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A method for synthesizing bnc105

A solvent and reaction temperature technology, applied in the field of BNC105 preparation, can solve the problems of long synthetic route, unsuitable for industrial production, increased energy consumption, etc., and achieve the effect of mild reaction conditions, simple and feasible operation, and cheap and easy-to-obtain raw materials

Inactive Publication Date: 2017-03-22
SHANGHAI QINGDONG BIOTECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above route, the protection of the hydroxyisopropyl group of o-vanillin needs to be heated at 110°C for a long time, which increases the energy consumption
The iodolation of 2-isopropoxy-3-methoxyphenol requires the use of copper acetate and results in a large amount of waste residue
The synthetic route is too long, and the total yield is only 18.8%, which is not suitable for industrial production

Method used

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  • A method for synthesizing bnc105
  • A method for synthesizing bnc105
  • A method for synthesizing bnc105

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Experimental program
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Effect test

Embodiment 1

[0028] Embodiment 1 prepares the method for BNC105

[0029] A kind of preparation method of BNC105, see figure 2 , using o-vanillin and 3,4,5-trimethoxybenzaldehyde as starting materials, respectively through hydroxyl protection, aldehyde group oxidation hydrolysis to phenol, iodide to generate o-iodophenol intermediates and nucleophilic addition, oxidation The method of producing acetylene ketone intermediate; acetylene ketone and o-iodophenol intermediate is subjected to Michael addition, free radical ring closure and deprotection to obtain the product BNC105.

[0030] Concrete preparation steps are as follows:

[0031] A: o-vanillin and 2-bromopropane or benzyl bromide react with a base and a phase transfer catalyst at room temperature and in a specific solvent to obtain 2-isopropoxy-3-methoxybenzaldehyde or 2-benzyloxy-3 -Methoxybenzaldehyde. The base used in the reaction is sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, calcium hydri...

Embodiment 2

[0038] The specific preparation steps of embodiment 2 BNC105

[0039] (1) Synthesis of 2-isopropoxy-3-methoxybenzaldehyde

[0040] Weigh o-vanillin (500g, 3.286mol, 1.0eq), potassium carbonate (908g, 6.572mol, 2.0eq) and dissolve in 2L acetone, add tetrabutylammonium bromide (54g, 0.165mol, 0.05eq), Stir at room temperature for 15 minutes, drop in 2-bromopropane (405mL, 4.272mol, 1.3eq), dropwise, stir at room temperature for 24 hours, filter, concentrate, dissolve the residue in ethyl acetate, wash with water three times, distill under reduced pressure, and dry in vacuo to obtain 612 g of light yellow oily liquid product, HPLC content 98%, yield 96%.

[0041] 1 H NMR (500MHz, CDCl 3 )δ10.45(d, J=0.7Hz, 1H), 7.41(dd, J=7.3, 2.1Hz, 1H), 7.16-7.04(m, 2H), 4.62(dt, J=12.3, 6.2Hz, 1H ), 3.87(s, 3H), 1.32(d, J=6.2Hz, 6H); 13 CNMR (125MHz, CDCl 3 )δ191.0, 153.4, 150.7, 131.0, 123.8, 119.1, 118.0, 76.4, 56.1, 22.4; ESI-MS: [M+H] + 195.1[M+Na] + 217.2.

[0042] (2) Synthesis ...

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Abstract

The invention relates to a method for compounding BNC 105, which uses o-vanillin and 3,4,5- trimethoxy-benzaldehyde as starting materials. The o-vanillin is subjected to hydroxy protection and aldehyde oxidation to be hydrolyzed into phenol, and the phenol is subjected to iodination to generate o-iodophenol intermediates. The 3,4,5-trimethoxy benzaldehyde is subjected to nucleophilic addition and oxidation to generate acetylenic ketone intermediates. The acetylenic ketone intermediates and the o-iodophenol intermediates are processed to obtain the BNC 105 through Michael addition, free-radical ring closing and deprotection. The method for compounding the BNC 105 is low in cost of raw materials, easy to obtain the raw materials, mild in reaction conditions and simple and feasible in operation, and is suitable for commercial process.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of BNC105. Background technique [0002] BNC105 is a precursor compound of the anti-tumor phosphate prodrug BNC105P developed by the Australian Bionomics company through structural modification of the natural anti-tumor compound combretastatin A-4 (CA4), which can bind to tubulin and selectively Destroy tumor primary blood vessels, quickly cut off tumor blood supply, and cause tumor center necrosis. Compared with CA4, which is already in Phase III clinical research, BNC105 has 8 times the ability of CA4 to inhibit the growth of blood vessels, and can more effectively inhibit the growth of tumor tissue, and is safer and more effective. Currently, BNC105P has entered phase II clinical trials. [0003] The chemical name of BNC105 is 2-methyl-3-(3,4,5-trimethoxybenzophenone)-6-methoxy-7-hydroxybenzofuran, and its chemical structure is: [0004] [0005] Th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/86
CPCC07D307/86
Inventor 孙青张卫东袁虎
Owner SHANGHAI QINGDONG BIOTECH CO LTD
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