JP2014151285A - New optically active imidazoline-phosphoric acid catalyst and derivative thereof - Google Patents
New optically active imidazoline-phosphoric acid catalyst and derivative thereof Download PDFInfo
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Abstract
Description
本発明は、新規な光学活性イミダゾリン-リン酸触媒に関するものである。 The present invention relates to a novel optically active imidazoline-phosphate catalyst.
新規な不斉合成手法の開発は、医薬品合成、ファインケミカル合成において非常に重要な研究であり、そのために新規な高機能性不斉触媒の開発が強く望まれている。そこで近年では、キラルな酸触媒として機能する光学活性リン酸触媒が開発され、好成績を与える触媒として利用されている（非特許文献１〜３）。しかしながら、これら触媒においても高度の立体選択性を発現することができない場合も有り、より高度な不斉反応場を設計した不斉触媒の創製が強く望まれている。
Development of a new asymmetric synthesis method is very important research in pharmaceutical synthesis and fine chemical synthesis, and for this purpose, development of a new highly functional asymmetric catalyst is strongly desired. Therefore, in recent years, optically active phosphoric acid catalysts that function as chiral acid catalysts have been developed and used as catalysts that give good results (Non-Patent Documents 1 to 3). However, there are cases where these catalysts cannot exhibit a high degree of stereoselectivity, and the creation of asymmetric catalysts designed with a more advanced asymmetric reaction field is strongly desired.
この出願の発明が解決しようとする課題は、これまでに開発されている従来触媒では、高度の立体選択性の発現、収率、反応性に課題がある点である。本発明は、上記点に鑑みて、新規な光学活性イミダゾリン-リン酸触媒を提供することにある。 The problem to be solved by the invention of this application is that the conventional catalysts developed so far have problems in the expression, yield, and reactivity of a high degree of stereoselectivity. In view of the above points, the present invention is to provide a novel optically active imidazoline-phosphate catalyst.
この出願の発明は、上記目的を達成するものとして、次式（１）乃至（６）で示される光学活性イミダゾリン-リン酸触媒を提供する (請求項１乃至７)。 The invention of this application provides an optically active imidazoline-phosphate catalyst represented by the following formulas (1) to (6) to achieve the above object (claims 1 to 7).
また、この出願の発明は、
請求項１乃至６に記載の触媒のうちのいずれかの不斉触媒とジメトキシカルシウムの存在下で、次式（７）の反応式により、メソアジリジン類にトリメチルシリルイソチオシアネートを反応させてアジリジンmL不斉開環反応を行い、β-アミノチオールおよびβ-アミノスルホン酸誘導体を製造する方法を提供する。
The invention of this application is
7. In the presence of any one of the catalysts according to claim 1 and dimethoxycalcium and dimethoxycalcium, a mesoaziridine is reacted with trimethylsilylisothiocyanate according to the reaction formula of the following formula (7). Provided is a method for producing a β-aminothiol and a β-aminosulfonic acid derivative by performing a ring-opening reaction.
（式中、R2は、環状アルキル基である。ここで、R1はトシル基、2-ピリジンスルホニル基、2-キノリンスルホニル基、チエニル基、ピコリノイル基のいずれか一つであり、また、前記触媒は、光学活性イミダゾリン-リン酸触媒または、他のキラルブレンステッド酸触媒である。） (Wherein R 2 is a cyclic alkyl group, wherein R 1 is any one of a tosyl group, a 2-pyridinesulfonyl group, a 2-quinolinesulfonyl group, a thienyl group, and a picolinoyl group, and The catalyst is an optically active imidazoline-phosphate catalyst or other chiral Bronsted acid catalyst.)
発明者らは，アジリジンの窒素上にヘテロアレーンスルホニル基を導入し、トリメチルシリルイソチオシアネートを求核剤として用いる触媒的不斉開環反応を実施検討した。また、これまでに高エナンチオ選択的な成功例のない本手法を成功させるために、これまでに使用例のない光学活性イミダゾリン-リン酸触媒を新規不斉触媒として用い、新しい合成手法の実施検討を行った。 The inventors conducted a catalytic asymmetric ring-opening reaction using a heteroarenesulfonyl group on the nitrogen of aziridine and using trimethylsilylisothiocyanate as a nucleophile. In addition, in order to succeed in this method, which has not been successful with high enantioselectivity so far, we will investigate the implementation of a new synthetic method using an optically active imidazoline-phosphate catalyst that has not been used so far as a novel asymmetric catalyst. Went.
（第１実施形態）
光学活性イミダゾリン-リン酸触媒の合成法について説明する。
次式（８）
(First embodiment)
A method for synthesizing an optically active imidazoline-phosphate catalyst will be described.
The following formula (8)
式中、Ｒはｐ−トルエンスルホニル基、ｐ−メトキシベンゼンスルホニル基、２−ナフチルスルホニル基、またはベンジル基を示す。ここで、ＭＯＭＣｌは、クロロメチルメチルエーテルを、ＮａＨは、水素化ナトリウムを、ＴＨＦは、テトラヒドロフランを、ｎＢｕＬｉは、ｎ−ブチルリチウムを、ＤＭＦは、ジメチルホルムアミドを、（１Ｓ，２Ｓ）−ＤＰＥＤＡは、（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミンを、ＮＢＳは、Ｎ−ブロモスクシンイミドを、ＤＭＡＰは、4−ジメチルアミノピリジンを、ｃｏｎｃ．ＨＣｌは、濃塩酸を、ＭｅＯＨは、メタノールを、ＰＯＣｌ３は、塩化ホスホリルを、Ｅｔ３Ｎは、トリエチルアミンを、また、ＣＨ２Ｃｌ２は、ジクロロメタンを示す。式（８）は、第２実施形態で記述する反応に使用する前記式（１）乃至（６）の新規不斉触媒である光学活性イミダゾリン-リン酸触媒の合成法である。また、(Ｒ)−ＢＩＮＯＬも同手法にて対応するイミダゾリン-リン酸触媒が合成可能である。
前記式（８）の合成法の実施により上記式（１）乃至（６）の新規不斉触媒の合成したことについて次の実施例１乃至６に記述する。
次式（９）
In the formula, R represents a p-toluenesulfonyl group, a p-methoxybenzenesulfonyl group, a 2-naphthylsulfonyl group, or a benzyl group. Here, MOMCl is chloromethyl methyl ether, NaH is sodium hydride, THF is tetrahydrofuran, nBuLi is n-butyllithium, DMF is dimethylformamide, and (1S, 2S) -DPEDA is , (1S, 2S) -1,2-diphenyl-1,2-ethanediamine, NBS for N-bromosuccinimide, DMAP for 4-dimethylaminopyridine, conc. HCl is concentrated hydrochloric acid, MeOH is methanol, POCl 3 is phosphoryl chloride, Et 3 N is triethylamine, and CH 2 Cl 2 is dichloromethane. Formula (8) is a method for synthesizing an optically active imidazoline-phosphate catalyst, which is a novel asymmetric catalyst of formulas (1) to (6) used in the reaction described in the second embodiment. In addition, (R) -BINOL can be synthesized by the same method with a corresponding imidazoline-phosphate catalyst.
The synthesis of novel asymmetric catalysts of the above formulas (1) to (6) by carrying out the synthesis method of the above formula (8) will be described in the following Examples 1 to 6.
Formula (9)
式中、ＳＯＣｌ２は、塩化チオニルを、Ｅｔ３Ｎは、トリエチルアミンを、ＣＨ２Ｃｌ２は、ジクロロメタンを、ＰＰｈ３Ｏは、トリフェニルホスフィンオキシドを、Ｔｆ２Ｏは、トリフルオロメタンスルホン酸無水物を、また、ＰＯＣｌ３は、塩化ホスホリルを示す。式（１２）は、第２実施形態で記述する反応に使用する前記式（６）の新規不斉触媒である光学活性イミダゾリン-リン酸触媒の合成法である。
前記式（９）の合成法の実施により上記式（６）の新規不斉触媒の合成したことについて次の実施例６に記述する。
（実施例１）
前記式（１）の化学式で与えられる目的生成物(S)-3-(1-[toluene-4-sulfonyl]-[4S,5S]
-4,5-dihydro-1H-imidazol-2-yl)-1,1’-binaphthalene-2,2’diyl hydrogen phosphateを前記式（８）の合成法により次のようにして合成した。
(S)-BINOLより既知反応にてヒドロキシ基をメトキシメチル保護した後、3位をホルミル化した。ナスフラスコに前記アルデヒド（3.0 g, 7.45 mmol）と(1S,2S)-1,2-ジフェニル-1,2-エタンジアミン（2.0 g, 9.31 mmol）をジクロロメタン75 mLに溶かし、24時間攪拌を行った後、0 °Cまで冷却した。ここへ、Ｎ−ブロモスクシンイミド（1.7 g, 9.31 mmol）のジクロロメタン溶液75 mLをゆっくり滴下した後、反応温度を室温に昇温し、24時間撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液、ジクロロメタンで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (Hexane:AcOEt = 1:1)で行い、次式（１０）で表わされる目的生成物を4.02 g (91 %)で得た。
In the formula, SOCl 2 is thionyl chloride, Et 3 N is triethylamine, CH 2 Cl 2 is dichloromethane, PPh 3 O is triphenylphosphine oxide, and Tf 2 O is trifluoromethanesulfonic anhydride. And POCl 3 represents phosphoryl chloride. Formula (12) is a method for synthesizing an optically active imidazoline-phosphate catalyst which is a novel asymmetric catalyst of the formula (6) used in the reaction described in the second embodiment.
The synthesis of the novel asymmetric catalyst of the above formula (6) by carrying out the synthesis method of the above formula (9) is described in Example 6 below.
Example 1
Target product (S) -3- (1- [toluene-4-sulfonyl]-[4S, 5S] given by the chemical formula of formula (1)
-4,5-dihydro-1H-imidazol-2-yl) -1,1'-binaphthalene-2,2'diyl hydrogen phosphate was synthesized by the synthesis method of the above formula (8) as follows.
After protecting the hydroxy group with methoxymethyl by a known reaction from (S) -BINOL, the 3-position was formylated. Dissolve the aldehyde (3.0 g, 7.45 mmol) and (1S, 2S) -1,2-diphenyl-1,2-ethanediamine (2.0 g, 9.31 mmol) in 75 mL of dichloromethane in an eggplant flask and stir for 24 hours. Then, it was cooled to 0 ° C. To this, 75 mL of a dichloromethane solution of N-bromosuccinimide (1.7 g, 9.31 mmol) was slowly added dropwise, and then the reaction temperature was raised to room temperature and stirred for 24 hours. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution and dichloromethane, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Hexane: AcOEt = 1: 1). ) Was obtained in 4.02 g (91%).
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.76 (s, 3H, CH3), 3.18 (s, 3H, CH3), 4.64 (d, J = 4.8 Hz, 2H, CH2), 4.78 (d, J = 5.1 Hz, 2H, CH2), 5.06 (d, J= 6.9 Hz, 2H, CH2), 5.14 (d, J = 6.9 Hz, 2H, CH2), 7.19-7.46 (m, 19H, CH, Ph, Naph), 7.60 (d, J = 9.0 Hz, 1H, Naph), 7.88 (d, J = 8.4 Hz, 1H, Naph), 8.00 (dd, J = 3.9, J = 9.0 Hz, 2H, Naph), 8.93 (s, 1H, NH)
MS (ESI, positive) m/z 594.8 [M+H]+
前記式（１０）の化合物（1.0 g, 1.68 mmol）と4-ジメチルアミノピリジン（514.3 mg, 4.21 mmol）をジクロロメタン16 mLに溶かした後、0 oCまで冷却した。ここへ、p-トルエンスルホニルクロライド（802.6 mg, 4.21 mmol）のジクロロメタン溶液16 mLをゆっくり滴下した後、反応温度を室温に昇温し、1時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液、ジクロロメタンで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (Hexane:AcOEt = 80:20)で行い、次式（１１）で表わされる目的生成物を1.23 g (98 %)で得た。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.76 (s, 3H, CH 3 ), 3.18 (s, 3H, CH 3 ), 4.64 (d, J = 4.8 Hz, 2H, CH 2 ), 4.78 (d, J = 5.1 Hz, 2H, CH 2 ), 5.06 (d, J = 6.9 Hz, 2H, CH 2 ), 5.14 (d, J = 6.9 Hz, 2H, CH 2 ), 7.19-7.46 (m, 19H, CH, Ph, Naph), 7.60 (d, J = 9.0 Hz, 1H, Naph), 7.88 (d, J = 8.4 Hz, 1H, Naph), 8.00 (dd, J = 3.9, J = 9.0 Hz, 2H, Naph), 8.93 (s, 1H, NH)
MS (ESI, positive) m / z 594.8 [M + H] +
The compound of formula (10) (1.0 g, 1.68 mmol) and 4-dimethylaminopyridine (514.3 mg, 4.21 mmol) were dissolved in 16 mL of dichloromethane, and then cooled to 0 ° C. To this, 16 mL of dichloromethane solution of p-toluenesulfonyl chloride (802.6 mg, 4.21 mmol) was slowly added dropwise, and then the reaction temperature was raised to room temperature and stirred for 1 hour. The reaction solution was washed with a saturated aqueous ammonium chloride solution and dichloromethane, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Hexane: AcOEt = 80: 20). 1.23 g (98%) of the expected product represented by
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.38 (s, 3H, CH3), 2.53 (s, 3H, CH3), 3.26 (s, 3H, CH3), 4.75 (s, 2H, CH2), 5.05 (d, J = 5.1 Hz, 1H, CH2), 5.13-5.19 (m, 3H, CH, CH2), 6.96 (d, J = 6.6 Hz, 2H, Ph), 7.05 (s, 2H, Ph), 7.21 (s, 2H, Ph), 7.31-7.51 (m, 14H, Ph, Naph), 7.64 (d, J = 9.0 Hz, 1H, Naph), 7.88 (d, J = 8.1 Hz, 2H, Naph), 7.97-8.02 (m, 2H, Naph)
MS (ESI, positive) m/z 749.1 [M+H]+, 771.1 [M+Na]
前記式（１１）の化合物（1.23 g, 1.64 mmol）をメタノール100 mLに溶かし、反応温度65 °Cで30分間攪拌を行った後、室温まで冷却した。ここへ、濃塩酸（3.20 mL）をゆっくり滴下した後、反応温度を65 °Cに昇温し、2時間撹拌した。溶媒を減圧下で留去し、反応溶液を飽和炭酸水素ナトリウム水溶液、ジクロロメタンで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (CH2Cl2 = 100)で行い、次式（１２）で表わされる目的生成物を1.05 g (91 %)で得た。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.38 (s, 3H, CH 3 ), 2.53 (s, 3H, CH 3 ), 3.26 (s, 3H, CH 3 ), 4.75 (s, 2H, CH 2 ), 5.05 ( d, J = 5.1 Hz, 1H, CH 2 ), 5.13-5.19 (m, 3H, CH , CH 2 ), 6.96 (d, J = 6.6 Hz, 2H, Ph), 7.05 (s, 2H, Ph), 7.21 (s, 2H, Ph), 7.31-7.51 (m, 14H, Ph, Naph), 7.64 (d, J = 9.0 Hz, 1H, Naph), 7.88 (d, J = 8.1 Hz, 2H, Naph), 7.97-8.02 (m, 2H, Naph)
MS (ESI, positive) m / z 749.1 [M + H] + , 771.1 [M + Na]
The compound of formula (11) (1.23 g, 1.64 mmol) was dissolved in 100 mL of methanol, stirred at a reaction temperature of 65 ° C. for 30 minutes, and then cooled to room temperature. Concentrated hydrochloric acid (3.20 mL) was slowly added dropwise thereto, and then the reaction temperature was raised to 65 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure, the reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution and dichloromethane, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and silica gel column chromatography (CH 2 Cl 2 = 100 ) To obtain 1.05 g (91%) of the desired product represented by the following formula (12).
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.33 (s, 3H, CH3), 5.19 (s, 1H, CH), 5.28 (d, J = 0.6 Hz, 1H, CH), 6.69 (d, J = 8.1 Hz, 2H, Ph), 7.02-7.12 (m, 4H, Naph), 7.16-7.24 (m, 2H, Naph), 7.30 (d, J = 8.1 Hz, 3H, Ph), 7.35-7.56 (m, 10H, Ph, Naph), 7.90-8.01 (m, 3H, Naph), 8.80 (s, 1H, Naph)
MS (ESI, positive) m/z 660.9 [M+H]+
前記式（１２）の化合物（1.05 g, 1.59 mmol）をジクロロメタン50 mLに溶かし、トリエチルアミン（7.40 mL, 52.9 mmol）を加えた。室温で5分間攪拌を行った後、塩化ホスホリル（0.29 mL, 3.18 mmol）をゆっくり滴下した後、12時間撹拌した。これに純水（27 mL）を加え、さらに4時間撹拌した。反応溶液を1規定の塩酸、ジクロロメタンで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (CH2Cl2:MeOH = 95:5)で行い、次式（１）で表わされる目的生成物を539.9 mg (47 %)で得た。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.33 (s, 3H, CH 3 ), 5.19 (s, 1H, CH), 5.28 (d, J = 0.6 Hz, 1H, CH), 6.69 (d, J = 8.1 Hz, 2H, Ph), 7.02-7.12 (m, 4H, Naph), 7.16-7.24 (m, 2H, Naph), 7.30 (d, J = 8.1 Hz, 3H, Ph), 7.35-7.56 (m, 10H, Ph , Naph), 7.90-8.01 (m, 3H, Naph), 8.80 (s, 1H, Naph)
MS (ESI, positive) m / z 660.9 [M + H] +
The compound of the formula (12) (1.05 g, 1.59 mmol) was dissolved in 50 mL of dichloromethane, and triethylamine (7.40 mL, 52.9 mmol) was added. After stirring at room temperature for 5 minutes, phosphoryl chloride (0.29 mL, 3.18 mmol) was slowly added dropwise, followed by stirring for 12 hours. Pure water (27 mL) was added thereto, and the mixture was further stirred for 4 hours. The reaction solution was washed with 1N hydrochloric acid and dichloromethane, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CH 2 Cl 2 : MeOH = 95: 5). The desired product represented by (1) was obtained in 539.9 mg (47%).
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.10 (s, 3H, CH3), 5.36 (d, J = 3.9 Hz, 1H, CH), 5.44 (d, J = 4.2 Hz, 1H, CH), 7.02 (d, J = 8.1 Hz, 2H, Naph), 7.12-7.15 (m, 2H, Naph), 7.25-7.66 (m, 16H, Naph, Ph), 7.97-8.12 (m, 4H, Naph), 8.68 (s, 1H, Naph)
MS (ESI, positive) m/z 723.2 [M+H]+
（実施例２）
前記式（２）の化学式で与えられる目的生成物(R)-3-(1-[toluene-4-sulfonyl]-[4S,5S]
-4,5-dihydro-1H-imidazol-2-yl)-1,1’-binaphthalene-2,2’diyl hydrogen phosphateを前記式（８）の合成法により、(R)-BINOLを用いて合成した。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.10 (s, 3H, CH 3 ), 5.36 (d, J = 3.9 Hz, 1H, CH), 5.44 (d, J = 4.2 Hz, 1H, CH), 7.02 (d, J = 8.1 Hz, 2H, Naph), 7.12-7.15 (m, 2H, Naph), 7.25-7.66 (m, 16H, Naph, Ph), 7.97-8.12 (m, 4H, Naph), 8.68 (s, 1H , Naph)
MS (ESI, positive) m / z 723.2 [M + H] +
(Example 2)
The desired product (R) -3- (1- [toluene-4-sulfonyl]-[4S, 5S] given by the chemical formula of the above formula (2)
-4,5-dihydro-1H-imidazol-2-yl) -1,1'-binaphthalene-2,2'diyl hydrogen phosphate using (R) -BINOL by the synthesis method of formula (8) did.
当該目的生成物のスペクトル等を以下に示す。
1H NMR (300 MHz, CDCl3) δ 1.85 (s, 1H, CH3), 5.32 (br, 1H, CH), 5.65 (br, 1H, CH), 6.55 (br, 1H, Ph), 6.60 (br, 1H, Ph), 7.22-7.44 (m, 17H, Naph, Ph), 7.92-7.95 (m, 2H, Naph), 8.05 (d, J = 8.1 Hz, 1H, Naph), 8.58 (s, 1H, Naph)
MS (ESI, negative) m/z 721.1 [M+H]+
（実施例３）
前記式（３）の化学式で与えられる目的生成物(S)-3-(1-[4-methoxybenzenesulfonyl]-[4S,5S]-4,5-dihydro-1H-imidazol-2-yl)-1,1’-binaphthalene-2,2’diyl hydrogen phosphateを前記式（８）の合成法により、R-Clにp-メトキシベンゼンスルホニルクロライドを用いて合成した。
The spectrum of the target product is shown below.
1 H NMR (300 MHz, CDCl 3 ) δ 1.85 (s, 1H, CH 3 ), 5.32 (br, 1H, CH), 5.65 (br, 1H, CH), 6.55 (br, 1H, Ph), 6.60 ( br, 1H, Ph), 7.22-7.44 (m, 17H, Naph, Ph), 7.92-7.95 (m, 2H, Naph), 8.05 (d, J = 8.1 Hz, 1H, Naph), 8.58 (s, 1H , Naph)
MS (ESI, negative) m / z 721.1 [M + H] +
Example 3
The target product (S) -3- (1- [4-methoxybenzenesulfonyl]-[4S, 5S] -4,5-dihydro-1H-imidazol-2-yl) -1 given by the chemical formula (3) 1,1'-binaphthalene-2,2'diyl hydrogen phosphate was synthesized by the synthesis method of the above formula (8) using p-methoxybenzenesulfonyl chloride as R-Cl.
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 3.48 (s, 3H, CH3), 5.36 (d, J = 3.9 Hz, 1H, CH), 5.43 (d, J = 4.2 Hz, 1H, CH), 6.64 (d, J = 8.7 Hz, 2H, Ph), 7.15-7.18 (m, 2H, Ph), 7.30-7.68 (m, 17H, Ph, Naph), 7.98-8.15 (m, 3H, Naph), 8.70 (s, 1H, Naph)
MS (ESI, negative) m/z 737.2 [M+H]+
（実施例４）
前記式（４）の化学式で与えられる目的生成物(S)-3-(1-[2-naphthylsulfonyl]-[4S,5S]-4,5-dihydro-1H-imidazol-2-yl)-1,1’-binaphthalene-2,2’diyl hydrogen phosphateを前記式（８）の合成法により、R-Clに２−ナフタレンスルホニルクロライドを用いて合成した。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 3.48 (s, 3H, CH 3 ), 5.36 (d, J = 3.9 Hz, 1H, CH), 5.43 (d, J = 4.2 Hz, 1H, CH), 6.64 (d, J = 8.7 Hz, 2H, Ph), 7.15-7.18 (m, 2H, Ph), 7.30-7.68 (m, 17H, Ph, Naph), 7.98-8.15 (m, 3H, Naph), 8.70 (s, 1H , Naph)
MS (ESI, negative) m / z 737.2 [M + H] +
Example 4
The desired product (S) -3- (1- [2-naphthylsulfonyl]-[4S, 5S] -4,5-dihydro-1H-imidazol-2-yl) -1 given by the chemical formula of the above formula (4) 1,1'-binaphthalene-2,2'diyl hydrogen phosphate was synthesized by the synthesis method of the above formula (8) using 2-naphthalenesulfonyl chloride as R-Cl.
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 5.35 (s, 1H, CH), 5.46 (d, J = 3.0 Hz, 1H, CH), 6.95 (s, 5H, Naph), 7.30-7.35 (m, 3H, Naph, Ph), 7.48-7.79 (m, 15H, Naph, Ph), 7.97-8.08 (m, 4H, Naph), 8.69 (s, 1H, Naph)
MS (ESI, negative) m/z 757.1 [M+H]+
（実施例５）
前記式（５）の化学式で与えられる目的生成物(S)-3-(1-benzyl-[4S,5S]-4,5-dihydro-1H-imidazol-2-yl)-1,1’-binaphthalene-2,2’diyl hydrogen phosphateを前記式（８）の合成法により、R-Brにベンジルブロミドを用いて合成した。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 5.35 (s, 1H, CH), 5.46 (d, J = 3.0 Hz, 1H, CH), 6.95 (s, 5H, Naph), 7.30-7.35 (m, 3H, Naph, Ph), 7.48-7.79 (m, 15H, Naph, Ph), 7.97-8.08 (m, 4H, Naph), 8.69 (s, 1H, Naph)
MS (ESI, negative) m / z 757.1 [M + H] +
(Example 5)
The desired product (S) -3- (1-benzyl- [4S, 5S] -4,5-dihydro-1H-imidazol-2-yl) -1,1′- given by the chemical formula of formula (5) Binaphthalene-2,2'diyl hydrogen phosphate was synthesized using benzyl bromide as R-Br by the synthesis method of the above formula (8).
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 4.18 (d, J = 15 Hz, 1H, CH), 4.60 (d, J = 7.2 Hz, 1H, CH), 5.30 (s, 2H, CH2), 6.99 (s, 2H, Ph), 7.22 (s, 4H, Naph), 7.65-7.39 (m, 10H, Ph), 7.58-7.58 (m, 5H, Naph, Ph), 7.74 (d, J = 8.7 Hz, 1H, Naph), 7.94-8.08 (m, 3H, Naph), 8.22 (s, 1H, Ph)
MS (ESI, negative) m/z 657.2 [M+H]+
（実施例６）
前記式（６）の化学式で与えられる目的生成物(S)-3,3’-bis(1-[toluene-4-sulfonyl]-[4S,5S]-4,5-dihydro-1H-imidazol-2-yl)-1,1’-binaphthalene-2,2’diyl hydrogen phosphateを前記式（９）の合成法により次のようにして合成した。
(S)-BINOLより既知反応にて3,3’位をカルボン酸にした。ナスフラスコに前記カルボン酸（1.7 g, 4.54 mmol）を塩化チオニル50 mLに溶かし、4時間還流を行った後、室温まで冷却した。減圧下で過剰な塩化チオニルを留去し、ジクロロメタン20 mLに溶かした。これを既知反応にてｐ−トルエンスルホニル化させた（１Ｓ，２Ｓ）−１，２−ジフェニル−１，２−エタンジアミン（3.3 g, 9.11 mmol）とトリエチルアミン（3.8 mL, 27.24 mmol）のジクロロメタン溶液10 mLへゆっくり滴下した後、反応温度を室温にて、24時間撹拌した。反応溶液を飽和塩化アンモニウム水溶液、ジエチルエーテルで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (AcOEt:CH2Cl2 = 5:95)で行い、次式（１３）で表わされる目的生成物を2.0 g (42 %)で得た。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 4.18 (d, J = 15 Hz, 1H, CH), 4.60 (d, J = 7.2 Hz, 1H, CH), 5.30 (s, 2H, CH 2 ), 6.99 (s, 2H, Ph), 7.22 (s, 4H, Naph), 7.65-7.39 (m, 10H, Ph), 7.58-7.58 (m, 5H, Naph, Ph), 7.74 (d, J = 8.7 Hz, 1H, Naph ), 7.94-8.08 (m, 3H, Naph), 8.22 (s, 1H, Ph)
MS (ESI, negative) m / z 657.2 [M + H] +
(Example 6)
The desired product (S) -3,3′-bis (1- [toluene-4-sulfonyl]-[4S, 5S] -4,5-dihydro-1H-imidazole- given by the chemical formula of the above formula (6) 2-yl) -1,1′-binaphthalene-2,2′diyl hydrogen phosphate was synthesized by the synthesis method of the formula (9) as follows.
From the (S) -BINOL, the 3,3 ′ position was converted to a carboxylic acid by a known reaction. The carboxylic acid (1.7 g, 4.54 mmol) was dissolved in 50 mL of thionyl chloride in an eggplant flask, refluxed for 4 hours, and then cooled to room temperature. Excess thionyl chloride was distilled off under reduced pressure and dissolved in 20 mL of dichloromethane. A dichloromethane solution of (1S, 2S) -1,2-diphenyl-1,2-ethanediamine (3.3 g, 9.11 mmol) and triethylamine (3.8 mL, 27.24 mmol), which was p-toluenesulfonylated by a known reaction. After slowly dropping into 10 mL, the reaction temperature was stirred at room temperature for 24 hours. The reaction solution was washed with a saturated aqueous solution of ammonium chloride and diethyl ether, and then dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, followed by silica gel column chromatography (AcOEt: CH 2 Cl 2 = 5:95). The desired product of formula (13) was obtained in 2.0 g (42%).
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.10 (s, 6H, CH3), 4.64 (dd, J = 8.1, 9.9 Hz, 2H, CH), 5.36 (dd, J = 6.6, 10.1 Hz, 2H, CH), 5.97 (d, J = 7.8 Hz, 2H, NH), 6.86 (d, J = 6.9 Hz, 2H, Ph), 7.06-7.32 (m, 24H, Ph, Naph), 7.60 (d, J = 8.1 Hz, 4H, Naph), 7.89 (d, J = 8.7 Hz, 2H, Naph), 8.01 (d, J = 6.0 Hz, 2H, Naph), 8.34 (s, 2H, Naph), 11.04 (s, 2H, OH)
MS (ESI, positive) m/z 1093.2 [M+Na]+
フラスコにトリフェニルホスフィンオキシド（2.3 g, 8.4 mmol）をジクロロメタン10 mLに溶かした後、0 °Cまで冷却した。ここへトリフルオロメタンスルホン酸無水物0.71 mLを加えた後、0 °Cにて30分撹拌した。ここへ前記式（１３）の化合物（1.5 g, 1.4 mmol）のジクロロメタン30 mL溶液をゆっくり滴下した後、１２時間撹拌した。反応溶液を飽和炭酸水素ナトリウム水溶液、ジクロロメタンで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (Hexane:AcOEt = 80:20)で行い、次式（１４）で表わされる目的生成物を800 mg (55 %)で得た。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.10 (s, 6H, CH 3 ), 4.64 (dd, J = 8.1, 9.9 Hz, 2H, CH), 5.36 (dd, J = 6.6, 10.1 Hz, 2H, CH), 5.97 (d, J = 7.8 Hz, 2H, NH), 6.86 (d, J = 6.9 Hz, 2H, Ph), 7.06-7.32 (m, 24H, Ph, Naph), 7.60 (d, J = 8.1 Hz, 4H, Naph), 7.89 (d, J = 8.7 Hz, 2H, Naph), 8.01 (d, J = 6.0 Hz, 2H, Naph), 8.34 (s, 2H, Naph), 11.04 (s, 2H, OH)
MS (ESI, positive) m / z 1093.2 [M + Na] +
Triphenylphosphine oxide (2.3 g, 8.4 mmol) was dissolved in 10 mL of dichloromethane in the flask, and then cooled to 0 ° C. To this was added 0.71 mL of trifluoromethanesulfonic anhydride, and the mixture was stirred at 0 ° C. for 30 minutes. To this was slowly added dropwise a 30 mL solution of the compound of the formula (13) (1.5 g, 1.4 mmol) in dichloromethane, followed by stirring for 12 hours. The reaction solution was washed with a saturated aqueous solution of sodium bicarbonate and dichloromethane, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Hexane: AcOEt = 80: 20). ) Was obtained in 800 mg (55%).
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.32 (s, 6H, CH3), 5.15 (d, J = 3.6 Hz, 2H, CH), 5.22 (d, J = 4.2 Hz, 2H, CH), 6.69 (d, J = 7.5 Hz, 2H, Ph), 6.99-7.52 (m, 30H, Ph, Naph), 8.02 (d, J = 8.4 Hz, 2H, Naph), 8.82 (s, 2H, Naph), 10.74 (s, 2H, OH)
MS (ESI, positive) m/z 1035.1 [M+H]+, 1057.1 [M+Na]+
前記式（１４）の化合物（45.0 mg, 0.04 mmol）をジクロロメタン1.3 mLに溶かし、トリエチルアミン（0.33 mL, 2.37 mmol）を加えた。室温で5分間攪拌を行った後、塩化ホスホリル（16.0 μl, 0.17 mmol）をゆっくり滴下した後、12時間撹拌した。これに純水（0.7 mL）を加え、さらに4時間撹拌した。反応溶液を1規定の塩酸、ジクロロメタンで洗浄した後、無水硫酸ナトリウムで乾燥、溶媒を減圧下で留去し、シリカゲルカラムクロマトグラフィー (CH2Cl2:MeOH = 95:5)で行い、次式（６）で表わされる目的生成物を16.6 mg (35 %)得た。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.32 (s, 6H, CH 3 ), 5.15 (d, J = 3.6 Hz, 2H, CH), 5.22 (d, J = 4.2 Hz, 2H, CH), 6.69 (d, J = 7.5 Hz, 2H, Ph), 6.99-7.52 (m, 30H, Ph, Naph), 8.02 (d, J = 8.4 Hz, 2H, Naph), 8.82 (s, 2H, Naph), 10.74 (s, 2H, OH)
MS (ESI, positive) m / z 1035.1 [M + H] + , 1057.1 [M + Na] +
The compound of the formula (14) (45.0 mg, 0.04 mmol) was dissolved in 1.3 mL of dichloromethane, and triethylamine (0.33 mL, 2.37 mmol) was added. After stirring at room temperature for 5 minutes, phosphoryl chloride (16.0 μl, 0.17 mmol) was slowly added dropwise, followed by stirring for 12 hours. Pure water (0.7 mL) was added thereto, and the mixture was further stirred for 4 hours. The reaction solution was washed with 1N hydrochloric acid and dichloromethane, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (CH 2 Cl 2 : MeOH = 95: 5). 16.6 mg (35%) of the desired product represented by (6) was obtained.
当該目的生成物のスペクトル等を以下に示す。
1H NMR (CDCl3) δ 2.07 (s, 6H, CH3), 4.89 (d, J = 4.5 Hz, 2H, CH), 5.38 (d, J = 5.1 Hz, 2H, CH), 6.66 (d, J = 8.4 Hz, 2H, Ph), 7.05-7.15 (m, 15H, Ph, Naph), 7.26-7.54 (m, 15H, Ph, Naph), 8.83 (d, J = 7.8 Hz, 2H, Naph), 7.99 (s, 2H, Naph)
MS (ESI, positive) m/z 1097.6 [M+H]+
（第２実施形態）アジリジンの不斉開環反応
次式（１５）は本発明の反応の概要である。この式（１５）のような種々のメソアジリジン類にジメトキシカルシウムと不斉触媒存在下でトリメチルシリルイソチオシアネートを反応させると、高エナンチオ選択的に生成物を与える。式中、R2は、環状アルキル基である。
The spectrum of the target product is shown below.
1 H NMR (CDCl 3 ) δ 2.07 (s, 6H, CH 3 ), 4.89 (d, J = 4.5 Hz, 2H, CH), 5.38 (d, J = 5.1 Hz, 2H, CH), 6.66 (d, J = 8.4 Hz, 2H, Ph), 7.05-7.15 (m, 15H, Ph, Naph), 7.26-7.54 (m, 15H, Ph, Naph), 8.83 (d, J = 7.8 Hz, 2H, Naph), 7.99 (s, 2H, Naph)
MS (ESI, positive) m / z 1097.6 [M + H] +
(Second Embodiment) Asymmetric Ring-Opening Reaction of Aziridine The following formula (15) is an outline of the reaction of the present invention. When various mesoaziridines such as the formula (15) are reacted with trimethoxysilyl isothiocyanate in the presence of asymmetric catalyst with dimethoxycalcium, a product is obtained with high enantioselectivity. In the formula, R 2 is a cyclic alkyl group.
ここで、R1は2-ピリジンスルホニル基が最もよく、トシル基、2-キノリンスルホニル基、チエニル基、ピコリノイル基でも良い。また、用いる不斉触媒は、第１実施形態に記述したｐ−メトキシベンゼンスルホニル基を導入したイミダゾリン−リン酸触媒が最も良い。
（他の実施形態）
用いる触媒はVAPOL由来のキラルブレンステッド酸触媒、または他の光学活性ビナフチルリン酸触媒でもよい。
（参考例１）
本発明の原料として用いる下記化学式で与えられるN-(2-ピリジンスルホニル)シクロヘキサンアジリジンは、次のようにして得られる。
Here, R 1 is most preferably a 2-pyridinesulfonyl group, and may be a tosyl group, a 2-quinolinesulfonyl group, a thienyl group, or a picolinoyl group. The asymmetric catalyst used is best the imidazoline-phosphate catalyst introduced with the p-methoxybenzenesulfonyl group described in the first embodiment.
(Other embodiments)
The catalyst used may be a chiral Bronsted acid catalyst derived from VAPOL or another optically active binaphthyl phosphate catalyst.
(Reference Example 1)
N- (2-pyridinesulfonyl) cyclohexaneaziridine represented by the following chemical formula used as a raw material of the present invention is obtained as follows.
シクロヘキセン由来の無置換のアジリジン(1.47 g, 15.2 mmol)、4-ジメチルアミノピリジン(18.0 mg, 0.152 mmol)、トリエチルアミン(5.30 mL, 38.0 mmol)をTHF 9.0 mLに溶かし、氷浴下2-ピリジンスルホニルクロライド(3.23 g, 18.2 mmol)を加えた。24時間攪拌後水を加え、塩化メチレンで抽出、飽和食塩水で洗浄をし、無水硫酸ナトリウムで乾燥した。精製はシリカゲルカラムクロマトグラフィー (Benzene:AcOEt = 95:5)で行い、目的生成物を2.00 g (55%)で得た。
得られたN-(2-ピリジンスルホニル)シクロヘキサンアジリジンのスペクトル等は次のとおりである。
m.p. 81.5-82.0 °C
1H NMR (CDCl3) δ 1.10-1.52 (m, 4H, CH2), 1.84-1.90 (m, 4H, CH2), 3.23-3.25 (m, 2H, CH), 7.49-7.55 (m, 1H, Py), 7.88-7.97 (m, 1H, Py), 8.07-8.11 (m, 1H, Py), 8.72-8.76 (m, 1H, Py)
13C NMR (CDCl3) δ 19.3, 22.7, 40.5, 122.5, 127.0, 137.9, 150.1, 156.7
IR(KBr) 2946, 1434, 1316, 1172, 1115, 990, 970, 926, 850, 794, 776, 605, 569 cm−1
APCIMS m/z 239.1 [M+H]
（実施例１）
乾燥させたフラスコに光学活性イミダゾリン-リン酸触媒（3.1 mg, 0.00420 mmol）、ジメトキシカルシウム(0.4 mg, 0.00420mmol)をメタノール0.08 mLに溶解させ、室温で1時間攪拌した。減圧下で溶媒を留去し，N-(2-ピリジンスルホニル)シクロヘキサンアジリジン（20.0 mg, 0.0839 mmol）、トルエン1.68 mLを加えた後、トリメチルシリルイソチオシアネート（14.2 μL，0.101 mmol）を加えて室温で反応させた。反応はTLCにて確認後、水を加え、塩化メチレンで抽出、無水硫酸ナトリウムで乾燥させた。減圧下で溶媒を留去後、精製はシリカゲルカラムクロマトグラフィー（Hexane:AcOEt = 50:50）で行い、下式で表わされる開環生成物の2-(2-ピリジンスルホニル)アミノシクロヘキサンチオシアネートを 96 %の収率で得た。
Unsubstituted aziridine derived from cyclohexene (1.47 g, 15.2 mmol), 4-dimethylaminopyridine (18.0 mg, 0.152 mmol) and triethylamine (5.30 mL, 38.0 mmol) are dissolved in 9.0 mL of THF and 2-pyridinesulfonyl in an ice bath. Chloride (3.23 g, 18.2 mmol) was added. After stirring for 24 hours, water was added, extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. Purification was performed by silica gel column chromatography (Benzene: AcOEt = 95: 5) to obtain 2.00 g (55%) of the desired product.
The spectrum of the obtained N- (2-pyridinesulfonyl) cyclohexaneaziridine is as follows.
mp 81.5-82.0 ° C
1 H NMR (CDCl 3 ) δ 1.10-1.52 (m, 4H, CH 2 ), 1.84-1.90 (m, 4H, CH 2 ), 3.23-3.25 (m, 2H, CH), 7.49-7.55 (m, 1H , Py), 7.88-7.97 (m, 1H, Py), 8.07-8.11 (m, 1H, Py), 8.72-8.76 (m, 1H, Py)
13 C NMR (CDCl 3 ) δ 19.3, 22.7, 40.5, 122.5, 127.0, 137.9, 150.1, 156.7
IR (KBr) 2946, 1434, 1316, 1172, 1115, 990, 970, 926, 850, 794, 776, 605, 569 cm -1
APCIMS m / z 239.1 [M + H]
Example 1
In the dried flask, optically active imidazoline-phosphate catalyst (3.1 mg, 0.00420 mmol) and dimethoxycalcium (0.4 mg, 0.00420 mmol) were dissolved in 0.08 mL of methanol and stirred at room temperature for 1 hour. Evaporate the solvent under reduced pressure, add N- (2-pyridinesulfonyl) cyclohexaneaziridine (20.0 mg, 0.0839 mmol) and 1.68 mL of toluene, then add trimethylsilyl isothiocyanate (14.2 μL, 0.101 mmol) at room temperature. Reacted. The reaction was confirmed by TLC, water was added, extracted with methylene chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, purification was performed by silica gel column chromatography (Hexane: AcOEt = 50: 50), and the ring-opening product 2- (2-pyridinesulfonyl) aminocyclohexane thiocyanate represented by the following formula was obtained. % Yield.
得られた2-(2-ピリジンスルホニル)アミノシクロヘキサンチオシアネートのスペクトル等は次のとおりである。
1H NMR (CDCl3) δ 1.26-1.47 (m, 3H, CH2), 1.64-1.78 (m, 3H, CH2), 2.01-2.11 (m, 1H, CH2), 2.30-2.35 (m, 1H, CH2), 3.02-3.11 (m, 1H, CH), 3.37 (s, 1H, CH), 6.12 (s, 1H, NH ), 7.54-7.58 (m, 1H, Py), 7.97 (t, J = 7.7 Hz, 1H, Py), 8.08 (d, J = 7.8 Hz, 1H, Py), 8.76 (d, J = 4.8 Hz, 1H, Py),
ESIMS m/z 319.86 [M+Na, 100]
HPLC (CHIRALPAK(R) OD-H, hexane/i-PrOH=70:30, 1.0 mL/min) tf8.8 (fast), tS 10.6 (slow) min.
（実施例２−１８）
下記反応式（化２４）で示すN-(2-ピリジンスルホニル)-シクロヘキサンアジリジンの代わりに窒素上の置換基を種々変更したメソアジリジンへ種々の不斉触媒を用いた実施例の結果を表１に示す。
The spectrum of the obtained 2- (2-pyridinesulfonyl) aminocyclohexane thiocyanate is as follows.
1 H NMR (CDCl 3 ) δ 1.26-1.47 (m, 3H, CH 2 ), 1.64-1.78 (m, 3H, CH 2 ), 2.01-2.11 (m, 1H, CH 2 ), 2.30-2.35 (m, 1H, CH 2 ), 3.02-3.11 (m, 1H, CH), 3.37 (s, 1H, CH), 6.12 (s, 1H, NH), 7.54-7.58 (m, 1H, Py), 7.97 (t, J = 7.7 Hz, 1H, Py), 8.08 (d, J = 7.8 Hz, 1H, Py), 8.76 (d, J = 4.8 Hz, 1H, Py),
ESIMS m / z 319.86 [M + Na, 100]
HPLC (CHIRALPAK (R) OD-H, hexane / i-PrOH = 70: 30, 1.0 mL / min) t f 8.8 (fast), t S 10.6 (slow) min.
(Example 2-18)
Table 1 shows the results of Examples using various asymmetric catalysts to mesoaziridine in which the substituents on nitrogen were changed in place of N- (2-pyridinesulfonyl) -cyclohexaneaziridine represented by the following reaction formula (Chemical Formula 24). Shown in
表１から、Rとしては、2-ピリジンスルホニル基が最も良く、触媒はｐ−メトキシベンゼンスルホニル基を導入したイミダゾリン−リン酸触媒が最も良い。さらに、モレキュラーシーブス4A (8.4 mg)の添加により反応性が向上し、また、反応温度を下げることにより、エナンチオ選択性が向上する。また、触媒をカルシウム塩の代わりにマグネシウム塩を用いることにより、反対の立体選択性を有する目的生成物が得られる。
（実施例１９−２３）
下式でN-(2-ピリジンスルホニル)-シクロヘキサンアジリジンの代わりに、他のアジリジン類に対するトリメチルシリルイソチオシアネートによる付加開環反応を示す。ここで用いるアジリジン類は、参考例1の合成法に従い、他の無置換のアジリジンと2-ピリジンスルホニルクロライドを反応させ合成した。
From Table 1, as R, 2-pyridinesulfonyl group is the best, and as the catalyst, an imidazoline-phosphate catalyst into which a p-methoxybenzenesulfonyl group is introduced is the best. Furthermore, the reactivity is improved by adding Molecular Sieves 4A (8.4 mg), and the enantioselectivity is improved by lowering the reaction temperature. Moreover, the target product which has the opposite stereoselectivity can be obtained by using a magnesium salt for a catalyst instead of a calcium salt.
(Examples 19-23)
The following formula shows addition ring-opening reaction with trimethylsilylisothiocyanate for other aziridines instead of N- (2-pyridinesulfonyl) -cyclohexaneaziridine. The aziridines used here were synthesized by reacting other unsubstituted aziridines with 2-pyridinesulfonyl chloride according to the synthesis method of Reference Example 1.
以下、上記式で生成した化合物９〜１３について説明する。
化合物９（化学式２６参照）のスペクトルテータ等（実施例１９）
Hereinafter, the compounds 9 to 13 produced by the above formula will be described.
Spectral data of compound 9 (see chemical formula 26), etc. (Example 19)
白色結晶
シリカゲルカラムクロマトグラフィー (Hexane:AcOEt = 50:50)
1H NMR (CDCl3) δ 1.57-1.86 (m, 4H, CH2), 1.73-1.77 (m, 3H, CH2), 2.04-2.10 (m, 1H, CH2), 2.22-2.35 (m, 1H, CH2), 3.40-3.47 (m, 1H, CH), 3.67-3.77 (m, 1H, CH), 6.38 (d, J = 6.6 Hz, 1H, NH ),7.56-7.60 (m, 1H, Py), 7.96-8.02 (m, 1H, Py), 8.12 (d, J = 7.8 Hz, 1H, Py), 8.76 (d, J = 4.2 Hz, 1H, Py),
HPLC (CHIRALPAK(R) OD-H, hexane/i-PrOH=70:30, 0.5 mL/min) tf 18.2 (fast), tS 19.9 (slow) min.
化合物１１（化学式２７参照）のスペクトルテータ等（実施例２１）
White crystalline silica gel column chromatography (Hexane: AcOEt = 50:50)
1 H NMR (CDCl 3 ) δ 1.57-1.86 (m, 4H, CH 2 ), 1.73-1.77 (m, 3H, CH 2 ), 2.04-2.10 (m, 1H, CH 2 ), 2.22-2.35 (m, 1H, CH 2 ), 3.40-3.47 (m, 1H, CH), 3.67-3.77 (m, 1H, CH), 6.38 (d, J = 6.6 Hz, 1H, NH), 7.56-7.60 (m, 1H, Py), 7.96-8.02 (m, 1H, Py), 8.12 (d, J = 7.8 Hz, 1H, Py), 8.76 (d, J = 4.2 Hz, 1H, Py),
HPLC (CHIRALPAK (R) OD-H, hexane / i-PrOH = 70: 30, 0.5 mL / min) t f 18.2 (fast), t S 19.9 (slow) min.
Spectrum data of compound 11 (see chemical formula 27), etc. (Example 21)
白色結晶
シリカゲルカラムクロマトグラフィー (Hexane:AcOEt = 60:40)
1H NMR (CDCl3) δ 1.55-2.25 (m, 10H, CH2), 3.32-3.39 (m, 1H, CH), 3.59-3.63 (m, 1H, CH), 5.54 (d, J = 7.5 Hz, 1H, NH ),7.52-7.56 (m, 1H, Py), 7.96 (t, J = 6.9 Hz, 1H, Py), 8.06 (d, J = 7.8 Hz, 1H, Py), 8.75 (d, J = 3.6 Hz, 1H, Py),
HPLC (CHIRALPAK(R) OD-H, hexane/i-PrOH=70:30, 0.5 mL/min) tf 21.0 (fast), tS 30.3 (slow) min.
化合物１２（化学式２８参照）のスペクトルテータ等（実施例２２）
White crystalline silica gel column chromatography (Hexane: AcOEt = 60:40)
1 H NMR (CDCl 3 ) δ 1.55-2.25 (m, 10H, CH 2 ), 3.32-3.39 (m, 1H, CH), 3.59-3.63 (m, 1H, CH), 5.54 (d, J = 7.5 Hz , 1H, NH), 7.52-7.56 (m, 1H, Py), 7.96 (t, J = 6.9 Hz, 1H, Py), 8.06 (d, J = 7.8 Hz, 1H, Py), 8.75 (d, J = 3.6 Hz, 1H, Py),
HPLC (CHIRALPAK (R) OD-H, hexane / i-PrOH = 70: 30, 0.5 mL / min) t f 21.0 (fast), t S 30.3 (slow) min.
Spectrum data of compound 12 (see chemical formula 28), etc. (Example 22)
白色結晶
1H NMR (CDCl3) δ 2.11-2.19 (m, 1H, CH2), 2.36-2.56 (m, 2H, CH2), 2.81-2.89 (m, 1H, CH2), 3.58-3.65 (m, 1H, CH), 3.72-3.79 (m, 1H, CH), 5.56-5.65 (m, 2H, CH), 5.83 (s,1H, NH ),7.56 (t, J = 6.2 Hz, 1H, Py), 7.97 (t, J = 7.7 Hz, 1H, Py), 8.07 (d, J = 7.8 Hz, 1H, Py), 8.76 (d, J = 4.5 Hz, 1H, Py),
HPLC (CHIRALPAK(R) OD-H, hexane/i-PrOH=70:30, 0.5 mL/min) tf 20.9 (fast), tS 24.5 (slow) min.
化合物１３（化学式２９参照）のスペクトルテータ等（実施例２３）
White crystals
1 H NMR (CDCl 3 ) δ 2.11-2.19 (m, 1H, CH 2 ), 2.36-2.56 (m, 2H, CH 2 ), 2.81-2.89 (m, 1H, CH 2 ), 3.58-3.65 (m, 1H, CH), 3.72-3.79 (m, 1H, CH), 5.56-5.65 (m, 2H, CH), 5.83 (s, 1H, NH), 7.56 (t, J = 6.2 Hz, 1H, Py), 7.97 (t, J = 7.7 Hz, 1H, Py), 8.07 (d, J = 7.8 Hz, 1H, Py), 8.76 (d, J = 4.5 Hz, 1H, Py),
HPLC (CHIRALPAK (R) OD-H, hexane / i-PrOH = 70: 30, 0.5 mL / min) t f 20.9 (fast), t S 24.5 (slow) min.
Spectrum data of compound 13 (see chemical formula 29), etc. (Example 23)
白色結晶
1H NMR (CDCl3) δ 2.86-2.94 (m, 1H, CH2), 3.06-3.27 (m, 2H, CH2), 3.51-3.59 (m, 1H, CH2), 3.76-3.94 (m, 2H, CH), 6.22 (s, 1H, NH), 6.98-7.23 (m, 4H, Ph), 7.52-7.56 (m, 1H, Py), 7.93-7.99 (m, 1H, Py), 8.05-8.08 (m, 1H, Py), 8.66-8.68 (m, 1H, Py),
HPLC (CHIRALPAK(R) OJ-H, hexane/i-PrOH=70:30, 1.0 mL/min) tf 21.3 (fast), tS 28.0 (slow) min.
（実施例２４）
表２の実施例２０で得られた生成物を出発物質として下式により光学活性アミノチオールが合成できる。
White crystals
1 H NMR (CDCl 3 ) δ 2.86-2.94 (m, 1H, CH 2 ), 3.06-3.27 (m, 2H, CH 2 ), 3.51-3.59 (m, 1H, CH 2 ), 3.76-3.94 (m, 2H, CH), 6.22 (s, 1H, NH), 6.98-7.23 (m, 4H, Ph), 7.52-7.56 (m, 1H, Py), 7.93-7.99 (m, 1H, Py), 8.05-8.08 (m, 1H, Py), 8.66-8.68 (m, 1H, Py),
HPLC (CHIRALPAK (R) OJ-H, hexane / i-PrOH = 70: 30, 1.0 mL / min) t f 21.3 (fast), t S 28.0 (slow) min.
(Example 24)
Using the product obtained in Example 20 of Table 2 as a starting material, an optically active aminothiol can be synthesized according to the following formula.
水素化リチウムアルミニウム（10mg, 0.28 mmol）のジエチルエーテル（0.4 mL）溶液に、イソチオシアネート（29mg, 0.10 mmol）のジエチルエーテル、ベンゼン１：１溶液（0.8 mL）をゆっくり滴下した。その後2時間攪拌した後、氷浴下で6規定塩酸を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過を行った後、減圧下で溶媒を留去した後シリカゲルカラムクロマトグラフィーにより精製を行うことで、目的生成物を35％収率で得た。 A solution of isothiocyanate (29 mg, 0.10 mmol) in diethyl ether and benzene 1: 1 (0.8 mL) was slowly added dropwise to a solution of lithium aluminum hydride (10 mg, 0.28 mmol) in diethyl ether (0.4 mL). After stirring for 2 hours, 6N hydrochloric acid was added in an ice bath, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography to obtain the desired product in 35% yield.
表２の実施例２０で得られた生成物を出発物質として下式によりアミノスルホン酸が合成できる。
Aminosulfonic acid can be synthesized by the following formula using the product obtained in Example 20 of Table 2 as a starting material.
マグネシウム (184 mg、 7.58 mmol) を減圧下、加熱することで活性化させ、メタノール7.0 mLを加え、氷浴下で冷却し、メタノール5.6 mLに溶かしたイソチオシアネート (150 mg、 0.505 mmol) を加え、0℃で反応させた。2時間攪拌後、飽和塩化アンモニウム水溶液を加え、塩化メチレンで抽出、無水硫酸ナトリウムで乾燥させ、減圧下で溶媒を留去し、目的生成物14を81.1 mg (99%) で得た。
次に、14 (27.9 mg、 0.179 mmol) にアセトニトリル3.58 mL、 二炭酸ジ-tert-ブチル (45.3 μL、 0.197 mmol) 、4-ジメチルアミノピリジン (2.2 mg、 0.0179 mmol)、 トリエチルアミン (37.7 μL、 0.269 mmol) を加え、室温で反応させた。4時間攪拌後、減圧下で溶媒を留去し、シリカゲルカラムクロマトグラフィー(Hexane:AcOEt = 80:20) により精製を行うことで、目的生成物15を15.7 mg (34%) で得た。
次に、15 (22.9 mg、 0.0894 mmol) にギ酸3.2 mL、50%過酸化水素水溶液0.053 mLを加え、室温で反応させた。15時間攪拌後、水を加え、ジエチルエーテル、塩化メチレンで洗浄し、減圧下で水相の水を留去させた。精製はメタノールとジエチルエーテルによる再沈殿で行い、目的生成物であるアミノスルホン酸を13.1 mg (82%) で得た。
Magnesium (184 mg, 7.58 mmol) was activated by heating under reduced pressure, 7.0 mL of methanol was added, cooled in an ice bath, and isothiocyanate (150 mg, 0.505 mmol) dissolved in 5.6 mL of methanol was added. , Reacted at 0 ° C. After stirring for 2 hours, saturated aqueous ammonium chloride solution was added, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 81.1 mg (99%) of the desired product 14.
Next, 14 (27.9 mg, 0.179 mmol) to 3.58 mL of acetonitrile, di-tert-butyl dicarbonate (45.3 μL, 0.197 mmol), 4-dimethylaminopyridine (2.2 mg, 0.0179 mmol), triethylamine (37.7 μL, 0.269 mmol) was added and allowed to react at room temperature. After stirring for 4 hours, the solvent was distilled off under reduced pressure, and purification was performed by silica gel column chromatography (Hexane: AcOEt = 80: 20) to obtain 15.7 mg (34%) of the desired product 15.
Next, 3.2 mL of formic acid and 0.053 mL of 50% aqueous hydrogen peroxide solution were added to 15 (22.9 mg, 0.0894 mmol), and reacted at room temperature. After stirring for 15 hours, water was added, the mixture was washed with diethyl ether and methylene chloride, and water in the aqueous phase was distilled off under reduced pressure. Purification was performed by reprecipitation with methanol and diethyl ether to obtain 13.1 mg (82%) of the target product, aminosulfonic acid.
Claims (7)
で示されるイミダゾリン−リン酸触媒。 The following formula (1)
An imidazoline-phosphate catalyst represented by
で示されるイミダゾリン−リン酸触媒。 The following formula (2)
An imidazoline-phosphate catalyst represented by
で示されるイミダゾリン−リン酸触媒。 The following formula (3)
An imidazoline-phosphate catalyst represented by
で示されるイミダゾリン−リン酸触媒。 The following formula (4)
An imidazoline-phosphate catalyst represented by
で示されるイミダゾリン−リン酸触媒。 Formula (5)
An imidazoline-phosphate catalyst represented by
で示されるイミダゾリン−リン酸触媒。 Formula (6)
An imidazoline-phosphate catalyst represented by
（式中、R2は、環状アルキル基である。ここで、R1はトシル基、2-ピリジンスルホニル基、2-キノリンスルホニル基、チエニル基、ピコリノイル基のいずれか一つであり、また、前記触媒は、光学活性イミダゾリン-リン酸触媒または、他のキラルブレンステッド酸触媒である。）
Asymmetric cleavage of aziridine by reacting mesoaziridines with trimethylsilylisothiocyanate by the reaction of the following formula (7) in the presence of any one of the asymmetric catalysts according to claim 1 and dimethoxycalcium: A method for producing β-aminothiol and β-aminosulfonic acid derivatives by a ring reaction.
(Wherein R 2 is a cyclic alkyl group, wherein R 1 is any one of a tosyl group, a 2-pyridinesulfonyl group, a 2-quinolinesulfonyl group, a thienyl group, and a picolinoyl group, and The catalyst is an optically active imidazoline-phosphate catalyst or other chiral Bronsted acid catalyst.)
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| CN105753752A (en) * | 2016-04-15 | 2016-07-13 | 安徽师范大学 | Chiral vicinal diamine compound and method for preparing same |
| KR20160132536A (en) * | 2015-05-11 | 2016-11-21 | 한국화학연구원 | Novel chiral resolving agent and Method for optically resolving preparation of (RS)-Bepotastine using thereof |
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| KR20160132536A (en) * | 2015-05-11 | 2016-11-21 | 한국화학연구원 | Novel chiral resolving agent and Method for optically resolving preparation of (RS)-Bepotastine using thereof |
| KR101717599B1 (en) * | 2015-05-11 | 2017-03-17 | 한국화학연구원 | Novel chiral resolving agent and Method for optically resolving preparation of (RS)-Bepotastine using thereof |
| CN105753752A (en) * | 2016-04-15 | 2016-07-13 | 安徽师范大学 | Chiral vicinal diamine compound and method for preparing same |
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