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A class of chiral azapolycyclic alkaloids and their synthetic methods

A synthetic method and technology of benzene rings, applied in the field of chiral azapolycyclic alkaloids and their synthesis, achieving high site selectivity, high stereoselectivity, and novel reaction mechanism

Active Publication Date: 2020-06-09
SOUTH CENTRAL UNIVERSITY FOR NATIONALITIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, isolated rat thoracic aorta is a main method for studying vascular endothelium, smooth muscle cells and vasodilation. It has a regulatory effect and is likely to have an inhibitory effect on the occurrence and development of hypertension

Method used

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  • A class of chiral azapolycyclic alkaloids and their synthetic methods
  • A class of chiral azapolycyclic alkaloids and their synthetic methods
  • A class of chiral azapolycyclic alkaloids and their synthetic methods

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0025] (1) Preparation of compound (-)-3:

[0026]

[0027] The procedure was as follows: (-)-cis-Myrtanylamine (680 mg, 4.4 mmol), picolinic acid (652 mg, 5.3 mmol), EDCI (1.26 g, 6.6 mmol), DMAP (54 mg, 0.44 mmol) and dichloromethane (6 mL) Added to a 15mL round bottom flask, stirred and reacted overnight at room temperature. After the reaction was completed, 843 mg of the target product (-)-3 was obtained by separating directly through a silica gel chromatography column (petroleum ether: ethyl acetate = 10: 1), with a yield of 74%. [α] 25 D -8.6 (c 1.76, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ8.53(d, J=4.4Hz, 1H), 8.19(d, J=7.8Hz, 1H), 8.07(s, 1H), 7.95–7.72(m, 1H), 7.46–7.31(m, 1H ), 3.57–3.37(m,2H),2.41–2.28(m,2H),2.05–1.81(m,5H),1.62–1.50(m,1H), 1.20(s,3H),1.09(s,3H ),0.90(d,J=9.6Hz,1H); 13 C NMR (150MHz, CDCl 3 )δ164.2, 150.0, 148.0, 137.3, 126.0, 122.2, 45.0, 43.7, 41.4, 41.3, 38.7, 33.3, 28.0, 26.0, 23.2, 19.8; HRMS (EI) Calcd for C 16 h 22 N 2 O[M + ]: 2...

Embodiment 1

[0034] The preparation of embodiment 1 compound (+)-4:

[0035]

[0036] The operation is as follows: at room temperature, the pyridinecarboxamide derivative (-)-3 of (-)-cis-Myrtanylamine (ie compound (-)-3) (25.8mg, 0.1mmol), Pd(OAc) 2 (4.5mg, 0.02mmol), AgOAc (50mg, 0.3mmol), C 6 f 5 I (294mg, 1.0mmol), Na 3 PO 4 (49.2mg, 0.3mmol) and TCE (1mL) were added to a 10mL microwave reaction tube with a power of 20W and reacted at 175°C for 4 hours. After the reaction was completed, it was naturally cooled to room temperature, filtered through celite, and spin-dried. Using petroleum ether: ethyl acetate = 4:1 as the developing solvent, 15.7 mg of the target compound (+)-4 was obtained by separation on a preparative plate, with a yield of 61%, [α] 25 D +132.8 (c0.88, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ8.56(d,J=4.5Hz,1H),7.85–7.71(m,1H),7.67(d,J=7.8Hz,1H),7.30(dd,J=6.8and 5.6Hz,1H), 3.51(dd, J=10.8and 8.0Hz, 1H), 3.31(t, J=10.9Hz, 1H), 2.47(dt, J=10.7and 7.4Hz, 1H), 1.9...

Embodiment 2

[0037] The preparation of embodiment 2 compound (+)-6:

[0038]

[0039] The operation is as follows: at room temperature, the pyridinecarboxamide derivative (-)-5 of (-)-cis-Myrtanylamine (ie compound (-)-5) (33.7mg, 0.1mmol), Pd(OAc) 2 (4.5mg, 0.02mmol), AgOAc (50mg, 0.3mmol), C 6 f 5 I (294mg, 1.0mmol), Na 3 PO 4 (49.2mg, 0.3mmol) and TCE (1mL) were added to a 10mL microwave reaction tube with a power of 20W and reacted at 175°C for 4 hours. After the reaction was completed, it was naturally cooled to room temperature, filtered through celite, and spin-dried. Using petroleum ether: ethyl acetate = 4:1 as a developing solvent, 17.9 mg of the target compound (+)-6 was obtained by separation on a preparative plate, with a yield of 53%, [α] 25 D +70.9(c0.56, CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ8.53(d, J=4.6Hz, 1H), 7.89(d, J=8.1Hz, 1H), 7.17(dd, J=8.1and 4.7Hz, 1H), 3.16(dd, J=9.7and 8.3 Hz,1H),2.85(t,J=10.4Hz,1H),2.52(dt,J=10.6and 7.4Hz,1H),1.90–1.78(m,1H),1.72–1....

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Abstract

The invention relates to the technical field of chemical synthesis and disclosed are a chiral azapolycyclic alkaloid and a synthesis method thereof, wherein the target product azapolycyclic alkaloid has the structural formula (I) which is described in the description, the compound in the formula is a chiral azapolycyclic alkaloid in which the nitrogen atom in the skeleton is protected by 2-pyridinecarboxylic acid; the R group is hydrogen, halogen or a fused aromatic ring; the skeleton is (3S, 4S, 7R)-2-dimethyl-tetrahydropyrrolo[3,4]-cyclopropyl-cyclopentane; this molecule is a chiral optically pure compound. The compound of the formula (I) has a significant relaxing effect on KCl-precontracted rat thoracic aorta, suggesting that the sample has a modulatory effect on vascular endothelial cells or smooth muscle cells, and may have an inhibitory effect on the occurrence and development of hypertension.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and in particular relates to a class of chiral azapolycyclic alkaloids represented by formula (I) and a synthesis method thereof. Background technique [0002] Alkaloids are a kind of nitrogen-containing basic organic compounds in nature. The nitrogen element is mostly contained in the ring and has significant biological activity. Plants, animals, and microorganisms contain a large number of alkaloids, and nitrogen atoms in alkaloid molecules usually exist in the form of primary, secondary, and tertiary amine functional groups. The nitrogen atom makes a significant contribution to the activity of the drug: the lone pair of electrons on the nitrogen atom can accept protons and act as hydrogen acceptors; the primary and secondary amines can act as hydrogen donors when forming hydrogen bonds. Since the interaction between biomolecules is strongly dependent on hydrogen bonding, this property of bei...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/06C07D209/94C07D213/81C07D215/48C07B53/00A61P9/12
CPCC07B53/00C07B2200/07C07D209/94C07D213/81C07D215/48C07D401/06
Inventor 吴滨赵杰
Owner SOUTH CENTRAL UNIVERSITY FOR NATIONALITIES
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