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Multi-step synthesis method for 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepine

A technology of oxazepine and dihydrobenzene, applied in the field of drug synthesis, to achieve the effect of simple and reasonable synthetic route, easy to obtain raw materials, and solve the problem of low yield

Active Publication Date: 2018-12-14
山东三牧新材料科技有限公司
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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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  • Multi-step synthesis method for 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepine
  • Multi-step synthesis method for 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepine
  • Multi-step synthesis method for 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepine

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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. Add o-nitrobenzyl alcohol 3 (15.3g, 0.1mol) and propargyl bromide (14.3g, 0.12mol) to 110mL of anhydrous THF. After stirring uniformly, the temperature of the system drops to 0°C in batches. Add 60% NaH (4.8g, 0.12mol) and keep the temperature at -20°C to -10°C. After the addition, slowly rise to room temperature and stir to react for 4-5 hours. After detecting the disappearance of the raw materials by TLC, pour into 200g water and extract with MTBE100mL Three times, the organic phases were combined, washed with saturated sodium bicarbonate water, 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. The yield was 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...

Embodiment 2

[0070] Step 2: 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) to 220mL of ethanol and control the temperature Add acetic acid solution (2.5eq) dropwise at 55-65°C. After the dropwise addition, the temperature is raised to reflux for 3 hours. TLC detects that the raw materials have almost disappeared. The temperature is reduced to 50°C. The filter cake is washed with ethanol and the filtrate is decompressed. Concentrate to dryness, add 120 mL of dichloromethane, adjust the pH to 9-10 with saturated sodium carbonate aqueous solution, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, using n-heptane / ethyl acetate 10 :1 to 6:1 for column chromatography to obtain 16.9 g of yellow oily liquid with a yield of 88%. 1H NMR (400MHz, CDCl3): 7.44 (s, 2H), 7.10-7.13 (m, 1H), 6.91-...

Embodiment 3

[0075] The third step: the synthesis of 2-[(3-phenyl-2-ynyloxy)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%) to 100mL triethylamine, drop at room temperature Add a mixed solution containing 2-(propynyloxymethyl)-aniline 5 (8g, 0.05mol) and 18mL triethylamine. During the dripping process, the solution gradually becomes clear, and then react at room temperature overnight, and the system has salt precipitation. Gradually become a suspension solution. HPLC detects that the ratio of product to raw material is greater than 80:1. Concentrate under reduced pressure to remove triethylamine, add 80mL of dichloromethane for extraction, wash with saturated ammonia water, wash with saturated brine, dry with anhydrous magnesium sulfate, filter and rotate, and use n-heptane / Column chromatography was performed on ethyl acetate 15:1 to 6:1 to obtain 11.7 g of yellow oily liquid with a yi...

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Abstract

The invention discloses a multi-step synthesis method for 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepine, 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 used for ether formation, and 1-nitro-2-(propynyloxymethyl)-benzene is obtained; then, reduction is performed 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 2-benzyl-1,5-dihydrobenzo[e][1,4]oxazepine is obtained.

Description

Technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates 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 widespread 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-hypertension, anti-rheumatic, serotonin-3 (5-HT3) receptor antagonist, neuroprotective antioxidants and so on. [0003] Therefore, 1,4-benzoxazine is a highly effective framework in the drug discovery process for the development of potential anti-tuberculosis drugs. Considering its medicinal value, several synthetic strategies and...

Claims

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Application Information

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IPC IPC(8): C07D267/14
CPCC07D267/14
Inventor 高峰薛峰李瑞芳
Owner 山东三牧新材料科技有限公司
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