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Synthetic method for 3-hydroxyl multi-substituted tetrahydropyrrole derivative

A technology of tetrahydropyrrole and synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of low synthesis yield and many synthesis steps, and achieve the effects of mild reaction conditions, good selectivity and wide applicability of substrates

Inactive Publication Date: 2013-09-04
EAST CHINA NORMAL UNIV
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Problems solved by technology

This method mainly has the problems of many synthetic steps and low synthetic yield.
Not only that, although the above method can synthesize 3-hydroxyl polysubstituted tetrahydropyrrole derivatives with high enantioselectivity with one chiral center, when it comes to the synthesis of 3-hydroxyl derivatives with three or more chiral centers These methods exhibit more limitations when dealing with polysubstituted tetrahydropyrrole derivatives

Method used

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  • Synthetic method for 3-hydroxyl multi-substituted tetrahydropyrrole derivative
  • Synthetic method for 3-hydroxyl multi-substituted tetrahydropyrrole derivative
  • Synthetic method for 3-hydroxyl multi-substituted tetrahydropyrrole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Aniline (0.30mmol), methyl 4-carbonyl-4-phenyl-2-butenoate (0.36mmol), basic aluminum oxide (0.30mmol), A mixture of molecular sieves (300 mg) and rhodium acetate (0.3 mmol%) was dissolved in 1.5 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 40° C. for 1 hour. Then, methyl 2-diazo-2-phenylacetate (0.54 mmol) was dissolved in 1.5 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 40°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain pure product. The yield was 88%, and the dr value was greater than 93:7.

[0035] 1 H NMR (400MHz, CDCl 3 )δ7.48(br.s, 2H), 7.23(d, J=7.2Hz, 1H), 7.17-7.11(m, 5H), 7.09-7.03(m2H), 6.97(d, J=7.4Hz, 1H ), 6.75(t, J=6.9Hz, 1H), 6.44(d, J=7.7Hz, 2H), 5.08(dd, J=10.4, 4.8Hz, 1H), 4.54(s, 1H), 3.84(s , 3H), 3.58(s, 3H), 2.79(dd, J=11.5, 11.3Hz, 1H), 2.36(dd, J=11.6, 4.8Hz, 1H); 13 C NMR (1...

Embodiment 2

[0037]

[0038] Aniline (0.30mmol), methyl 4-carbonyl-4-phenyl-2-butenoate (0.36mmol), basic aluminum oxide (0.30mmol), A mixture of molecular sieves (300 mg) and rhodium propionate (0.3 mmol%) was dissolved in 1.5 mL of dichloromethane solvent to prepare a mixed solution A, which was stirred at 40° C. for 1 hour. Then, methyl 2-diazo-2-phenylacetate (0.54 mmol) was dissolved in 1.5 mL of dichloromethane solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 40°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain pure product. The yield was 90%, and the dr value was greater than 90:10.

[0039] 1 H NMR (400MHz, CDCl 3 )δ7.48(br.s, 2H), 7.23(d, J=7.2Hz, 1H), 7.17-7.11(m, 5H), 7.09-7.03(m2H), 6.97(d, J=7.4Hz, 1H ), 6.75(t, J=6.9Hz, 1H), 6.44(d, J=7.7Hz, 2H), 5.08(dd, J=10.4, 4.8Hz, 1H), 4.54(s, 1H), 3.84(s , 3H), 3.58(s, 3H), 2.79(dd, J=11.5, 11.3Hz, 1H), 2.36(dd, J=11.6, 4.8Hz, 1H); 13 C N...

Embodiment 3

[0041]

[0042] Aniline (0.30mmol), methyl 4-carbonyl-4-phenyl-2-butenoate (0.36mmol), acidic aluminum oxide (0.30mmol), A mixture of molecular sieves (300 mg) and rhodium acetate (0.3 mmol%) was dissolved in 1.5 mL of chloroform solvent to prepare a mixed solution A, which was stirred at 40° C. for 1 hour. Then, methyl 2-diazo-2-phenylacetate (0.54 mmol) was dissolved in 1.5 mL of chloroform solvent to prepare solution B. Solution B was added to mixed solution A with a syringe pump at 40°C within 1 hour. The reaction mixture was purified by flash column chromatography to obtain pure product. The yield was 80%, and the dr value was greater than 91:9.

[0043] 1 H NMR (400MHz, CDCl 3 )δ7.48(br.s, 2H), 7.23(d, J=7.2Hz, 1H), 7.17-7.11(m, 5H), 7.09-7.03(m2H), 6.97(d, J=7.4Hz, 1H ), 6.75(t, J=6.9Hz, 1H), 6.44(d, J=7.7Hz, 2H), 5.08(dd, J=10.4, 4.8Hz, 1H), 4.54(s, 1H), 3.84(s , 3H), 3.58(s, 3H), 2.79(dd, J=11.5, 11.3Hz, 1H), 2.36(dd, J=11.6, 4.8Hz, 1H); 13 C NMR (100MHz, C...

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Abstract

The invention relates to a synthetic method for a 3-hydroxyl multi-substituted tetrahydropyrrole derivative. The 3-hydroxyl multi-substituted tetrahydropyrrole derivative obtained by a one-step reaction by using a diazonium compound, aniline and 4-carbonyl butenolide as raw materials, aluminium oxide as an additive, a molecular sieve as a water absorbing agent, a metal Lewis acid as a catalyst and an organic solvent as a solvent and purifying by column chromatography. The synthetic method has the advantages of high atom economy, high selectivity and high yield, is mild in reaction conditions and simple and safe in operations. The 3-hydroxyl multi-substituted tetrahydropyrrole derivative with three chiral centers obtained by the method is an important chemical and medical intermediate, has wide applications in medical and chemical fields, and ahs great application prospects.

Description

technical field [0001] The invention belongs to the field of preparation of pharmaceutical intermediates, and relates to a chemical synthesis method of 3-hydroxy polysubstituted tetrahydropyrrole derivatives. Background technique [0002] 3-Hydroxy multi-substituted tetrahydropyrrole derivatives are important skeleton structures of a class of natural products and synthetic drugs, such as Radicamine A, Radicamine B, Codonopsinol, musk blue and wild hyacinth There are such skeletons in compounds such as the alkaloids (Hyacinthacines) and quinolizidine alkaloids ((-)-LasubineII) intermediates extracted from the plant (Tetrahedron Letter, 2012, 5297; Organic Letters, 2002, 1599). Among them, the hydroxyl-substituted derivatives are mainly azasaccharides, which have good inhibitory activity on α-glucosidase in organisms. Derivatives represented by quinolizidine alkaloids have effects on the central nervous system and cardiovascular system, and they also have good performance in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16C07D409/04
Inventor 胡文浩荆常诚吕思莹刘顺英邢栋
Owner EAST CHINA NORMAL UNIV
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