JP2005255660A - Polyfunctional group-containing lactams and method for producing the same - Google Patents
Polyfunctional group-containing lactams and method for producing the same Download PDFInfo
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Abstract
Description
本発明は、ラクタム類およびその製造方法に関する。The present invention relates to lactams and a method for producing the same.
ラクタム類の合成については、これまでにいくつかの手法が開発されてきた。それらはアミドとスルフィンイミンとの環化によるもの(例えば、非特許文献1参照。)、もしくはイミニウムカチオンの分子内環化によるもの(例えば、非特許文献2参照。)等である。 Several methods have been developed for the synthesis of lactams. They are those by cyclization of amide and sulfinimine (for example, see Non-patent Document 1), or by intramolecular cyclization of an iminium cation (for example, see Non-Patent Document 2).
しかしながら、上述した従来のラクタムの製造方法では、医農薬品でみられる多様な官能基を導入したラクタム類を合成するには多段階な合成ステップを経なければならないなどの問題がある。However, the conventional lactam production method described above has a problem that a multi-step synthesis step is required to synthesize lactams having various functional groups found in medical and agricultural chemicals.
本発明は、このような課題に鑑みてなされたものであり、新規な医農薬品となり得るラクタム類およびその簡便な製造方法を提供することを目的とする。 This invention is made | formed in view of such a subject, and it aims at providing the lactams which can become a novel medical agrochemical product, and its simple manufacturing method.
本発明者らは、研究の結果、5員環ラクタム類に強塩基を作用させることにより、多様な置換基を持つδ−ラクタム類または[3.3.0]−ラクタム類が得られることを見い出した。As a result of research, the present inventors have found that δ-lactams or [3.3.0] -lactams having various substituents can be obtained by allowing a strong base to act on 5-membered lactams. I found it.
以下、δ−ラクタム類、[3.3.0]−ラクタム類およびその製造方法に関わる発明の実施の形態について説明する。
アリール基としては、例えばフェニル基、トリチル基、ナフチル基、p−メトキシフェニル基、o−メトキシフェニル基、p−メチルフェニル基、o−メチルフェニル基などが挙げられる。
アルケニル基としては、ビニル基、1−プロペニル基、2−プロペニル基などが挙げられる。
アルキニル基としては、プロパルギル基、1−フェニルプロパルギル基、3−メチルプロパルギル基、1−トリメチルシリルプロパルギル基などが挙げられる。複素環基としては、ピリジニル基、フラニル基、チオフェニル基、ピロリル基などが挙げられる。
R1とR2が互いに結合して形成する環としては、シクロヘキセン、シクロペンテン、ジヒドロピラン等が挙げられる。
R11とR12が互いに結合して形成する環としては、シクロヘキセン、シクロペンテン、ジヒドロピラン等が挙げられる。
R5とR6が互いに独立して、強塩基に対し安定な置換基としては、ジメチル−t−ブチルシロキシ基などが挙げられる。
R5とR6が互いに結合して形成する環としては、フェニル基、メトキシフェニル基、ピリジニル基、フラニル基などが挙げられる。
R15とR16が互いに独立して、強塩基に対し安定な置換基としては、ジメチル−t−ブチルシロキシ基などが挙げられる。
R15とR16が互いに結合して形成する環としては、フェニル基、メトキシフェニル基、ピリジニル基、フラニル基などが挙げられる。
強塩基に対して安定な置換基としては、メチル基、エチル基、プロピル基、アリル基、フェニル基、メトキシ基、シアノ基、エチニル基、エチニルフェニル基、エチニルトリメチルシリル基、トリメチルシリル基、ヒドロキシプロピル基などが挙げられる。
アシル基としては、アセチル基、ベンゾイル基などが挙げられる。
アルキル基としては、メチル基、エチル基、プロピル基、ブチル基などが挙げられる。Hereinafter, embodiments of the invention relating to δ-lactams, [3.3.0] -lactams and methods for producing the same will be described.
Examples of the aryl group include a phenyl group, a trityl group, a naphthyl group, a p-methoxyphenyl group, an o-methoxyphenyl group, a p-methylphenyl group, and an o-methylphenyl group.
Examples of the alkenyl group include a vinyl group, 1-propenyl group, and 2-propenyl group.
Examples of the alkynyl group include a propargyl group, a 1-phenylpropargyl group, a 3-methylpropargyl group, and a 1-trimethylsilylpropargyl group. Examples of the heterocyclic group include a pyridinyl group, a furanyl group, a thiophenyl group, and a pyrrolyl group.
Examples of the ring formed by combining R 1 and R 2 with each other include cyclohexene, cyclopentene, dihydropyran and the like.
Examples of the ring formed by combining R 11 and R 12 with each other include cyclohexene, cyclopentene, dihydropyran and the like.
Examples of the substituent that R 5 and R 6 are independent of each other and are stable against a strong base include a dimethyl-t-butylsiloxy group.
Examples of the ring formed by combining R 5 and R 6 with each other include a phenyl group, a methoxyphenyl group, a pyridinyl group, and a furanyl group.
Examples of the substituent that R 15 and R 16 are independent of each other and are stable against a strong base include a dimethyl-t-butylsiloxy group.
Examples of the ring formed by combining R 15 and R 16 with each other include a phenyl group, a methoxyphenyl group, a pyridinyl group, and a furanyl group.
Substituents that are stable against strong bases include methyl, ethyl, propyl, allyl, phenyl, methoxy, cyano, ethynyl, ethynylphenyl, ethynyltrimethylsilyl, trimethylsilyl, hydroxypropyl Etc.
Examples of the acyl group include an acetyl group and a benzoyl group.
Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, and a butyl group.
本反応におけるラクタム類の製法は2つある。
1つは化9に示す反応である。There are two methods for producing lactams in this reaction.
One is the reaction shown in Chemical Formula 9.
もう1つは化10に示す反応である。 The other is the reaction shown in Chemical Formula 10.
ここで、LDAはリチウムジイソプロピルアミドである。使用する反応剤は、このLDAに限定されない。このほか、LTMP(リチウムテトラメチルピペリジド)、NaH、KH、LiHなどを使用することができる。
RLiとしては、n−BuLi、s−BuLi、t−BuLi、PhLi、MeLi、i−PrLi、n−HexLi等が挙げられる。
強塩基の使用量は、基質に対して、1〜10当量、好ましくは、1〜2当量である。E+としては、重水、ホルムアルデヒド、クロロギ酸メチル、ヨウ化メチル、ジョードエタン、ベンズアルデヒド、トリメチルシリルクロライド等が挙げられる。
反応溶媒としては、テトラヒドロフラン、ジエチルエーテル等のエーテル類、ジメチルアミド等のアミド類、ヘキサン、トルエン等が挙げられる。
反応溶媒の使用量は基質に対して、0〜10000倍である。
反応温度は、−78℃から溶媒の沸点、好ましくは、−78℃から室温である。Here, LDA is lithium diisopropylamide. The reactant used is not limited to this LDA. In addition, LTMP (lithium tetramethylpiperidide), NaH, KH, LiH, etc. can be used.
Examples of RLi include n-BuLi, s-BuLi, t-BuLi, PhLi, MeLi, i-PrLi, and n-HexLi.
The usage-amount of a strong base is 1-10 equivalent with respect to a substrate, Preferably, it is 1-2 equivalent. Examples of E + include heavy water, formaldehyde, methyl chloroformate, methyl iodide, jodoethane, benzaldehyde, and trimethylsilyl chloride.
Examples of the reaction solvent include ethers such as tetrahydrofuran and diethyl ether, amides such as dimethylamide, hexane, toluene and the like.
The amount of reaction solvent used is 0 to 10,000 times the substrate.
The reaction temperature is from -78 ° C to the boiling point of the solvent, preferably from -78 ° C to room temperature.
以上のことから、本実施の形態によれば、反応式化9〜10からなる方法を用いることにより、新規なラクタムおよびその製造方法を提供することができる。また、多官能基化された新規なラクタムを立体選択的に合成できる。また、医薬、農薬、各種機能性物質の開発に貢献し得る。また、そのもの自体が新規な医薬品や高機能性材料となり得る。 From the above, according to this embodiment, a novel lactam and a method for producing the same can be provided by using the method consisting of reaction formulas 9 to 10. In addition, a novel polyfunctionalized lactam can be synthesized stereoselectively. It can also contribute to the development of pharmaceuticals, agricultural chemicals and various functional substances. In addition, the product itself can be a new drug or a highly functional material.
なお、本発明は上述の実施の形態に限らず本発明の要旨を逸脱することなくその他種々の構成をとり得ることはもちろんである。 Of course, the present invention is not limited to the above-described embodiment, and various other configurations can be adopted without departing from the gist of the present invention.
つぎに、本発明にかかる実施例について具体的に説明する。ただし、本発明はこれら実施例に限定されるものではないことはもちろんである。
(試験1)δ−ラクタム類の合成(化11)
アルゴン雰囲気下、リチウムジイソプロピルアミド(0.91mmol)のTHF(5ml)溶液に−78℃下、2−ベンジル−3−メチル−3−フェニルエチニル−2,3−ジヒドロ−イソインド−1−オン(1)のTHF溶液(3ml)を加えた。−78℃で100分攪拌した後、pH7のリン酸緩衝液2mlで反応を停止した後、酢酸エチルで抽出し、油層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去後、シリカゲルクロマトグラフィー(溶出液−ヘキサン:酢酸エチル=1:1)で精製し、4−メチル−3−フェニル−4−フェニルエチニル−3,4−ジヒドロ−イソキノリン−1−オン(2)68.2mg(収率84%)、(ジアステレオマー比=82:18),(R1=フェニル,R2=水素,R3=エチニルベンゼン,R4=メチル,R5、R6=フェニル)を得た。4−メチル−3−フェニル−4−フェニルエチニル−3,4−ジヒドロ−イソキノリン−1−オン(化11)の物性データは
1H NMR(300MHz,CDCl3)δ(major)8.17−8.14(m,1H),7.91−7.88(m,1H),7.64−7.56(m,3H),7.48−7.40(m,6H),7.35−7.30(m,3H),6.27(brs,1H),5.14(s,1H),1.44(s,3H).(minor)6.55(d,J=2.1HZ,1H),4.70(d,J=2.7HZ,1H),1.78(s,3H);13C NMR(75MHz,CDCl3)δ(major)166.00,144.19,136.35,133.16,131.45,128.79,128.52,128.31,128.28,128.25,128.13,127.97,127.68,126.40,122.71,90.97,86.10,63.30,42.33,23.86.Next, specific examples of the present invention will be described. However, it goes without saying that the present invention is not limited to these examples.
(Test 1) Synthesis of δ-lactams (Chemical Formula 11)
Under an argon atmosphere, a solution of lithium diisopropylamide (0.91 mmol) in THF (5 ml) at −78 ° C. under 2-benzyl-3-methyl-3-phenylethynyl-2,3-dihydro-isoindo-1-one (1 ) In THF (3 ml) was added. After stirring at −78 ° C. for 100 minutes, the reaction was stopped with 2 ml of pH 7 phosphate buffer, followed by extraction with ethyl acetate, and the oil layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (eluent-hexane: ethyl acetate = 1: 1), and 4-methyl-3-phenyl-4-phenylethynyl-3,4-dihydro-isoquinolin-1-one. (2) 68.2 mg (84% yield), (diastereomeric ratio = 82: 18), (R 1 = phenyl, R 2 = hydrogen, R 3 = ethynylbenzene, R 4 = methyl, R 5 , R 6 = phenyl). The physical property data of 4-methyl-3-phenyl-4-phenylethynyl-3,4-dihydro-isoquinolin-1-one (Chemical Formula 11) is
1 H NMR (300 MHz, CDCl 3 ) δ (major) 8.17-8.14 (m, 1H), 7.91-7.88 (m, 1H), 7.64-7.56 (m, 3H ), 7.48-7.40 (m, 6H), 7.35-7.30 (m, 3H), 6.27 (brs, 1H), 5.14 (s, 1H), 1.44 ( s, 3H). (Minor) 6.55 (d, J = 2.1 HZ, 1 H), 4.70 (d, J = 2.7 HZ, 1 H), 1.78 (s, 3 H); 13 C NMR (75 MHz, CDCl 3 ) Δ (major) 166.00, 144.19, 136.35, 133.16, 131.45, 128.79, 128.52, 128.31, 128.28, 128.25, 128.13, 127 97, 127.68, 126.40, 122.71, 90.97, 86.10, 63.30, 42.33, 23.86.
同様にして2−ベンジル−3−メチル−3−フェニルエチニル−2,3−ジヒドロ−イソインド−1−オンを2−ベンジル−3−オキソ−1−フェニルエチニル−2,3−ジヒドロ−イソインドロン−1−カルボニトリル44.6mg(0.13mmol)とすることによって、1−オキソ−3−フェニル−4−フェニルエチニル−1,2,3,4−テトラハイドロ−イソキノリン−4−カルボニトリル(化12)を収率94%(ジアステレオマー比=6:4)で得た。1−オキソ−3−フェニル−4−フェニルエチニル−1,2,3,4−テトラハイドロ−イソキノリン−4−カルボニトリルの物性データは、
1H NMR(300MHz,CDCl3)δ(major)8.24−8.22(m,1H),7.97−7.94(m,1H),7.72−7.53(m,6H),7.51−7.27(m,6H),6.50(brs,1H),5.06(s,1H).(minor)8.22−8.20(m,1H),7.83−7.81(m,1H),7.97−7.94(m,1H),7.72−7.53(m,6H),7.51−7.27(m,6H),6.49(brs,1H),5.20(s,1H).Similarly, 2-benzyl-3-methyl-3-phenylethynyl-2,3-dihydro-isoindo-1-one is converted to 2-benzyl-3-oxo-1-phenylethynyl-2,3-dihydro-isoindolone-1 1-oxo-3-phenyl-4-phenylethynyl-1,2,3,4-tetrahydro-isoquinoline-4-carbonitrile (Chemical Formula 12) by making 44.6 mg (0.13 mmol) of carbonitrile Was obtained in a yield of 94% (diastereomer ratio = 6: 4). Physical property data of 1-oxo-3-phenyl-4-phenylethynyl-1,2,3,4-tetrahydro-isoquinoline-4-carbonitrile is
1 H NMR (300 MHz, CDCl 3 ) δ (major) 8.24-8.22 (m, 1H), 7.97-7.94 (m, 1H), 7.72-7.53 (m, 6H) ), 7.51-7.27 (m, 6H), 6.50 (brs, 1H), 5.06 (s, 1H). (Minor) 8.22-8.20 (m, 1H), 7.83-7.81 (m, 1H), 7.97-7.94 (m, 1H), 7.72-7.53 ( m, 6H), 7.51-7.27 (m, 6H), 6.49 (brs, 1H), 5.20 (s, 1H).
同様にして3−メトキシ−3−フェニル−2−(1−フェニル−エチル)−2,3−ジヒドロ−イソインド−1−オン105.6mg(0.31mmol)とすることによって、4−メトキシ−3−メチル−3,4−ジフェニル−3,4−ジヒドロ−イソキノリン−1−オンを収率80%(ジアステレオマー比=64:36)で得た。4−メトキシ−3−メチル−3,4−ジフェニル−3,4−ジヒドロ−イソキノリン−1−オン(化13)の物性データは、
1H NMR(300MHz,CDCl3)δ(major)8.38−8.34(m,1H),7.57−7.49(m,2H),7.39−6.92(m,10H),6.25(brs,1H),2.78(s,3H),1.76(s,3H).δ(b)2.67(s,3H),1.59(s,3H).;13C NMR(75MHz,CDCl3)δ(major)164.58,141.36,139.60,136.65,134.19,130.89,130.39,128.87,128.67,128.60,128.52,127.79,126.99,126.49,125.51,109.75,65.46,52.23,22.78.In the same manner, by making 105.6 mg (0.31 mmol) of 3-methoxy-3-phenyl-2- (1-phenyl-ethyl) -2,3-dihydro-isoindo-1-one, 4-methoxy-3 -Methyl-3,4-diphenyl-3,4-dihydro-isoquinolin-1-one was obtained in a yield of 80% (diastereomer ratio = 64: 36). The physical property data of 4-methoxy-3-methyl-3,4-diphenyl-3,4-dihydro-isoquinolin-1-one (Chemical Formula 13) is
1 H NMR (300 MHz, CDCl 3 ) δ (major) 8.38-8.34 (m, 1H), 7.57-7.49 (m, 2H), 7.39-6.92 (m, 10H) ), 6.25 (brs, 1H), 2.78 (s, 3H), 1.76 (s, 3H). δ (b) 2.67 (s, 3H), 1.59 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ (major) 164.58, 141.36, 139.60, 136.65, 134.19, 130.89, 130.39, 128.87, 128.67, 128.60, 128.52, 127.79, 126.99, 126.49, 125.51, 109.75, 65.46, 52.23, 22.78.
同様にして3−アリル−3−フェニル−2−(1−フェニル−エチル)−2,3−ジヒドロ−イソインド−1−オン230.7mg(0.66mmol)とすることによって、4−アリル−3−メチル−3,4−ジフェニル−3,4−ジヒドロ−イソキノリン−1−オンを収率88%(ジアステレオマー比=58:42)で得た。4−アリル−3−メチル−3,4−ジフェニル−3,4−ジヒドロ−イソキノリン−1−オン(化14)の物性データは、
1H NMR(300MHz,CDCl3)δ(major)8.35−8.28(m,1H),7.45−7.22(m,10H),7.10−6.80(m,3H),5.41−5.27(m,1H),4.70(dd,J=10.2,0.9Hz,1H),4.54(dd,J=16.8,1.5Hz,1H),2.82−2.68(m,2H),1.60(s,3H).(minor)8.30−8.27(m,1H),7.40−6.90(m,11H),6.80(brs,1H),6.57−6.54(m,1H),6.33(brs,1H),5.53−5.39(m,1H),4.81−4.73(m,2H),3.42(dd,J=14.7,6.0Hz,1H),2.98(dd,J=14.7,7.8Hz,1H),1.78(s,3H);13C NMR(75MHz,CDCl3)δ(major)165.87,142.91,140.36,137.03,133.78,131.02,130.92,128.38,127.85,127.78,127.69,127.44,127.00,126.91,126.71,126.46,118.39,65.29,56.46,39.81,27.74.(minor)165.60,143.18,142.43,137.61,134.22,131.21,130.21,128.97,128.39,128.16,127.81,127.45,127.00,126.98,126.91,126.63,118.06,64.15,56.48,40.00,24.93.Similarly, 3-allyl-3-phenyl-2- (1-phenyl-ethyl) -2,3-dihydro-isoindo-1-one was obtained as 230.7 mg (0.66 mmol) to give 4-allyl-3. -Methyl-3,4-diphenyl-3,4-dihydro-isoquinolin-1-one was obtained in a yield of 88% (diastereomer ratio = 58: 42). Physical property data of 4-allyl-3-methyl-3,4-diphenyl-3,4-dihydro-isoquinolin-1-one (Chemical Formula 14) is
1 H NMR (300 MHz, CDCl 3 ) δ (major) 8.35-8.28 (m, 1H), 7.45-7.22 (m, 10H), 7.10-6.80 (m, 3H) ), 5.41-5.27 (m, 1H), 4.70 (dd, J = 10.2, 0.9 Hz, 1H), 4.54 (dd, J = 16.8, 1.5 Hz, 1H), 2.82-2.68 (m, 2H), 1.60 (s, 3H). (Minor) 8.30-8.27 (m, 1H), 7.40-6.90 (m, 11H), 6.80 (brs, 1H), 6.57-6.54 (m, 1H) , 6.33 (brs, 1H), 5.53-5.39 (m, 1H), 4.81-4.73 (m, 2H), 3.42 (dd, J = 14.7, 6. 0 Hz, 1H), 2.98 (dd, J = 14.7, 7.8 Hz, 1H), 1.78 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ (major) 165.87, 142.91, 140.36, 137.03, 133.78, 131.02, 130.92, 128.38, 127.85, 127.78, 127.69, 127.44, 127.00, 126. 91, 126.71, 126.46, 118.39, 65.29, 56.46 , 39.81, 27.74. (Minor) 165.60, 143.18, 142.43, 137.61, 134.22, 131.21, 130.21, 128.97, 128.39, 128.16, 127.81, 127.45 , 127.00, 126.98, 126.91, 126.63, 118.06, 64.15, 56.48, 40.00, 24.93.
同様にして3−エチニル−3−メトキシ−2−(1−フェニル−エチル)−2,3−ジヒドロ−イソインド−1−オン58.7mg(0.20mmol)とすることによって、4−エチニル−4−メトキシ−3−メチル−3−フェニル−3,4−ジヒドロ−イソキノリン−1−オンを収率93%(ジアステレオマー比=63:37)で得た。4−エチニル−4−メトキシ−3−メチル−3−フェニル−3,4−ジヒドロ−イソキノリン−1−オン(化15)の物性データは、
1H NMR(300MHz,CDCl3)δ(a)8.18(dd,J=9.0,1.5Hz,1H),7.72−7.69(m,2H),7.61−7.37(m,5H),7.13−7.11(m,1H),6.29(brs,1H),2.90(s,3H),2.78(s,1H),1.75(s,1H).δ(b)8.11(d,J=7.5Hz,1H),7.80(dd,J=7.5,1.5Hz,2H),7.61−7.37(m,5H),7.13−7.11(m,1H),6.43(brs,1H),3.03(s,3H),2.90(s,1H),1.99(s,3H).;13C NMR(75MHz,CDCl3)δ(major)164.05,139.72,135.67,131.66,129.42,128.68,128.40,128.23,128.08,127.48,127.33,79.80,78.66,64.41,52.24,26.15.In the same manner, 4-ethynyl-4 was obtained by using 58.7 mg (0.20 mmol) of 3-ethynyl-3-methoxy-2- (1-phenyl-ethyl) -2,3-dihydro-isoindo-1-one. -Methoxy-3-methyl-3-phenyl-3,4-dihydro-isoquinolin-1-one was obtained in a yield of 93% (diastereomer ratio = 63: 37). The physical property data of 4-ethynyl-4-methoxy-3-methyl-3-phenyl-3,4-dihydro-isoquinolin-1-one (Chemical Formula 15) is
1 H NMR (300 MHz, CDCl 3 ) δ (a) 8.18 (dd, J = 9.0, 1.5 Hz, 1H), 7.72-7.69 (m, 2H), 7.61-7 .37 (m, 5H), 7.13-7.11 (m, 1H), 6.29 (brs, 1H), 2.90 (s, 3H), 2.78 (s, 1H), 1. 75 (s, 1H). δ (b) 8.11 (d, J = 7.5 Hz, 1H), 7.80 (dd, J = 7.5, 1.5 Hz, 2H), 7.61-7.37 (m, 5H) 7.13-7.11 (m, 1H), 6.43 (brs, 1H), 3.03 (s, 3H), 2.90 (s, 1H), 1.99 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ (major) 164.05, 139.72, 135.67, 131.66, 129.42, 128.68, 128.40, 128.23, 128.08, 127.48, 127.33, 79.80, 78.66, 64.41, 52.24, 26.15.
同様にして2−シクロヘ−2−セニル−3−メチル−3−フェニルエチニル−2,3−ジヒドロ−イソインド−1−オン118mg(0.36mmol)とすることによって、δ−ラクタムのスピロ環化合物を収率90%(ジアステレオマー比=92:8)で得た。δ−ラクタムのスピロ環化合物(化16)の物性データは、
1H NMR(300MHz,CDCl3)δ(major)8.05−8.03(m,1H),7.81−7.79(m,1H),7.58−7.53(m,1H),7.46−7.36(m,3H),7.33−7.31(m,3H),6.20−6.14(m,2H),5.96(m,1H),2.24−1.95(m,4H),1.80−1.63(m,2H),1.72(s,3H);13C NMR(75MHz,CDCl3)δ(major)164.22,143.32,135.01,132.97,131.53,128.25,128.21,128.16,127.96,127.38,126.48,126.03,125.38,123.01,90.78,86.06,58.21,45.46,32.88,25.99,25.16,18.77.In the same manner, 118 mg (0.36 mmol) of 2-cyclohex-2-cenyl-3-methyl-3-phenylethynyl-2,3-dihydro-isoindo-1-one was used to obtain the spirocyclic compound of δ-lactam. The yield was 90% (diastereomer ratio = 92: 8). Physical property data of the spiro ring compound of δ-lactam (Chemical Formula 16)
1 H NMR (300 MHz, CDCl 3 ) δ (major) 8.05-8.03 (m, 1H), 7.81-7.79 (m, 1H), 7.58-7.53 (m, 1H) ), 7.46-7.36 (m, 3H), 7.33-7.31 (m, 3H), 6.20-6.14 (m, 2H), 5.96 (m, 1H), 2.24-1.95 (m, 4H), 1.80-1.63 (m, 2H), 1.72 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ (major) 164. 22, 143.32, 135.01, 132.97, 131.53, 128.25, 128.21, 128.16, 127.96, 127.38, 126.48, 126.03, 125.38, 123.01, 90.78, 86.06, 58.21, 45.46, 32.88 , 25.99, 25.16, 18.77.
(試験2)[3.3.0]−ラクタム類の合成(化17)
アルゴン雰囲気下、リチウムテトラメチルピペリジド1.25mmolのTHF(10ml)溶液に−78℃下、(3R、4R)−1−ベンジル−3,4−ビス−(t−ブチル−ジメチル−シラニルオキシ)−5−メチル−5−フェニルエチニル−ピロリジン−2−オン(3)137.4mg(0.25mmol),(R11=フェニル,R12=水素,R13=フェニル,R14=メチル,R15=t−ブチル−ジメチルシロキシ、R16=t−ブチル−ジメチルシロキシ)を作用させた。その後−78℃で90分攪拌し、メタノール3mlで反応を停止した。酢酸エチルで抽出し、油層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。溶媒を留去後、シリカゲルクロマトグラフィー(溶出液−ヘキサン:酢酸エチル=10:1)で精製し、(1R、2R)−1,2−ビス−(t−ブチル−ジメチル−シラニルオキシ)−7a−メチル−5,6−ジフェニル1,2,5,7a−テトラヒドロ−ピロリジン−3−オン(4)113mg(収率82%)、(ジアステレオマー比=1:1),(R11=フェニル,R12=水素,R13=フェニル,R14=メチル,R15=t−ブチル−ジメチルシロキシ、R16=t−ブチル−ジメチルシロキシ)で得た。(1R、2R)−1,2−ビス−(t−ブチル−ジメチル−シラニルオキシ)−7a−メチル−5,6−ジフェニル−1,2,5,7a−テトラヒドロ−ピロリジン−3−オン(化17)の物性データは、
1H NMR(300MHz,CDCl3)(a)δ 7.44−7.42(m,2H),7.34−7.22(m,8H),6.48(d,J=1.8Hz,1H),6.23(d,J=1.5Hz,1H),4.48(d,J=8.7Hz,1H),4.09(d,J=9.3Hz,1H),1.37(s,3H),1.00(s,9H),0.99(s,9H),0.25(s,3H),0.20(s,3H),0.17(s,3H),0.15(s,3H).(b)δ 7.25−7.18(m,10H),6.32(d,J=1.8Hz,1H),5.66(d,J=1.8Hz,1H),4.37(d,J=8.1Hz,1H),4.18(d,J=8.4Hz,1H),1.40(s,3H),1.02(s,9H),0.87(s,9H),0.28(s,3H),0.24(s,3H),0.10(s,3H),0.06(s,3H);13C NMR(75MHz,CDCl3)(a)δ 172.62,140.60,139.33,132.50,129.49,128.73,128.60,128.35,128.28,127.76,126.75,83.27,77.15,72.28,65.38,26.06,26.03,21.30,18.55,18.13,−3.94,−3.99,−4.08,−4.41.(b)δ 168.81,142.76,136.48,132.98,128.90,128.34,128.28,128.00,127.85,126.43,83.17,76.68,71.88,66.97,26.03,21.76,18.51,18.15,−3.93,−3.99,−4.42;IR(neat,cm−1)(a)3480,3063,3031,2956,2930,2886,2858,1950,1722,1602,1495,1472, 1380,1363,1338,1252,1173,1122,1061,1006,888,838,781,757,701.(b)3351,3065,3031,2955,2930,2886,2857,1727,1601,1495,1472,1462,1377,1362,1338,1252,1173,1148,1118,1051,882,837,780,756,695.(Test 2) Synthesis of [3.3.0] -lactams
(3R, 4R) -1-benzyl-3,4-bis- (t-butyl-dimethyl-silanyloxy) in a THF (10 ml) solution of 1.25 mmol of lithium tetramethylpiperidide under argon atmosphere at −78 ° C. -5-Methyl-5-phenylethynyl-pyrrolidin-2-one (3) 137.4 mg (0.25 mmol), (R 11 = phenyl, R 12 = hydrogen, R 13 = phenyl, R 14 = methyl, R 15 = T-butyl-dimethylsiloxy, R 16 = t-butyl-dimethylsiloxy). Thereafter, the mixture was stirred at -78 ° C for 90 minutes, and the reaction was stopped with 3 ml of methanol. The mixture was extracted with ethyl acetate, and the oil layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by silica gel chromatography (eluent-hexane: ethyl acetate = 10: 1), and (1R, 2R) -1,2-bis- (t-butyl-dimethyl-silanyloxy) -7a- Methyl-5,6-diphenyl 1,2,5,7a-tetrahydro-pyrrolidin-3-one (4) 113 mg (82% yield), (diastereomeric ratio = 1: 1), (R 11 = phenyl, R 12 = hydrogen, R 13 = phenyl, R 14 = methyl, R 15 = t-butyl-dimethylsiloxy, R 16 = t-butyl-dimethylsiloxy). (1R, 2R) -1,2-bis- (t-butyl-dimethyl-silanyloxy) -7a-methyl-5,6-diphenyl-1,2,5,7a-tetrahydro-pyrrolidin-3-one ) Physical property data
1 H NMR (300 MHz, CDCl 3 ) (a) δ 7.44-7.42 (m, 2H), 7.34-7.22 (m, 8H), 6.48 (d, J = 1.8 Hz) , 1H), 6.23 (d, J = 1.5 Hz, 1H), 4.48 (d, J = 8.7 Hz, 1H), 4.09 (d, J = 9.3 Hz, 1H), 1 .37 (s, 3H), 1.00 (s, 9H), 0.99 (s, 9H), 0.25 (s, 3H), 0.20 (s, 3H), 0.17 (s, 3H), 0.15 (s, 3H). (B) δ 7.25-7.18 (m, 10H), 6.32 (d, J = 1.8 Hz, 1H), 5.66 (d, J = 1.8 Hz, 1H), 4.37 (D, J = 8.1 Hz, 1H), 4.18 (d, J = 8.4 Hz, 1H), 1.40 (s, 3H), 1.02 (s, 9H), 0.87 (s , 9H), 0.28 (s, 3H), 0.24 (s, 3H), 0.10 (s, 3H), 0.06 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) ( a) δ 172.62, 140.60, 139.33, 132.50, 129.49, 128.73, 128.60, 128.35, 128.28, 127.76, 126.75, 83.27 77.15, 72.28, 65.38, 26.06, 26.03, 21.30, 18.55, 18.13, -3. 4, -3.99, -4.08, -4.41. (B) δ 168.81, 142.76, 136.48, 132.98, 128.90, 128.34, 128.28, 128.00, 127.85, 126.43, 83.17, 76. 68, 71.88, 66.97, 26.03, 21.76, 18.51, 18.15, -3.93, -3.99, -4.42; IR (neat, cm- 1 ) ( a) 3480, 3063, 3031, 2956, 2930, 2886, 2858, 1950, 1722, 1602, 1495, 1472, 1380, 1363, 1338, 1252, 1173, 1122, 1061, 1006, 888, 838, 781, 757, 701. (B) 3351, 3065, 3031, 2955, 2930, 2886, 2857, 1727, 1601, 1495, 1472, 1462, 1377, 1362, 1338, 1252, 1173, 1148, 1118, 1051, 882, 837, 780, 756 695.
同様にしてE+をトリメチルシリルクロライドとすることにより、(1R、2R)−1,2−ビス−(t−ブチル−ジメチル−シラニルオキシ)−7a−メチル−5,6−ジフェニル−7−トリメチルシラニル−1,2,5,7a−テトラヒドロ−ピロリジン−3−オンを86.5mg(収率54%)で得た。(1R,2R)−1,2−ビス−(t−ブチル−ジメチル−シラニルオキシ)−7a−メチル−5,6−ジフェニル−7−トリメチルシラニル−1,2,5,7a−テトラヒドロ−ピロリジン−3−オン(化18)の物性データは、
1H NMR(300MHz,CDCl3)(a)δ 7.30−6.94(m,8H),6.69−6.68(m,2H),5.17(s,1H),4.50(d,J=6.9Hz,1H),4.40(d,J=7.2Hz,1H),1.47(s,3H),0.99(s,9H),0.89(s,9H),0.29(m,6H),0.14(s,3H),0.08(s,3H),−0.04(s,9H).(b)δ 7.56−7.00(m,10H),5.79(s,1H),4.45(d,J=7.8Hz,1H),4.15(d,J=8.1Hz,1H),1.37(s,3H),1.00(s,18H),0.33(s,6H),0.18(m,6H),0.03(s,9H).Similarly, (1R, 2R) -1,2-bis- (t-butyl-dimethyl-silanyloxy) -7a-methyl-5,6-diphenyl-7-trimethylsilanyl is obtained by changing E + to trimethylsilyl chloride. -1,2,5,7a-Tetrahydro-pyrrolidin-3-one was obtained in 86.5 mg (54% yield). (1R, 2R) -1,2-bis- (t-butyl-dimethyl-silanyloxy) -7a-methyl-5,6-diphenyl-7-trimethylsilanyl-1,2,5,7a-tetrahydro-pyrrolidine- The physical property data of 3-one (Chemical Formula 18) is
1 H NMR (300 MHz, CDCl 3 ) (a) δ 7.30-6.94 (m, 8H), 6.69-6.68 (m, 2H), 5.17 (s, 1H), 4. 50 (d, J = 6.9 Hz, 1H), 4.40 (d, J = 7.2 Hz, 1H), 1.47 (s, 3H), 0.99 (s, 9H), 0.89 ( s, 9H), 0.29 (m, 6H), 0.14 (s, 3H), 0.08 (s, 3H), -0.04 (s, 9H). (B) δ 7.56-7.00 (m, 10H), 5.79 (s, 1H), 4.45 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 8) .1 Hz, 1 H), 1.37 (s, 3 H), 1.00 (s, 18 H), 0.33 (s, 6 H), 0.18 (m, 6 H), 0.03 (s, 9 H) .
Claims (4)
(式中、R1とR2は、互いに独立して、水素原子、アルコキシ基、アミノ基、アリール基、アルケニル基、アルキニル基、または複素環基を表し、R1とR2が互いに結合して環を形成してもよい。R3とR4は互いに独立して、強塩基に対し安定な置換基を表す。R5とR6は、互いに独立して、強塩基に対し安定な置換基を表し、R5とR6が互いに結合して環を形成してもよい。)Δ-lactams represented by general formula 1.
(In the formula, R 1 and R 2 each independently represent a hydrogen atom, an alkoxy group, an amino group, an aryl group, an alkenyl group, an alkynyl group, or a heterocyclic group, and R 1 and R 2 are bonded to each other. R 3 and R 4 each independently represent a substituent that is stable against a strong base, and R 5 and R 6 are each independently a substituent that is stable against a strong base. Represents a group, and R 5 and R 6 may combine with each other to form a ring.)
(式中、R11とR12は、互いに独立して、水素原子、アルコキシ基、アミノ基、アリール基、アルケニル基、アルキニル基、または複素環基を表し、R11とR12が互いに結合して環を形成してもよい。R13とR14は互いに独立して、強塩基に対し安定な置換基を表す。R15とR16は、互いに独立して、酸素原子を含む強塩基に対し安定な置換基を表し、R15とR16が互いに結合して環を形成してもよい。Eは重水素原子、ヒドロメチル基、メチルエステル基、アルキル基、アシル基等を表す。)[3.3.0] -Lactams represented by general formula 2.
(In the formula, R 11 and R 12 independently represent a hydrogen atom, an alkoxy group, an amino group, an aryl group, an alkenyl group, an alkynyl group, or a heterocyclic group, and R 11 and R 12 are bonded to each other. R 13 and R 14 each independently represent a substituent that is stable against a strong base, and R 15 and R 16 independently represent a strong base containing an oxygen atom. R 15 and R 16 may be bonded to each other to form a ring, and E represents a deuterium atom, hydromethyl group, methyl ester group, alkyl group, acyl group, etc.)
を塩基存在下反応させることによる、
(式中、R1、R2、R3、R4、R5とR6は、上述のR1、R2、R3、R4、R5とR6と同様である。)
で表されるδ−ラクタム類の製造法。 (In the formula, R 1 and R 2 each independently represent a hydrogen atom, an alkoxy group, an amino group, an aryl group, an alkenyl group, an alkynyl group, or a heterocyclic group, and R 1 and R 2 are bonded to each other. R 3 and R 4 each independently represent a substituent that is stable against a strong base, and R 5 and R 6 are each independently a substituent that is stable against a strong base. Represents a group, and R 5 and R 6 may combine with each other to form a ring.)
By reacting in the presence of a base,
(In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as the above-mentioned R 1 , R 2 , R 3 , R 4 , R 5 and R 6. )
The manufacturing method of (delta) -lactam represented by these.
を塩基存在下、求電子反応剤と反応させることによる、
(式中、R11、R12、R13、R14、R15とR16は、上述のR11、R12、R13、R14、R15とR16と同様である。Eは重水素原子、ヒドロメチル基、メチルエステル基、アルキル基、アシル基、ホルミル基等を表す。)
で表される[3.3.0]−ラクタム類の製造法。 (In the formula, R 11 and R 12 independently represent a hydrogen atom, an alkoxy group, an amino group, an aryl group, an alkenyl group, an alkynyl group, or a heterocyclic group, and R 11 and R 12 are bonded to each other. R 13 and R 14 each independently represent a substituent that is stable against a strong base, and R 15 and R 16 independently represent a strong base containing an oxygen atom. Represents a stable substituent, and R 15 and R 16 may be bonded to each other to form a ring.)
By reacting with an electrophilic reagent in the presence of a base,
(In the formula, R 11 , R 12 , R 13 , R 14 , R 15 and R 16 are the same as R 11 , R 12 , R 13 , R 14 , R 15 and R 16 described above. E is heavy. Represents a hydrogen atom, a hydromethyl group, a methyl ester group, an alkyl group, an acyl group, a formyl group, etc.)
A process for producing [3.3.0] -lactams represented by:
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