JP5943319B2 - Heteroarenesulfonylated quinaalkaloid amine compounds - Google Patents
Heteroarenesulfonylated quinaalkaloid amine compounds Download PDFInfo
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- -1 amine compounds Chemical class 0.000 title claims description 14
- 229930013930 alkaloid Natural products 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 241000157855 Cinchona Species 0.000 claims description 10
- 235000021513 Cinchona Nutrition 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 5
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 5
- 229940124530 sulfonamide Drugs 0.000 claims description 5
- 150000003456 sulfonamides Chemical class 0.000 claims description 5
- 241000156724 Antirhea Species 0.000 claims 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000003054 catalyst Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001412 amines Chemical class 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- KOLPMNSDISYEBU-WJOKGBTCSA-N 2-[(3r)-1-(2,2-diethoxyethyl)-3-[(4-methylphenyl)carbamoylamino]-2-oxoindol-3-yl]-n-(4-methylphenyl)acetamide Chemical compound C([C@]1(NC(=O)NC=2C=CC(C)=CC=2)C(=O)N(C2=CC=CC=C21)CC(OCC)OCC)C(=O)NC1=CC=C(C)C=C1 KOLPMNSDISYEBU-WJOKGBTCSA-N 0.000 description 4
- 238000006683 Mannich reaction Methods 0.000 description 4
- 150000003797 alkaloid derivatives Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 150000007970 thio esters Chemical class 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UZMPOHKOMYCYCZ-UHFFFAOYSA-N tert-butyl 2-oxo-3h-indole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C(=O)CC2=C1 UZMPOHKOMYCYCZ-UHFFFAOYSA-N 0.000 description 3
- 150000003672 ureas Chemical class 0.000 description 3
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PJVTUFAWHRGOSV-UHFFFAOYSA-N 1,3,2-dioxathiane-4,6-dione Chemical compound O=C1CC(=O)OSO1 PJVTUFAWHRGOSV-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- LOUPRKONTZGTKE-LHHVKLHASA-N Quinidine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 1
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Natural products C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 150000001540 azides Chemical class 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000008863 intramolecular interaction Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000004658 ketimines Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 235000021110 pickles Nutrition 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- JUYUYCIJACTHMK-UHFFFAOYSA-N quinoline-8-sulfonyl chloride Chemical compound C1=CN=C2C(S(=O)(=O)Cl)=CC=CC2=C1 JUYUYCIJACTHMK-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
Landscapes
- Indole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は、ヘテロアレーンスルホニル化キナアルカロイドアミン触媒およびこれを用いるβ-アミノカルボニル化合物の製造方法
に関するものである。
The present invention relates to a heteroarenesulfonylated quinalkaloid amine catalyst and a method for producing a β-aminocarbonyl compound using the same.
不斉空間の制御は，最近まで金属錯体触媒を用いる手法が中心となって発展してきたが，近年，グリーンケミストリーの観点から不斉有機分子触媒が注目されている（非特許文献１）。特に、シンコナアルカロイドは天然に豊富に存在し、比較的安価に入手できることから、近年有機触媒として注目され、非常に多くの不斉炭素-炭素結合反応に用いられている（非特許文献２）。しかしながら、シンコナアルカロイド触媒そのものでは、反応性、選択性が低い場合があり、このため、シンコナアルカロイドの修飾化が検討されており、不斉点の窒素原子に対してアレーンスルホニル基の導入も検討されている（非特許文献３−８）。 The control of the asymmetric space has been developed mainly by a technique using a metal complex catalyst until recently, but in recent years, an asymmetric organic molecular catalyst has attracted attention from the viewpoint of green chemistry (Non-patent Document 1). In particular, since cinchona alkaloids are naturally abundant and can be obtained at a relatively low cost, they have recently attracted attention as organic catalysts and are used in a large number of asymmetric carbon-carbon bond reactions (Non-patent Document 2). . However, the cinchona alkaloid catalyst itself may have low reactivity and selectivity. For this reason, modification of the cinchona alkaloid has been studied, and the introduction of an arenesulfonyl group to the nitrogen atom at the asymmetric point is also considered. It has been studied (Non-patent Documents 3-8).
これまでに多くの不斉有機触媒が開発されている。また、不斉点の窒素原子に対してアレーンスルホニル基を導入したシンコナアルカロイド触媒も開発され、上記問題の一部は解決されたものの、いずれ有機触媒を用いても生成物の立体選択性・反応性が低い場合があり、すべての問題解決には至っていない。
本発明は、上記の実情に鑑みてなされたものであり、配位性官能基を不斉有機触媒の適切な位置に組み込むことにより，分子内相互作用によって新しい不斉空間を分子内に創成することで、上記問題点を解決することを目的とする。
Many asymmetric organic catalysts have been developed so far. In addition, a cinchona alkaloid catalyst in which an arenesulfonyl group is introduced to the nitrogen atom at the asymmetric point has also been developed, and although some of the above problems have been solved, the stereoselectivity of the product can be achieved using any organic catalyst. Reactivity may be low and not all problems have been solved.
The present invention has been made in view of the above circumstances, and creates a new asymmetric space in a molecule by intramolecular interaction by incorporating a coordinating functional group at an appropriate position of the asymmetric organic catalyst. Therefore, it aims at solving the above-mentioned problem.
この出願の発明は、上記目的を達成するものとして、シンコナアルカロイドの窒素原子上にヘテロアリールスルホニル基を有し、スルホンアミド水素とヘテロ原子とが分子内水素結合したことを特徴とする。
そして、この出願の発明は、次式（３）（４）（６）（７）で表わされることを特徴とする。
In order to achieve the above object, the invention of this application has a heteroarylsulfonyl group on a nitrogen atom of a cinchona alkaloid, and is characterized in that a sulfonamido hydrogen and a hetero atom are intramolecularly hydrogen bonded .
The invention of this application, it characterized by represented by the following formula (3) (4) (6) (7).
ヘテロアレーンスルホニル基を有するキナアルカロイドアミンおよびそれを利用した不斉合成反応について下記実施形態で説明する。 A quinaalkaloid amine having a heteroarenesulfonyl group and an asymmetric synthesis reaction using the quinaalkaloid amine are described in the following embodiments.
（第１実施形態）
ヘテロアレーンスルホニル化キナアルカロイドアミン触媒の合成について説明する。
ナスフラスコにシンコニジン(1.0 g, 3.40 mmol)とトリフェニルホスフィン(1.1 g, 4.08 mmol)を加え、テトラヒドロフラン(THF) (15 ml)に溶解させ, 0 °Cまで冷却させた。そこにジイソプロピルアゾカルボキシラート(DIAD) (0.81 ml, 3.40 mmol)を加え、さらにジフェニルホルホリルアジド(DPPA) (0.88 ml, 4.08 mmol)をテトラヒドロフラン(THF) (6.0 ml)に溶解させた溶液をゆっくりと滴下した後、室温にて12時間攪拌させた。その後、この溶液を50 °Cまで加熱し、 2時間攪拌させた。そこにトリフェニルホスフィン(1.8 g, 6.79 mmol)を加え、生成物溶液の発泡を確認した後、さらに2時間攪拌させた。その後、室温にて純水(0.4 ml)を加え、さらに3時間攪拌させた。反応終了後は、溶媒を減圧下にて留去し、塩化メチレンと3規定の塩酸水溶液を加え、塩化メチレンで抽出し、得られた水層に溶液がアルカリ性になるまでアンモニア水を加えた。この溶液を再び塩化メチレンで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥させ、減圧下にて溶媒を留去した。精製は、シリカゲルカラムクロマトグラフィー(塩化メチレン/メタノール = 100:5-90:10)により行い、次式（１）で表わされる目的生成物シンコニジンアミン(0.56 g,56%)を得た。
(First embodiment)
The synthesis of the heteroarenesulfonylated quinaalkaloid amine catalyst will be described.
Cinconidine (1.0 g, 3.40 mmol) and triphenylphosphine (1.1 g, 4.08 mmol) were added to the eggplant flask, dissolved in tetrahydrofuran (THF) (15 ml), and cooled to 0 ° C. Thereto was added diisopropyl azocarboxylate (DIAD) (0.81 ml, 3.40 mmol) and a solution of diphenylformyl azide (DPPA) (0.88 ml, 4.08 mmol) dissolved in tetrahydrofuran (THF) (6.0 ml). After the dropwise addition, the mixture was stirred at room temperature for 12 hours. Thereafter, this solution was heated to 50 ° C. and stirred for 2 hours. Triphenylphosphine (1.8 g, 6.79 mmol) was added thereto, and after the foaming of the product solution was confirmed, the mixture was further stirred for 2 hours. Thereafter, pure water (0.4 ml) was added at room temperature, and the mixture was further stirred for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, methylene chloride and 3N hydrochloric acid aqueous solution were added, extraction was performed with methylene chloride, and aqueous ammonia was added to the resulting aqueous layer until the solution became alkaline. This solution was extracted again with methylene chloride, and the resulting organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification was performed by silica gel column chromatography (methylene chloride / methanol = 100: 5-90: 10) to obtain the desired product cinchonidineamine (0.56 g, 56%) represented by the following formula (1).
このとき、Rf = 0.06 (dichloromethane/methanol = 95:5)である。
以下、この得られた化合物の1H NMR、IR、MS(ESI)による同定結果を示す。
1H NMR (300 MHz, CDCl3) δ 0.72-0.79 (m, 1H), 1.43 (t, J = 10.2 Hz, 1H), 1.57-1.63 (m, 3H), 2.28 (brs, 2H), 2.77-2.87 (m, 3H), 3.09-3.33 (m, 4H), 4.72 (d, J = 4.7 Hz), 4.96-5.04 (m, 2H), 5.75-5.87 (m, 1H), 7.53-7.75 (m, 3H), 8.14 (d, J = 4.4 Hz), 8.35 (s, 1H), 8.9 (d, J = 2.3 Hz)
IR(KBr) 3365, 2938, 1635, 1589, 1508, 1467, 1320, 1042, 990, 913, 819, 761, 629, 458 cm-1
MS(ESI) m/z 294.4 [M+H]
ナスフラスコに、前記目的生成物のシンコニジンアミン(0.60 g, 2.0 mmol)を加え、溶媒として塩化メチレン(15 ml)を加えた後に0 °Cまで冷却させた。そこにトリエチルアミン (0.34 ml, 2.5 mmol)を加え、さらに8-キノリルスルホニルクロリド (0.70 g, 3.1 mmol)を溶解させた後、室温にて12時間攪拌させた。その後、純水を加え、塩化メチレンで抽出し、得られた有機層を無水硫酸ナトリウムで乾燥させ、減圧下にて溶媒を留去した。精製は、シリカゲルカラムクロマトグラフィー(塩化メチレン/メタノール = 95:5)により行い、次式（２）で表わされる目的生成物のヘテロアレーンスルホニル化キナアルカロイドアミン触媒(0.88 g, 90%)を得た。
At this time, Rf = 0.06 (dichloromethane / methanol = 95: 5).
Hereinafter, identification results of the obtained compound by 1 H NMR, IR, and MS (ESI) are shown.
1 H NMR (300 MHz, CDCl 3 ) δ 0.72-0.79 (m, 1H), 1.43 (t, J = 10.2 Hz, 1H), 1.57-1.63 (m, 3H), 2.28 (brs, 2H), 2.77- 2.87 (m, 3H), 3.09-3.33 (m, 4H), 4.72 (d, J = 4.7 Hz), 4.96-5.04 (m, 2H), 5.75-5.87 (m, 1H), 7.53-7.75 (m, 3H), 8.14 (d, J = 4.4 Hz), 8.35 (s, 1H), 8.9 (d, J = 2.3 Hz)
IR (KBr) 3365, 2938, 1635, 1589, 1508, 1467, 1320, 1042, 990, 913, 819, 761, 629, 458 cm -1
MS (ESI) m / z 294.4 [M + H]
To the eggplant flask, cinchonidineamine (0.60 g, 2.0 mmol) as the target product was added, and methylene chloride (15 ml) was added as a solvent, and then cooled to 0 ° C. Triethylamine (0.34 ml, 2.5 mmol) was added thereto, and further 8-quinolylsulfonyl chloride (0.70 g, 3.1 mmol) was dissolved, followed by stirring at room temperature for 12 hours. Thereafter, pure water was added, extraction was performed with methylene chloride, the obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purification was performed by silica gel column chromatography (methylene chloride / methanol = 95: 5) to obtain a heteroarenesulfonylated quinaalkaloid amine catalyst (0.88 g, 90%) of the desired product represented by the following formula (2). .
このとき、Rf = 0.54 (dichloromethane/methanol = 90:10)である。
以下、この得られた化合物の1H NMR、IR、MS(ESI)による同定結果を示す。
1H NMR (300 MHz, CDCl3) δ 0.60 (m, 1H), 1.05-1.24 (m, 4H), 1.45-2.09 (m, 4H), 2.63 (d, J = 15.0 Hz) 2.84-2.98 (m, 2H), 4.88 (d, J = 15.9 Hz, 3H), 5.55-5.60 (m, 1H), 7.42-7.68 (m, 6H), 7.90-8.24 (m, 4H), 8.74 (d, J = 4.5 Hz, 1H), 9.07-9.09 (m, 1H)
IR(KBr) 3073, 2938, 2866, 1592, 1565, 1495, 1346, 1321, 1171, 1056, 989, 841, 754, 596, 492 cm-1
MS(ESI) m/z 485.6 [M+H].
同様に次式（３）で表わされるキニンアミン、次式（４）で表わされるキニジンアミン、次式（５）で表わされるシンコニンアミンも合成可能である。以下、各式の下にそれぞれの同定結果を示す。
At this time, Rf = 0.54 (dichloromethane / methanol = 90: 10).
Hereinafter, identification results of the obtained compound by 1 H NMR, IR, and MS (ESI) are shown.
1 H NMR (300 MHz, CDCl 3 ) δ 0.60 (m, 1H), 1.05-1.24 (m, 4H), 1.45-2.09 (m, 4H), 2.63 (d, J = 15.0 Hz) 2.84-2.98 (m , 2H), 4.88 (d, J = 15.9 Hz, 3H), 5.55-5.60 (m, 1H), 7.42-7.68 (m, 6H), 7.90-8.24 (m, 4H), 8.74 (d, J = 4.5 Hz, 1H), 9.07-9.09 (m, 1H)
IR (KBr) 3073, 2938, 2866, 1592, 1565, 1495, 1346, 1321, 1171, 1056, 989, 841, 754, 596, 492 cm -1
MS (ESI) m / z 485.6 [M + H].
Similarly, a quinine amine represented by the following formula (3), a quinidine amine represented by the following formula (4), and a cinchonine amine represented by the following formula (5) can also be synthesized. Hereinafter, each identification result is shown under each formula.
1H NMR (300 MHz, CDCl3) δ 0.64 (s, 1H), 1.19-1.26 (m, 3H), 1.50 (s, 1H), 1.75-1.90 (m, 3H), 2.12 (s, 2H), 2.60 (s, 1H), 2.93 (m, 2H), 3.90 (s, 3H), 4.90 (d, J = 16.8 Hz, 2H), 5.60 (s, 1H), 7.22-7.55 (m, 5H), 7.93 (d, J= 8.1 Hz, 2H), 8.10-8.12 (m, 2H), 8.52 (s, 1H), 9.08 (d, J = 2.7 Hz, 1H)
IR(KBr) 3396, 3183, 2941, 1620, 1508, 1474, 1359, 1321, 1230, 1145, 1029, 989, 913, 835, 790, 596 cm-1
MS(ESI) m/z 516.1 [M+H].
1 H NMR (300 MHz, CDCl 3 ) δ 0.64 (s, 1H), 1.19-1.26 (m, 3H), 1.50 (s, 1H), 1.75-1.90 (m, 3H), 2.12 (s, 2H), 2.60 (s, 1H), 2.93 (m, 2H), 3.90 (s, 3H), 4.90 (d, J = 16.8 Hz, 2H), 5.60 (s, 1H), 7.22-7.55 (m, 5H), 7.93 (d, J = 8.1 Hz, 2H), 8.10-8.12 (m, 2H), 8.52 (s, 1H), 9.08 (d, J = 2.7 Hz, 1H)
IR (KBr) 3396, 3183, 2941, 1620, 1508, 1474, 1359, 1321, 1230, 1145, 1029, 989, 913, 835, 790, 596 cm -1
MS (ESI) m / z 516.1 [M + H].
1H NMR (300 MHz, CDCl3) δ 0.72-0.95 (m, 2H), 1.26-1.45 (m, 3H), 1.61-1.90 (m, 2H), 2.60-2.80 (m, 3H), 3.83-3.95 (m, 4H), 4.47 (d, J = 17.4 Hz, 1H), 4.65 (d, J = 10.2 Hz, 1H), 4.84 (d, J = 10.5 Hz, 1H), 5.30 (s, 1H), 5.49-5.57 (m, 1H), 6.98-7.04 (m, 1H), 7.27-7.35 (m, 1H), 7.51-7.60 (m, 3H), 7.95-8.04 (m, 2H), 8.19-8.28 (m, 2H), 8.63 (s, 1H), 9.11 (s, 1H)
IR(KBr) 3396, 3159, 2936, 1620, 1592, 1508, 1361, 1323, 1226, 1168, 1145, 1029, 913, 790, 713, 680, 593, 495 cm-1
MS(ESI) m/z 515.8 [M+H].
1 H NMR (300 MHz, CDCl 3 ) δ 0.72-0.95 (m, 2H), 1.26-1.45 (m, 3H), 1.61-1.90 (m, 2H), 2.60-2.80 (m, 3H), 3.83-3.95 (m, 4H), 4.47 (d, J = 17.4 Hz, 1H), 4.65 (d, J = 10.2 Hz, 1H), 4.84 (d, J = 10.5 Hz, 1H), 5.30 (s, 1H), 5.49 -5.57 (m, 1H), 6.98-7.04 (m, 1H), 7.27-7.35 (m, 1H), 7.51-7.60 (m, 3H), 7.95-8.04 (m, 2H), 8.19-8.28 (m, 2H), 8.63 (s, 1H), 9.11 (s, 1H)
IR (KBr) 3396, 3159, 2936, 1620, 1592, 1508, 1361, 1323, 1226, 1168, 1145, 1029, 913, 790, 713, 680, 593, 495 cm -1
MS (ESI) m / z 515.8 [M + H].
1H NMR (300 MHz, CDCl3) δ 0.67 (m, 1H), 0.88-0.91 (m, 1H), 1.36-1.42 (m, 3H), 1.60 (s, 3H), 1.72-1.90 (m, 2H), 2.61-2.79 (m, 3H), 4.53 (d, J = 17.4 Hz), 4.75-4.93 (m, 2H), 5.45-5.52 (m, 1H), 7.51-7.60 (m, 3H), 7.65-7.81 (m, 3H), 8.02-8.05 (m, 2H), 8.18-8.26 (m, 2H), 8.80 (s, 1H), 9.11-9.12 (m, 1H)
IR(KBr) 3419, 3159, 2938, 2861, 1593, 1565, 1509, 1493, 1360, 1321, 1170, 1146, 1057, 994, 909, 841, 796, 754, 634, 594, 494 cm-1
MS(ESI) m/z 485.2 [M+H].
次式（６）及び(７)で表わされるその他のヘテロアレーンスルホニル化キナアルカロイド触媒も合成可能である。以下、各式の下にそれぞれの同定結果を示す。
1 H NMR (300 MHz, CDCl 3 ) δ 0.67 (m, 1H), 0.88-0.91 (m, 1H), 1.36-1.42 (m, 3H), 1.60 (s, 3H), 1.72-1.90 (m, 2H ), 2.61-2.79 (m, 3H), 4.53 (d, J = 17.4 Hz), 4.75-4.93 (m, 2H), 5.45-5.52 (m, 1H), 7.51-7.60 (m, 3H), 7.65- 7.81 (m, 3H), 8.02-8.05 (m, 2H), 8.18-8.26 (m, 2H), 8.80 (s, 1H), 9.11-9.12 (m, 1H)
IR (KBr) 3419, 3159, 2938, 2861, 1593, 1565, 1509, 1493, 1360, 1321, 1170, 1146, 1057, 994, 909, 841, 796, 754, 634, 594, 494 cm -1
MS (ESI) m / z 485.2 [M + H].
Other heteroarenesulfonylated quinaalkaloid catalysts represented by the following formulas (6) and (7) can also be synthesized. Hereinafter, each identification result is shown under each formula.
1H NMR (300 MHz, CDCl3) δ 0.83-0.91 (m, 1H), 1.24 (s, 1H), 1.54-1.68 (m, 3H), 2.26 (s, 1H), 2.56-2.85 (m, 4H), 3.15-3.38 (m, 1H), 4.33 (d, J = 10.5 Hz, 1H), 4.83-5.10 (m, 3H) 5.55-5.70 (m, 1H), 6.61-6.78 (m, 1H), 7.07-7.27 (m, 2H), 7.45-7.74 (m, 2H), 8.02-8.19 (m, 2H), 8.45 (s, 1H), 8.78 (s, 1H)
IR(KBr) 3160, 2935, 2860, 1593, 1508, 1493, 1360, 1322, 1169, 1146, 1029, 915, 789, 712, 594, 494 cm-1
MS(ESI) m/z 440.2 [M+H].
1 H NMR (300 MHz, CDCl 3 ) δ 0.83-0.91 (m, 1H), 1.24 (s, 1H), 1.54-1.68 (m, 3H), 2.26 (s, 1H), 2.56-2.85 (m, 4H ), 3.15-3.38 (m, 1H), 4.33 (d, J = 10.5 Hz, 1H), 4.83-5.10 (m, 3H) 5.55-5.70 (m, 1H), 6.61-6.78 (m, 1H), 7.07 -7.27 (m, 2H), 7.45-7.74 (m, 2H), 8.02-8.19 (m, 2H), 8.45 (s, 1H), 8.78 (s, 1H)
IR (KBr) 3160, 2935, 2860, 1593, 1508, 1493, 1360, 1322, 1169, 1146, 1029, 915, 789, 712, 594, 494 cm -1
MS (ESI) m / z 440.2 [M + H].
1H NMR (300 MHz, CDCl3) δ 0.78-0.90 (m, 1H), 1.25 (s, 1H), 1.57-1.68 (m, 2H), 2.27 (s, 1H), 2.69-2.93 (m, 4H), 3.16-3.39 (m, 2H), 4.51 (d, J = 10.8 Hz, 1H), 4.83-4.97 (m, 2H), 5.24 (d, J = 10.5 Hz, 1H), 5.60-5.71 (m, 1H), 7.03 (s, 1H), 7.27-7.34 (m, 3H), 7.47-7.75 (m, 2H), 7.94-8.36 (m, 2H), 8.62 (s, 1H), 8.76 (s, 1H)
IR(KBr) 3159, 2938, 2866, 1593, 1565, 1508, 1495, 1345, 1321, 1170, 1057, 990, 839, 755, 630, 596, 493 cm-1
MS(ESI) m/z 435.6 [M+H].
（第２実施形態）β-アミノカルボニル化合物の製造方法
次に、上記した化合物を触媒として用いるマンニッヒ反応によるβ-アミノカルボニル化合物の製造方法について説明する。
β-アミノカルボニル化合物は、医薬品、農薬などの基本骨格として重要な化合物であり、この化合物としては、例えば、AG-041R等が挙げられる。特に４置換不斉炭素を有するβ-アミノカルボニル化合物の合成は困難とされているが、本発明のヘテロアレーンスルホニル化キナアルカロイドアミン触媒を用いることで、ケチミン類へのマロン酸モノチオエステルの脱炭酸型マンニッヒ反応が、高収率・高エナンチオ選択的に進行する。
例えば、従来の触媒による反応生成物の立体選択性が30%ee程度であったものを80%ee以上とすることができる。 これは、上記したキナアルカロイドアミン誘導体では、スルホンアミドのアミド水素と、ヘテロアリール基のヘテロ原子との分子内水素結合が形成されることで、分子内に不斉空間が存在することが要因であると考えられる。
1 H NMR (300 MHz, CDCl 3 ) δ 0.78-0.90 (m, 1H), 1.25 (s, 1H), 1.57-1.68 (m, 2H), 2.27 (s, 1H), 2.69-2.93 (m, 4H ), 3.16-3.39 (m, 2H), 4.51 (d, J = 10.8 Hz, 1H), 4.83-4.97 (m, 2H), 5.24 (d, J = 10.5 Hz, 1H), 5.60-5.71 (m, 1H), 7.03 (s, 1H), 7.27-7.34 (m, 3H), 7.47-7.75 (m, 2H), 7.94-8.36 (m, 2H), 8.62 (s, 1H), 8.76 (s, 1H)
IR (KBr) 3159, 2938, 2866, 1593, 1565, 1508, 1495, 1345, 1321, 1170, 1057, 990, 839, 755, 630, 596, 493 cm -1
MS (ESI) m / z 435.6 [M + H].
Second Embodiment Method for Producing β-Aminocarbonyl Compound Next, a method for producing a β-aminocarbonyl compound by the Mannich reaction using the above compound as a catalyst will be described.
The β-aminocarbonyl compound is an important compound as a basic skeleton for pharmaceuticals, agricultural chemicals, and the like, and examples of this compound include AG-041R. In particular, it is considered difficult to synthesize β-aminocarbonyl compounds having a 4-substituted asymmetric carbon, but by using the heteroarenesulfonylated quinaalkaloid amine catalyst of the present invention, decarboxylation of malonic acid monothioester to ketimines. Type Mannich reaction proceeds with high yield and high enantioselectivity.
For example, a conventional product having a stereoselectivity of about 30% ee can be made 80% ee or more. This is because the quinaalkaloid amine derivative described above has an asymmetric space in the molecule due to the formation of an intramolecular hydrogen bond between the amide hydrogen of the sulfonamide and the heteroatom of the heteroaryl group. It is believed that there is.
ヘテロアリール基が８−キノリル基であるキナアルカロイドアミンを触媒として用いたケチミノイサチンに対するマンニッヒ反応によるβ-アミノカルボニル化合物の製造方法について説明する。 A method for producing a β-aminocarbonyl compound by a Mannich reaction on ketiminoisatin using a quinaalkaloid amine whose heteroaryl group is an 8-quinolyl group as a catalyst will be described.
スリ付き試験管に、触媒として、8-キノリルスルホニルシンコニジンアミン触媒(3.7 mg, 0.079 mmol)を加えて窒素置換をした後、N-Boc-1-メチル-2-オキソインドリン(10 mg, 0.038 mmol)、S-フェニルマロン酸ハーフチオエステル(16.5 mg, 0.84 mmol)を加えた。その後、シクロペンチルメチルエーテル(0.5 ml)を溶媒として加え室温下で48時間撹拌した。その後、減圧下で溶媒を留去した。 そして、シリカゲルクロマトグラフィー(hexane/ethyl acetate=80/20)により精製を行い、次式（８）で表わされる生成物(14.1 mg, 90%, 83% ee)を得た。 After adding 8-quinolylsulfonyl cinchonidine amine catalyst (3.7 mg, 0.079 mmol) as a catalyst in a test tube with a pickle and replacing with nitrogen, N-Boc-1-methyl-2-oxoindoline (10 mg, 0.038 mmol), S-phenylmalonic acid half thioester (16.5 mg, 0.84 mmol) was added. Thereafter, cyclopentyl methyl ether (0.5 ml) was added as a solvent, and the mixture was stirred at room temperature for 48 hours. Thereafter, the solvent was distilled off under reduced pressure. The product was purified by silica gel chromatography (hexane / ethyl acetate = 80/20) to obtain a product (14.1 mg, 90%, 83% ee) represented by the following formula (8).
以下、この得られた化合物のNMR、IR、MS(ESI)による同定結果を示す。
1H NMR (300 MHz, CDCl3) δ1.24 (s, 9H), 2.80 (d, J = 14.7 Hz, 1H), 3.23 (d, J = 14.7 Hz, 1H), 3.27 (s, 1H), 6.28 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 7.08 (t, J= 6.9 Hz, 1H), 7.29-7.36 (m, 4H), 7.43-7.45 (m, 3H)
IR (KBr) 3330, 2972, 1726, 1702, 1616, 1472, 1366, 1252, 1166, 1020, 748, 680 cm-1
MS(ESI) m/z 435.55 [M + Na]+
HRMS (ESI) calcd. for [C22H24N2O4S+Na]+: 435.1354, Found: 435.1360
なお、開発した8-キノリルスルホニルシンコニジンアミン触媒の代わりに、一般的なベンゼンスルホニルシンコニジンアミン触媒を用いて、同様の反応を行うと、収率７５％、エナンチオ過剰率25% eeで生成物が得られることからも、従来触媒からの優位な効果が得られていると判断できる。また、もちいるN-Boc-2-オキソインドリンは、実施形態３に示すように様々な置換基R1を有するイミンが使用でき、マロン酸ハーフチオエステルも様々な化合物が使用可能である。
The identification results of the obtained compound by NMR, IR and MS (ESI) are shown below.
1 H NMR (300 MHz, CDCl 3 ) δ1.24 (s, 9H), 2.80 (d, J = 14.7 Hz, 1H), 3.23 (d, J = 14.7 Hz, 1H), 3.27 (s, 1H), 6.28 (s, 1H), 6.88 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 6.9 Hz, 1H), 7.29-7.36 (m, 4H), 7.43-7.45 (m, 3H)
IR (KBr) 3330, 2972, 1726, 1702, 1616, 1472, 1366, 1252, 1166, 1020, 748, 680 cm- 1
MS (ESI) m / z 435.55 [M + Na] +
HRMS (ESI) calcd. For [C 22 H 24 N 2 O 4 S + Na] + : 435.1354, Found: 435.1360
In addition, instead of the developed 8-quinolylsulfonyl cinchonidine amine catalyst, when a similar reaction was performed using a general benzenesulfonyl cinchonidine amine catalyst, a yield of 75% and an enantio excess ratio of 25% ee were produced. From the fact that the product can be obtained, it can be judged that a superior effect from the conventional catalyst is obtained. As N-Boc-2-oxoindoline used, imines having various substituents R 1 can be used as shown in Embodiment 3, and various compounds can also be used as malonic acid half thioesters.
（第３実施形態）
次式（９）で表わされるマンニッヒ反応によりβ-アミノカルボニル化合物の製造を行った。
(Third embodiment)
A β-aminocarbonyl compound was produced by a Mannich reaction represented by the following formula (9).
下記表１の実施例中ＥｎｔｒｙＮｏ.１では、N-Boc-2-オキソインドリンのＲ1としてメチル基を、マロン酸ハーフチオエステルのＲ２としてフェニル基を用いて実施することにより収率（Ｙｉｅｌｄ）９０％，エナンチオ過剰率８３% eeで生成物が得られた。
下記表１のＥｎｔｒｙＮｏ.２から１６に示した置換基Ｒ1とＲ２とを有するN-Boc-2-オキソインドリン及びマロン酸ハーフチオエステルを用いてＥｎｔｒｙＮｏ.１と同様にして実施することにより各ＥｎｔｒｙＮｏ.に示す収率及びエナンチオ過剰率で生成物が得られた。
In Entry No. 1 in the examples of Table 1 below, the yield (Yield) is obtained by carrying out using a methyl group as R 1 of N-Boc-2-oxoindoline and a phenyl group as R 2 of malonic acid half thioester. The product was obtained with 90%, enantio excess 83% ee.
By carrying out in the same manner as Entry No. 1 using N-Boc-2-oxoindoline and malonic acid half thioester having substituents R 1 and R 2 shown in Entry No. 2 to 16 shown in Table 1 below, The product was obtained in the yield and enantiomeric excess shown in Entry No.
なお、表１中、Ｍｅはメチル基を示し、Ｅｔはエチル基を示し、iPrはイソプロピル基を示し、Ｐｈはフェニル基を示し、Allyl はアリル基を示し、Ｂｎはベンジル基を示し、ｔ−Ｂｕはターシャルブチル基を示し、Yieldは収率を示し、Eeは、エナンチオ過剰率を示す。 In Table 1, Me represents a methyl group, Et represents an ethyl group, iPr represents an isopropyl group, Ph represents a phenyl group, Allyl represents an allyl group, Bn represents a benzyl group, t- Bu represents a tertiary butyl group, Yield represents the yield, and Ee represents the enantio excess.
[参考例１]生理活性物質AG-041Rの合成
実施例３で合成した化合物を用い、次のようにして次式の合成的変換を行うことで逆流性食道炎、胃潰瘍の改善治療候補薬であるAG-041Rを合成することが可能である。
脱炭酸付加生成物を得た後に、マグネシウムメトキシドと反応させることで、エステル交換を行い、ヘキサフルオロイソプロピルアルコール（HFIP）にて脱Boc保護を行い、得られたアミンに対してパラトルエンイソシアナートを反応させることで、尿素誘導体が合成できた。この尿素誘導体は、結晶性が高く、ヘキサン、酢酸エチル中で再結晶を行うことにより、光学的に純粋な尿素誘導体へ変換できた。その後水酸化カリウムを用いて加水分解を行った後パラトルイジンと縮合することで、簡便に光学的に純粋なAG-041Rに変換することが可能であった。
[Reference Example 1] Synthesis of physiologically active substance AG-041R By using the compound synthesized in Example 3 and performing synthetic conversion of the following formula as follows, it is a candidate drug for the treatment of reflux esophagitis and gastric ulcer. It is possible to synthesize a certain AG-041R.
After obtaining the decarboxylated addition product, transesterification is performed by reacting with magnesium methoxide, de-Boc protection is performed with hexafluoroisopropyl alcohol (HFIP), and para-toluene isocyanate is obtained for the obtained amine. By reacting, a urea derivative could be synthesized. This urea derivative had high crystallinity and could be converted to an optically pure urea derivative by recrystallization in hexane and ethyl acetate. Subsequent hydrolysis with potassium hydroxide followed by condensation with paratoluidine enabled easy conversion to optically pure AG-041R.
Claims (4)
On the nitrogen atom of the cinchona alkaloids has a heteroarylsulfonyl group, an amide hydrogen and hetero atoms of the sulfonamide has intramolecular hydrogen bond, wherein the to Ruhe Teroa lanes sulphonyl that represented by the following formula (3) Quina alkaloid amine compounds.
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