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Method for synthesizing optically active tetrahydro-beta-carboline derivative through catalysis of chiral spirocyclic phosphoric acid

A technology of spirophosphoric acid catalysis and spirophosphoric acid catalyst, which is applied in the directions of organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve the problems such as insufficient enantioselectivity, narrow use range of substrates, etc. Highly selective effect

Inactive Publication Date: 2012-05-02
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the narrow range of substrates used in the current method, the enantioselectivity is not high enough, so further development of efficient preparation methods for optically active tetrahydro-β-carboline derivatives is of great significance for new drug screening, etc.

Method used

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  • Method for synthesizing optically active tetrahydro-beta-carboline derivative through catalysis of chiral spirocyclic phosphoric acid
  • Method for synthesizing optically active tetrahydro-beta-carboline derivative through catalysis of chiral spirocyclic phosphoric acid
  • Method for synthesizing optically active tetrahydro-beta-carboline derivative through catalysis of chiral spirocyclic phosphoric acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Under nitrogen protection, put 1 mmol N b -α-Naphthylmethyltryptamine, 0.02 mmol ( S )-O,O'-{7,7'-[6,6'-di-(1-naphthyl)-1,1'-spirobidihydroindane]} phosphoric acid catalyst and 1.5 grams of 4? Molecular sieve powder mixed In 5 ml of benzene solvent, then add 3 mmol of p-bromobenzaldehyde, at 30 oC After reacting for 24 hours, the optically active (S)-(4-bromophenyl)-2-(α-naphthylmethyl)-2,3,4,9-tetrahydro-β-carba phenoline, yield 96%. The optical purity of the product was 98% ee by HPLC. [Daicel Chiralpak AD-H, n -Hexane / i -propanol = 90 / 10, 1.0 mL / min, λ = 254 nm, t (minor) = 8.646 min, t (major) = 11.146 min]. [α] D 20 = +51.2°(c = 1.03, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 2.66-2.81 (m, 3H), 3.13-3.19 (m, 1H), 3.85 (d, J = 13.6 Hz, 1H), 4.20 (d, J = 13.6 Hz, 1H), 4.63 (s, 1H), 7.07-7.22 (m, 6H), 7.38-7.51 (m, 7H), 7.75 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ) Δ 20.5, 47.7, 56.4...

Embodiment 2～17

[0021] As in the feeding process of Example 1, where the type of aldehyde is changed, the experimental results in Table 1 can be obtained.

[0022]

[0023] Here the catalyst structural formula is:

[0024] Table 1: Experimental results of asymmetric reaction

[0025] Entry R time [h] product number Yield ee [%] 2 m -BrC 6 h 4 12 5h 94 95 3 m -ClC 6 h 4 12 5i 99 97 4 m -FC 6 h 4 12 5j 97 97 5 p -NO 2 C 6 h 4 12 5k 99 96 6 m -NO 2 C 6 h 4 12 5l 99 94 7 3,5-(CF 3 ) 2 C 6 h 3 16 5m 98 90 8 Ph 30 5n 90 97 9 p -MeOC 6 h 4 40 5o 94 93 10 piperonyl 44 5p 95 90 11 dihydrobenzofuryl 48 5q 91 92 12 furyl 10 5r 92 98 13 Et 4 5s 76 90 14 n -pentyl 5 5t 98 91 15 i -Pr 5 5u 96 97 16 Cy 6 5v 99 98 17 i -Pr 3 5w 96 95

[0026] T...

Embodiment 18

[0030] Example of deprotection of N-protected optically active tetrahydro-β-carboline derivatives: 0.2 mmol of compound (S)-isopropyl-2-(α-naphthylmethyl)-2,3,4, 9-tetrahydro-β-carboline 5u and 0.02 mmol of 10% Pd(OH) 2 / C was dissolved in a mixed solvent of 3 milliliters of ethyl acetate and 1.2 milliliters of methanol, and the air in the reactor was replaced three times with hydrogen, and then the reaction mixture was heated at 40 o C hydrogenation reaction at normal pressure for 4 hours, and then through silica gel powder column chromatography to obtain optically active (S)-isopropyl-2,3,4,9-tetrahydro-β-carboline, the structure is shown in the figure below, and the yield 98%, 97% ee.

[0031]

[0032] HPLC [Daicel Chiralcel OD-H, n -Hexane / i -propanol = 85 / 15, 1.0 mL / min, λ = 254 nm, t (major) = 8.820 min, t (minor) = 12.766 min]. [α] D 20 = -99.0°(c = 1.03, MeOH); 1 H NMR (500 MHz, CDCl 3 ) δ 0.88 (d, J = 7.0 Hz, 3H), 1.14 (d, J = 7.0 Hz, 3H), 2.09 (br,...

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Abstract

The invention discloses a method for synthesizing an optically active tetrahydro-beta-carboline derivative through the catalysis of chiral spirocyclic phosphoric acid. The method comprises the following steps of: reacting at the temperature of between 20 and 40 DEG C for 3 to 50 hours by taking Nb-alpha-naphthylmethyl tryptamine and aldehyde as raw materials, the chiral spirocyclic phosphoric acid as a catalyst and benzene as a reaction solvent in the presence of 4 angstrom molecular sieve powder under the protection of nitrogen, and performing column chromatographic purification and separation to obtain the optically active tetrahydro-beta-carboline derivative. Reaction conditions are mild, and the process is simple and convenient to operate; and the obtained optically active tetrahydro-beta-carboline derivative has high potential bioactivity, and can be used as an intermediate for pharmaceutical synthesis.

Description

technical field [0001] The invention relates to a method for catalytically synthesizing optically active tetrahydro-β-carboline derivatives with chiral spirocyclic phosphoric acid. Background technique [0002] Optically active tetrahydro-β-carboline derivatives are alkaloids with important biological activities, which can be used as important intermediates of fine chemical products, in medicine, food, pesticides, daily chemicals, coatings, textiles, printing and dyeing, Papermaking, photosensitive materials, polymer materials and other fields have a wide range of uses, see ( J. Med. Chem . 2003, 46 , 4525-4532; Chem. Rev. 1995, 95 , 1797-1842; Nat. Prod. Rep. 2004, 21 , 278-311; Nat. Prod. Rep. 2005, 22 , 761-793; Nat. Prod. Rep. 2006, 23 , 532-547; Chem. Pharm, Bull. 2005, 53 , 32-36). An example of this is the synthesis of the drug Tadalafil, whose key intermediate is an optically active tetrahydro-β-carboline derivative. [0003] The synthesis of optic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07B53/00
Inventor 林旭锋黄丹徐方曦王彦广
Owner ZHEJIANG UNIV
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