Optically active tryptamine derivative and synthetic method and application thereof

Abstract

The invention discloses a synthetic method of an optically active trytamine derivative. The optically active trytamine derivative is obtained by taking a diazo compound, imine and an indole derivative as raw materials, taking rhodium acetate and chiral phosphoric acid as catalysts, taking an organic solvent as a solvent, taking a molecular sieve as a water absorbent and undergoing a one-step reaction at the temperature of -10 DEG C to 50 DEG C. The synthetic method of the optically active trytamine derivative has the advantages of efficient atom economy, high selectivity, high yield, low catalyst using amount, easiness and safety for operating, and the like. The optically active trytamine derivative obtained with the method has high antitumor activity, and can be widely applied in the field of chemical industry.

Description

technical field

[0001] The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to an optically active tryptamine derivative and its synthesis method and application. Background technique

[0002] Optically active tryptamine derivatives have good anticancer activity and are an important framework structure for building natural products and drugs. Such as naratriptan, sumatriptan, rizatriptan, eletriptan, almotriptan, and zomotriptan. Optically active tryptamine derivatives can also be used to synthesize numerous antineoplastic drugs, antibiotics, and antifungal drugs.

[0003] The traditional chemical synthesis method of optically active tryptamine derivatives uses indole as a raw material to synthesize tryptamine derivatives with only one chiral center through a five-step reaction (J.Med.Chem.1988, 31, 1406-1412). It has the disadvantages of high cost, low yield and cumbersome operation.

[0004] The present invention overcomes ...

Examples

Embodiment 1

[0049]

[0050] N-methylindole (0.3mmol), N-benzylidene aniline (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), chiral small molecule catalyst PPA (0.005mmol) and Molecular sieves (0.1g) were dissolved in toluene (2ml), then, methyl phenyldiazoacetate (0.25mmol,) dissolved in toluene (2.0ml) was added dropwise in the reaction system in 2 hours, and the reaction system was At -10°C, after the dropwise addition, the mixture was stirred for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-1). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. Yield 94%, dr > 20:1, ee% = 97%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 1 As shown, the product 4a 1 H NMR (400MHz, CDCl 3 )δ (ppm) 3.65 (s, 3H), 3.78 (s, 3H), 5.06 (br, 1H), 5.79 (d, J = 8.2Hz, 1H), 6.39 (d, J = 8.0Hz, 2H), 6.53(d, J=...

Embodiment 2

[0052]

[0053] N-methylindole (0.3mmol), N-(4-bromobenzylidene) aniline (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), chiral small molecule catalyst PPA (0.005mmol) and Molecular sieves (0.1g) were dissolved in toluene (2ml), then, methyl phenyldiazoacetate (0.25mmol,) dissolved in toluene (2.0ml) was added dropwise in the reaction system in 2 hours, and the reaction system was At -10°C, after the dropwise addition was completed, the mixture was stirred for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-2). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. Yield 93%, dr > 20:1, ee% = 99%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 2 As shown, the product 4b 1 H NMR (400MHz, CDCl 3 )δ(ppm) 3.55(s, 3H), 3.68(s, 3H), 4.98(d, J=8.5Hz, 1H), 5.69(d, J=8.9Hz, 1H), 6.30(d, J=...

Embodiment 3

[0055]

[0056] N-methylindole (0.3mmol), N-(4-bromobenzylidene) aniline (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), chiral small molecule catalyst PPA (0.005mmol) and Molecular sieves (0.1g) were dissolved in toluene (2ml), then, 4-bromophenyldiazoacetic acid methyl ester (0.25mmol,) dissolved in toluene (2.0ml) was added dropwise in the reaction system within 2 hours, The reaction system was kept at -10°C. After the dropwise addition was completed, it was stirred for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-3). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. Yield 85%, dr > 20:1, ee% = 91%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as image 3 As shown, the product 4c 1 H NMR (500MHz, CDCl 3 )δ(ppm) 3.67(s, 3H), 3.79(s, 3H), 5.05(br, 1H), 5.76(d, J=7.3Hz, 1H), 6.41(d...

technical field

[0001] The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to an optically active tryptamine derivative and its synthesis method and application. Background technique

[0002] Optically active tryptamine derivatives have good anticancer activity and are an important framework structure for building natural products and drugs. Such as naratriptan, sumatriptan, rizatriptan, eletriptan, almotriptan, and zomotriptan. Optically active tryptamine derivatives can also be used to synthesize numerous antineoplastic drugs, antibiotics, and antifungal drugs.

[0003] The traditional chemical synthesis method of optically active tryptamine derivatives uses indole as a raw material to synthesize tryptamine derivatives with only one chiral center through a five-step reaction (J.Med.Chem.1988, 31, 1406-1412). It has the disadvantages of high cost, low yield and cumbersome operation.

[0004] The present invention overcomes ...

Examples

Embodiment 1

[0049]

[0050] N-methylindole (0.3mmol), N-benzylidene aniline (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), chiral small molecule catalyst PPA (0.005mmol) and Molecular sieves (0.1g) were dissolved in toluene (2ml), then, methyl phenyldiazoacetate (0.25mmol,) dissolved in toluene (2.0ml) was added dropwise in the reaction system in 2 hours, and the reaction system was At -10°C, after the dropwise addition, the mixture was stirred for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-1). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. Yield 94%, dr > 20:1, ee% = 97%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 1 As shown, the product 4a 1 H NMR (400MHz, CDCl 3 )δ (ppm) 3.65 (s, 3H), 3.78 (s, 3H), 5.06 (br, 1H), 5.79 (d, J = 8.2Hz, 1H), 6.39 (d, J = 8.0Hz, 2H), 6.53(d, J=...

Embodiment 2

[0052]

[0053] N-methylindole (0.3mmol), N-(4-bromobenzylidene) aniline (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), chiral small molecule catalyst PPA (0.005mmol) and Molecular sieves (0.1g) were dissolved in toluene (2ml), then, methyl phenyldiazoacetate (0.25mmol,) dissolved in toluene (2.0ml) was added dropwise in the reaction system in 2 hours, and the reaction system was At -10°C, after the dropwise addition was completed, the mixture was stirred for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-2). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. Yield 93%, dr > 20:1, ee% = 99%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 2 As shown, the product 4b 1 H NMR (400MHz, CDCl 3 )δ(ppm) 3.55(s, 3H), 3.68(s, 3H), 4.98(d, J=8.5Hz, 1H), 5.69(d, J=8.9Hz, 1H), 6.30(d, J=...

Embodiment 3

[0055]

[0056] N-methylindole (0.3mmol), N-(4-bromobenzylidene) aniline (0.3mmol), Rh 2 (OAc) 4 (0.0025mmol), chiral small molecule catalyst PPA (0.005mmol) and Molecular sieves (0.1g) were dissolved in toluene (2ml), then, 4-bromophenyldiazoacetic acid methyl ester (0.25mmol,) dissolved in toluene (2.0ml) was added dropwise in the reaction system within 2 hours, The reaction system was kept at -10°C. After the dropwise addition was completed, it was stirred for 12 hours, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product, the structure of which was shown in formula (2-3). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:100~1:40) to obtain a pure product. Yield 85%, dr > 20:1, ee% = 91%. nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as image 3 As shown, the product 4c 1 H NMR (500MHz, CDCl 3 )δ(ppm) 3.67(s, 3H), 3.79(s, 3H), 5.05(br, 1H), 5.76(d, J=7.3Hz, 1H), 6.41(d...

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