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Application and application method of cinchona alkaloid squaramide derivative as catalyst in asymmetric P-S reaction

A technology of cinchona square amide and base square amide, which is applied to the application and application field of cinchona square amide derivatives as catalysts in asymmetric P‑S reactions, and can solve the constraints of large-scale application of catalysts and complex catalyst preparation processes , modifying groups cannot be removed, etc., to achieve good application value, rich variety, high yield and high enantioselectivity

Active Publication Date: 2018-01-09
ZHEJIANG UNIV OF TECH
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Problems solved by technology

[0005] In 2004, the Jacobsen group reported for the first time the method for the preparation of β-tetrahydrocarboline derivatives by the asymmetric Pictet-Spengler reaction catalyzed by organic small molecules (reaction formula 2), the yield was 65-81%, and the ee value of the target compound was 86- 95%, the reaction needs to be carried out at low temperature (-78°C), and the operation is cumbersome [Jacobsen, Eric N.J.Am.Chem.Soc.2004,126,10558]
[0007] In 2006, the List group first reported the asymmetric Pictet-Spengler reaction (reaction formula 3) catalyzed by the chiral phosphoric acid catalyst II of binaphthol (BINOL) skeleton. This type of catalyst has high catalytic activity and can effectively control the enantioselection of products The highest ee value is 94%. However, the reaction substrate needs to be modified, and the modification group cannot be removed after the reaction, which limits the application of this reaction [List, B.J.Am.Chem.Soc.2006,128,1086]
[0013] After nearly ten years of development, there have been more and more catalytic systems for the asymmetric Pictet-Spengler reaction, but they are mainly concentrated on chiral phosphoric acid catalysts. The preparation process of this type of catalyst is complicated and the preparation cost is high. The price is generally 1,800-2,500 yuan / 100mg, the price of SPINOL chiral phosphoric acid B is generally 2,500-3,500 yuan / 100mg, and the polymeric chiral phosphoric acid C has not yet been sold on a large scale.
Expensive price, complex preparation process have seriously restricted the large-scale application of this catalyst in industry, therefore, seek the new catalyst or catalytic system of the catalytic asymmetric Pictet-Spengler reaction of simple and easy preparation, good stability, high activity of the present invention technical issues to be resolved

Method used

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  • Application and application method of cinchona alkaloid squaramide derivative as catalyst in asymmetric P-S reaction
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  • Application and application method of cinchona alkaloid squaramide derivative as catalyst in asymmetric P-S reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Synthesis of (S)-2-benzyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-indole.

[0035] In a 25mL single-neck flask, add cinchonaine squarine derivative catalyst Ia (0.5mmol, 0.32g), benzyltryptamine (5mmol, 1.25g), benzaldehyde (7.5mmol, 0.80g), toluene (5mL), 100 After reacting at ℃ for 6h, the reaction solution was concentrated and separated by column chromatography to obtain (S)-2-benzyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4- b]-Indole 1.59g, white solid, the yield was 94%, and the ee value was 89%.

[0036]

[0037] 1 H NMR(500MHz, CDCl 3 )δ2.65-2.70(m,1H), 2.79-2.83(m,1H), 2.90-2.96(m,1H), 3.23-3.27(m,1H), 3.37(d,J=13.5Hz,1H) ,3.90(d,J=13.5Hz,1H),4.65(s,1H),7.10-7.14(m,2H),7.18-7.19(m,1H),7.25-7.28(m,1H),7.32-7.35 (m,3H),7.36-7.39(m,4H),7.47(m,2H),7.53-7.54(m,1H). 13 C NMR(125MHz, CDCl 3 )δ141.46,139.57,136.29,134.86,129.02(2C),128.76(2C),128.70(2C),128.23(2C),128.08,127.21,126.92,121.49,119.35,118.30,110.78,108.95,64.60,58.33,48.35 ,21.18.HPLC[Daicel...

Embodiment 2

[0038] Example 2: Synthesis of (S)-2-benzyl-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-indole .

[0039] In a 25mL single-neck flask, add cinchonaine squaraamide derivative catalyst Ib (1.5mmol, 0.94g), benzyltryptamine (5mmol, 1.25g), 4-fluorobenzaldehyde (7.5mmol, 0.93g), dichloromethane (5mL), reacted at 40℃ for 18h, the reaction solution was concentrated and separated by column chromatography to obtain (S)-2-benzyl-1-(4-fluorophenyl)-2,3,4,9-tetrahydro -1H-pyrido[3,4-b]-indole 1.71g, white solid, the yield was 96%, and the ee value was 84%.

[0040]

[0041] 1 H NMR(500MHz, CDCl 3 )δ2.68-2.73(m,1H),2.81-2.86(m,1H),2.90-2.96(m,1H),3.22-3.27(m,1H), 3.39(d,J=8.5Hz,1H) ,3.89(d,J=8.5Hz,1H),4.67(s,1H),7.04-7.08(m,2H),7.10-7.15(m,2H),7.20-7.23(m,1H),7.26-7.28 (m, 1H), 7.32-7.36 (m, 4H), 7.39-7.43 (m, 2H), 7.53 (d, J = 6.0 Hz, 1H). 13 C NMR(125MHz, CDCl 3 )δ163.50,161.54,139.39,137.24,136.31,134.47,130.59,130.53,128.68,128.29(2C),127.16,127.02,121.67,119.47,118.37,115.70...

Embodiment 3

[0042] Example 3: Synthesis of (S)-2-(1-naphthylmethyl)-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-indole .

[0043] In a 25mL single-necked flask, add cinchonaine squarine derivative catalyst Ic (1mmol, 0.59g), 1-naphthyltryptamine (5mmol, 1.51g), benzaldehyde (5mmol, 0.53g), DMF (10mL), 25 After reacting at ℃ for 70h, the reaction solution was concentrated and separated by column chromatography to obtain (S)-2-(1-naphthylmethyl)-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido [3,4-b]-Indole 1.49g, white solid, the yield was 77%, and the ee value was 87%.

[0044]

[0045] 1 H NMR(500MHz, CDCl 3 )δ2.69-2.74(m,1H), 2.80-2.91(m,2H), 3.22-3.26(m,1H), 3.83(d,J=13.5Hz,1H), 4.30(d,J=13.0Hz ,1H),4.73(s,1H),7.10-7.16(m,2H),7.21-7.22(m,1H),7.32-7.35(m,2H),7.36-7.37(m,1H),7.38-7.41 (m,1H),7.42-7.48(m,4H),7.53-7.55(m,1H),7.58(d,J=8.4Hz,1H),7.77(d,J=10.2Hz,1H),7.84( d, J = 9.6 Hz, 1H), 8.04 (d, J = 10.2 Hz, 1H). 13 C NMR(125MHz, CDCl 3 )δ141.32,136.31,134.97,134.68,133.80,132.38,129.39,128.60,128...

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Abstract

The invention particularly relates to an application and an application method of a cinchona alkaloid squaramide derivative as a catalyst in an asymmetric P-S reaction. The application method comprises the steps as follows: a tetrahydro-beta-carboline derivative shown in formula (IV) is prepared through a cyclization reaction in an anhydrous organic solvent A at 0-100 DEG C with a tryptamine derivative and an aldehyde compound as substrates and the cinchona alkaloid squaramide derivative as the catalyst, the yield is 60%-99%, and the ee value is 80%-99%. Compared with the prior art, the asymmetric Pictet-Spengler reaction is promoted by use of the organic alkali catalyst for the first time, the ee value of the tetrahydro-beta-carboline derivative is significantly increased, and the application method has the characteristics of being convenient to operate, lower in cost and the like and has higher application value and potential social and economic benefits.

Description

Technical field [0001] The invention specifically relates to the application and application method of a cinchonaine squaraamide derivative as a catalyst in the asymmetric Pictet-Spengler reaction. Background technique [0002] The Pictet-Spengler reaction was discovered in 1911 when Ame Pictet and Theodor Spengler, chemists at the University of Geneva, studied the preparation of phenylethylamine and aldehyde in acidic medium to prepare tetrahydroisoquinoline (THIQ). This reaction is widely used in the preparation of nitrogen-containing heterocyclic compounds. Among them is one of the important methods for preparing isoquinoline and indole alkaloids [Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.]. [0003] In 1998, the Nakagawa group first reported a chiral Lewis acid-catalyzed asymmetric Pictet-Spengler reaction (reaction formula 1). The reaction requires an equivalent chiral Lewis acid catalyst with a maximum ee value of 90%. The substrate has a narrow applicati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): B01J31/02C07D471/04
Inventor 钟为慧亓亮其他发明人请求不公开姓名
Owner ZHEJIANG UNIV OF TECH
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