の方法を用いた。
1. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA.2009;302:1993−2000.
2. Cholesterol Treatment Trialists (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta−analysis of data from 170000 participants in 26 randomised trials. Lancet. 2010;13:1670−1681.
3.Roger VL, Go AS, Lloyd−Jones DM et al.,Heart disease and stroke statistics−2012 Update: A report from the American Heart Association. Circulation. 2012;125:e12−e230.
4.Barter PJ, Caulfield M, Eriksson M et al.,Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357:21009−2122.
5.Kastelein JJP, van Leuven SI, Burgess L et al., Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med.2007;356:1620−1630.
6.Nicholls SJ, Tuzcu EM, Brennan DM, Tardif J−C, Nissen SE. Cholesteryl ester transfer protein inhibition, high−density lipoprotein raising, and progression of coronary atherosclerosis. Insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation. 2008;118:2506−2514.
7.Vergeer M, Bots ML, van Leuven SI, Basart DC, Sijbrands EJ, Evans GW, Grobbee DE, Visseren FL, Stalenhoef AF, Stroes ES, Kastelein JJP. Cholesteryl ester transfer protein inhibitor torcetrapib and off−target toxicity: pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials. Circulation.2008;118:2515−2522.
8.Forrest MJ, Bloomfield D, Briscoe RJ et al., Torcetrapib−induced blood pressure elevation is independent of CETP inhibition and is accompanied by increasing circulating levels of aldosterone. Br J Pharmacol.2008;154:1465−1473.
9.Simic B, Hermann M, Shaw SG et al., Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33:1615−1624.
10.Barter PJ, Rye K−A, Beltangady MS et al., Relationship between atorvastatin dose and the harm caused by torcetrapib. J Lipid Res.2012;53:2436−2442.
11.Schwartz GG, Olsson AG, Abt M et al.,Effects of dalcetrapib in patients with recent acute coronary syndrome. N Engl J Med.2012;367:2089−2099.
12.Stein EA, Stroes ES, Steiner G, et al., Safety and tolerability of dalcetrapib. Am J Cardiol. 2009;104:82−91.
13.Luscher TF, Taddei S, Kaski JC, et al., Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal−VESSEL randomized clinical trial. Eur Heart J. 2012;33:857−65.
14.Krishna R, Bergman AJ, Fallon et al., Multiple−dose pharmacodynamics and pharmacokinetics of anacetrapib, a potent cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Clin Pharmacol Ther.2008;84:679−683.
15.Bloomfield D, Carlson GL, Aditi Sapre BS et al., Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J. 2009;157:352−360.
16.Nicholls SJ, Brewer HB, Kastelein JJP et al., Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol. JAMA.2011;306:2099−2109.
17.Am. J. Cardiol., 2014 Jan 1;113(1):76−83: Evaluation of Lipids, Drug Concentration, and Safety Parameters Following Cessation of Treatment With the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Patients With or at High Risk for Coronary Heart Disease. Antonio M. Gotto Jr. et al.
18.Okamoto M, Sakuragi A, Mori Y, Hamada T, Kubota H, Nakamura Y, Higashijima T, Hayashi N. Tanabe Seiyako Co. Ltd. A process for preparing tetrahydroquinoline derivatives WO2007/116922 A1.
19.Govindan CK. An improved process for the preparation of benzyl−N−vinyl carbamate. Org Proc Res Dev. 2002;6:74−77.
20.Am Ende DJ, DeVries KM, Clifford PJ, Brenek SJ. A Calorimetric Investigation To Safely Scale−Up a Curtius Rearrangement of Acryloyl Azide Org Proc Res Dev. 1998;2:382−392.
21.Damon DB, Dugger RW, Magnus−Aryitey G, Ruggeri RB, Wester RT, Tu M, Abramov Y. Synthesis of the CETP Inhibitor Torcetrapib: The Resolution Route and Origin of Stereoselectivity in the Iminium Ion Cyclization. Org Proc Res Dev. 2006;10:464−471.
22.Liu H, Dagousset G, Masson G, Retailleau P, Zhu J.Chiral Bronsted Acid−Catalyzed Enantioselective Three−Component Povarov Reaction. J Am Chem Soc. 2009;131:4598−4599.
23.Dagousset G, Zhu J, Masson G. Chiral Phosphoric Acid−Catalyzed Enantioselective Three−Component Povarov Reaction Using Enecarbamates as Dienophiles: Highly Diastereo− and Enantioselective Synthesis of Substituted 4−Aminotetrahydroquinolines. J Am Chem Soc. 2011;133:14804−14813.
24.Huang D, Xu F, Chen T, Wang Y, Lin X. Highly enantioselective three−component Povarov reaction catalyzed by SPINOL−phosphoric acids. RSC Advances. 2013;3:573.
Claims (20)
- R1がCH2CH3であり、R2がHである、請求項1に記載の方法。
- 前記使用される溶剤がジクロロメタン、アセトニトリル、酢酸エチル、トルエン、またはこれらの混合物である、請求項1または2に記載の方法。
- 前記工程a)で使用される触媒が酸、好ましくはブレンステッド酸またはルイス酸である、請求項1〜3のいずれかに記載の方法。
- 前記触媒が4−トルエンスルホン酸である、請求項4に記載の方法。
- 前記工程b)の前に、前記式Vの化合物を、前記工程a)の反応混合物から、好ましくは沈殿及び/または濾過により分離する、請求項1〜5のいずれかに記載の方法。
- 前記式Vの化合物を、非極性溶剤を前記反応混合物に添加することにより前記反応混合物から沈殿させる、請求項6に記載の方法。
- 前記非極性溶剤がヘプタン、シクロヘキサン、またはこれらの混合物である、請求項7に記載の方法。
- 前記工程b)において、前記式Vの化合物を、水溶性酸の存在下、前記化合物を含む混合物を45〜80℃で1〜3時間温めることにより加水分解する、請求項1〜8のいずれかに記載の方法。
- 前記加水分解がアルコール及び水溶性酸の存在下で行われる、請求項9に記載の方法。
- 前記酸が塩酸である、請求項9または10に記載の方法。
- 前記アルコールがエタノールである、請求項10または11に記載の方法。
- 前記式I−aに従うエナンチオマーの分離を、L−酒石酸、またはジ−p−トルオイル−L−酒石酸等のその誘導体等のキラル分割剤で分割することにより行う、請求項13に記載の方法。
- R1がC2アルキルである、請求項13または14に記載の方法。
- R1がCH2CH3であり、R2がHである、請求項17に記載の化合物。
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Publication number | Priority date | Publication date | Assignee | Title |
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Non-Patent Citations (4)
Title |
---|
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. VOL:22, NR:11, JPN6019011041, 2012, pages PAGE(S):3671 - 3675 * |
ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 10, no. 3, JPN6019011042, 2006, pages 464 - 471 * |
RSC ADVANCES, vol. 3, no. 2, JPN6019011043, 2013, pages 573 - 578 * |
TETRAHEDRON, vol. 65, no. 14, JPN6019011044, 2009, pages 2721 - 2750 * |
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