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Heteroatom-containing novel high B-ring berberine analogues and C-H activation synthesis method thereof

A heteroatom and berberine technology, applied in the field of synthesis of new high-B-ring berberine analogs and their C-H activation, can solve the problems of difficult discovery of candidate compounds, few chemical transformations of berberine, and high cost

Pending Publication Date: 2020-10-23
SICHUAN UNIV
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

But so far, there are still major limitations in the research, including: the reported structural modification is mainly concentrated on the peripheral position of berberine, and there are few chemical modifications targeting the basic skeleton and atomic species of berberine; Most of the transformation strategies are to transform into alkoxy groups, hydrocarbon groups, etc., and the types of functional groups are relatively small; each transformation needs to be fully synthesized from scratch, the route is cumbersome, and the cost is high
The above limitations greatly reduce the structural diversity of berberine analogues, making it difficult to find candidate compounds with superior properties

Method used

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  • Heteroatom-containing novel high B-ring berberine analogues and C-H activation synthesis method thereof
  • Heteroatom-containing novel high B-ring berberine analogues and C-H activation synthesis method thereof
  • Heteroatom-containing novel high B-ring berberine analogues and C-H activation synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Implementation example 1: Synthesis of 5-oxahomo-B ring berberine (Ber-1)

[0019]

[0020]

[0021] Starting with 2,3-dimethoxybenzylamine and 3,4-methylenedioxybromobenzene, acylation, iodolation, Sonogashira coupling, C–H activation / cyclization, nucleophilic substitution, and cyclization and other steps to obtain the target compound 5-oxahomoB ring berberine (Ber-1).

[0022] (1) Synthesis of compound 3:

[0023] Add 2,3-dimethoxybenzylamine 1 (4 mmol) and 2-pyridinecarboxylic acid 2 (4 mmol, 1.0 equiv.) into a dry 50 mL two-necked flask, replace with argon 3 times, inject DCM ( 20 mL) was dissolved, and the reaction solution was pre-cooled at -10 °C for 5 minutes. Join Et 3 N (8 mmol, 2.0 equiv.), after stirring evenly, slowly drop POCl 3 (8 mmol, 2.0 equiv.). After dropping, react at -10°C for 5 hours and then move to room temperature overnight. After the completion of the TLC monitoring reaction, it was transferred to a separatory funnel, followed by s...

Embodiment 2

[0040] Implementation example 2: Synthesis of 5-azahomo-B ring berberine (Ber-2)

[0041]

[0042] As shown in the above synthetic route, the target compound 5-azahomoB-ring berberine (Ber-2) was obtained by using the key intermediate 7 as a raw material through nucleophilic substitution, cyclization and other steps.

[0043] (1) Synthesis of Compound 9:

[0044] Compound 7 (0.26 mmol), CuCl (0.026 mmol, 0.1 equiv.), KOH (0.52 mmol, 2.0 equiv.) and 4.0 mL of aminoethanol were sequentially added into a 10 mL round bottom flask. The reaction solution was placed at 90°C for 8 hours. After the completion of the reaction monitored by TLC, compound 9 was separated and purified by direct column chromatography (eluent: petroleum ether / ethyl acetate = 2 / 1), with a yield of 45%.

[0045] Compound 9 is a yellow solid, 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.36 (s, 1H), 8.06 –8.03 (m, 2H), 7.74 (s, 2H), 7.22 (s, 1H), 6.45 (s, 1H), 5.94 (s, 2H), 4.78(t, J = 5.2 Hz, 1H), 4.00 (s, 3H), 3...

Embodiment 3

[0049] Example 3: Synthesis of 5-thiahomoB-ring berberine (Ber-3)

[0050]

[0051] As shown in the above synthetic route, the target compound 5-thiahomoB-ring berberine (Ber-3) was obtained by using the key intermediate 7 as a raw material through nucleophilic substitution, cyclization and other steps.

[0052] (1) Synthesis of compound 10:

[0053] Compound 7 (0.13 mmol), CuO (0.26 mmol, 2.0 equiv.), mercaptoethanol (1.3 mmol, 10.0 equiv.) and 2.0 mL of dioxane were sequentially added to a 15 mL sealed tube. The reaction solution was reacted at 130° C. for 24 hours. After the completion of the reaction monitored by TLC, water and ethyl acetate were added for extraction, and the organic layer was concentrated and then column chromatographed (eluent: petroleum ether / ethyl acetate = 2 / 1) to obtain compound 10 with a yield of 85%.

[0054] Compound 10 is a yellow solid, 1 H NMR (400 MHz, DMSO- d 6 ) δ 9.40 (s, 1H), 7.87 –7.77 (m, 3H), 7.19 (s, 1H), 7.08 (s, 1H), 6.10 (s,...

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Abstract

The invention provides a heteroatom-containing novel high B-ring berberine analogue and a C-H activation synthesis method thereof. The novel high-B-ring berberine analogue with the potential p300 histone acetyltransferase inhibitory activity is prepared from 5-oxa-high B-ring berberine, 5-aza-high B-ring berberine and 5-thia-high B-ring berberine. According to the method, total synthesis is completed by virtue of desilicication and C-H activation / cyclization of cobalt-catalyzed N-picolinamide and arylacetylene silane. Compared with an existing report, the limitation of basic skeleton transformation of berberine is broken through, a novel structure type is provided, meanwhile, a more economical and efficient synthetic method of the berberine analogue is invented, and the berberine analoguehas a wide application prospect.

Description

technical field [0001] The invention belongs to the field of compound drugs, and specifically relates to a novel high-B-ring berberine analog containing heteroatoms and a C-H activation synthesis method thereof. Background technique [0002] Berberine (Berberine) is an isoquinoline alkaloid isolated from the Chinese medicine Coptis chinensis. Clinically, it is mainly used for arrhythmia, hypertension, congestive heart failure, transient cerebral hemorrhage, diarrhea-predominant irritable bowel syndrome, bacillary dysentery, peptic ulcer, hyperlipidemia, type 2 diabetes and its complications disease, tumor, postoperative adhesion and inflammation, Chlamydia trachomatis infection and other diseases [1-2] . Because berberine has definite curative effect and stable quality in long-term clinical use, it can be used safely without the guidance of professional medical staff. It was listed in the first batch of over-the-counter drugs by the state in 1999. [0003] Berberine has a...

Claims

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Application Information

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IPC IPC(8): C07D498/14C07D491/147C07D513/14
CPCC07D498/14C07D491/147C07D513/14
Inventor 吴勇海俐聂瑞芳胡瑶吕珊
Owner SICHUAN UNIV
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