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Method for synthesizing (e)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine

A technology of oxazepine and benzylidene is applied in the field of pharmaceutical synthesis and achieves the effects of easy availability of raw materials, low solution yield and mild reaction conditions

Active Publication Date: 2020-07-14
上海三牧化工技术有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these methods have certain limitations for the generation of molecular diversity
Although there are many reports on the synthesis of 2H-1,4-benzoxazepines, few stereoselective syntheses of (E)-2-benzylidene-1,2,3,5-tetrahydrobenzo Methods for [e][1,4]oxazepines and 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepines

Method used

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  • Method for synthesizing (e)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine
  • Method for synthesizing (e)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine
  • Method for synthesizing (e)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] The first step: the synthesis of 1-nitro-2-(propynyloxymethyl)-benzene 4.

[0062]

[0063] Method 1. After adding o-nitrobenzyl alcohol 3 (15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) into 110mL of anhydrous THF, after stirring evenly, the temperature of the system was lowered to 0°C, and batchwise Add 60% NaH (4.8g, 0.12mol) and keep the temperature at -20°C to -10°C. After the addition is complete, slowly rise to room temperature and stir for 4-5 hours. After TLC detects that the raw material disappears, pour it into 200g of water and extract with MTBE100mL Three times, the organic phases were combined, washed with saturated sodium bicarbonate, washed with saturated brine, concentrated the organic phase, and separated by column chromatography using n-heptane / ethyl acetate 10:1 to 6:1 to obtain 6.3 g of light yellow oily liquid 4, Yield 33%. 1H NMR(400MHz, CDCl3):7.78(dd,1H),7.54-7.58(m,2H),7.50(d,1H),7.06-7.09(m,1H),4.86(s,2H),4.79(d ,2H), 2.58(t,1H); m...

Embodiment 2

[0070] The second step: the synthesis of 2-(propynyloxymethyl)-aniline 5

[0071]

[0072] Method 1. Under mechanical stirring, add 1-nitro-2-(propynyloxymethyl)-benzene 4 (19.1g, 0.1mol) and reduced iron powder (4.5eq) into 220mL of ethanol, and control the temperature Add acetic acid solution (2.5eq) dropwise at 55-65°C, heat up to reflux for 3 hours after the dropwise addition, TLC detects that the raw materials basically disappear, cool down to 50°C, filter with diatomaceous earth, rinse the filter cake with ethanol, and decompress the filtrate Concentrate to dryness, add 120 mL of dichloromethane, adjust the pH of the aqueous layer to 9-10 with saturated aqueous sodium carbonate solution, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, use n-heptane / ethyl acetate 10 :1 to 6:1 were separated by column chromatography to obtain 16.9 g of yellow oily liquid with a yield of 88%. 1H NMR(400MHz, CDCl3):7....

Embodiment 3

[0075] The third step: the synthesis of 2-[(3-phenyl-2-alkynyloxy)methyl]-aniline 6

[0076]

[0077] Add iodobenzene (10.7g, 1.05eq), cuprous iodide (0.5g, 5mol%) and bis(triphenyl)palladium dichloride (0.86g, 2.5mol%) into 100mL triethylamine, drop at room temperature Add a mixed solution containing 2-(propynyloxymethyl)-aniline 5 (8g, 0.05mol) and 18mL triethylamine. During the dropwise addition, the solution gradually becomes clear, and then react at room temperature overnight, and the system has salt precipitation. Gradually become a suspension solution. HPLC detected that the ratio of the product to the raw material was greater than 80:1, concentrated under reduced pressure to remove triethylamine, added 80mL of dichloromethane for extraction, washed with saturated ammonia water, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and rotary evaporated, and then used n-heptane / Ethyl acetate 15:1 to 6:1 was separated by column chromatography...

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Abstract

The invention discloses a method for synthesizing (E)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine by multiple steps, and belongs to the technical field of organic synthesis. The method comprises the following steps: 2-nitrobenzyl alcohol and propargyl bromide or propargyl alcohol are subjected to ether formation, and 1-nitro-2-(propynyloxymethyl)-benzene is obtained; then, reduction isperformed with iron powder / acetic acid or NiCl2(dppp) / tetrahydroxydiboron / organic base, and 2-(propynyloxymethyl)-aniline is obtained; 2-(propynyloxymethyl)-aniline is subjected to Sonogashira coupling with iodobenzene, and 2-[(3-phenyl-2-alkynyloxy)methyl]-aniline is obtained; amino is subjected to p-toluenesulfonyl protection, cuprous bromide / cesium carbonate ring closing is performed, deprotection is performed under the condition of metal sodium / naphthalene, and (E)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine is obtained.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis, in particular to a multi-step synthesis of (E)-2-benzylidene-1,2,3,5-tetrahydrobenzo[e][1,4]oxazepine and 2-Benzyl-1,5-dihydrobenzo[e][1,4]oxazepine method. Background technique [0002] Organic compounds containing 1,4-benzoxazine derivatives have attracted extensive attention in chemical and medical research in recent years, which may be due to the diversity of their pharmacological effects, especially N / O-containing heterocyclic compounds, and Some of its derivatives show a wide range of biological activities such as anti-cancer, anti-tuberculosis, anti-hypertensive, anti-rheumatic, 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, neuroprotective antioxidant and so on. [0003] Therefore, 1,4-benzoxazine is a highly specific scaffold in the drug discovery process for the development of potential anti-TB drugs. Considering its medicinal value, several synthetic strategies a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D267/14
CPCC07D267/14
Inventor 徐小波高峰薛峰李瑞芳
Owner 上海三牧化工技术有限公司
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