Preparation method of water-soluble magnolol derivative, honokiol derivative and intermediate of magnolol derivative and honokiol derivative and related monohydroxyl protection intermediate

A technology of phenol derivatives and intermediates, applied in the field of organic synthesis, can solve problems such as inability to produce on a large scale, low selectivity, and complicated procedures, and achieve the effects of eliminating column chromatography steps, improving selectivity, and simplifying the synthesis process

Active Publication Date: 2020-12-25
BEIJING HONGHUI MEDITECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The main purpose of the present invention is to provide a kind of preparation method of water-soluble magnolol derivatives and honokiol derivatives and its intermediates, and related single hydroxyl protection intermediates, to solve the problem of preparing water-soluble magnolol derivatives in the prior art. When using nokiol derivatives and honokiol derivatives, the selectivity is low and the process is complicated, resulting in problems that cannot be mass-produced

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  • Preparation method of water-soluble magnolol derivative, honokiol derivative and intermediate of magnolol derivative and honokiol derivative and related monohydroxyl protection intermediate
  • Preparation method of water-soluble magnolol derivative, honokiol derivative and intermediate of magnolol derivative and honokiol derivative and related monohydroxyl protection intermediate
  • Preparation method of water-soluble magnolol derivative, honokiol derivative and intermediate of magnolol derivative and honokiol derivative and related monohydroxyl protection intermediate

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preparation example Construction

[0037] In formula I, R 2 is hydroxyl, and R 3 is H; or, R 2 is H, and R 3 is hydroxyl; R 1 and R 4 are independently selected from C 1 ~C 12 The electron-donating group; The preparation method comprises the following steps: compound A Carry out single hydroxyl protection with hydroxyl protection reagent in the presence of acid-binding agent to form single hydroxyl protection compound; wherein R in compound A 1 , R 2 , R 3 , R 4 With the same definition as above, the hydroxyl protection reagent is p-toluenesulfonyl chloride and 1-hydroxybenzotriazole; the single hydroxyl protection compound is subjected to nitration reaction and deprotection reaction in sequence to obtain a nitration intermediate.

[0038] Compound A has the core structure of magnolol or honokiol, and its two benzene rings each have a hydroxyl group. The present invention utilizes the activated ester formed by p-toluenesulfonyl chloride and 1-hydroxybenzotriazole under the action of an acid-binding ...

Embodiment 1

[0069] The nitration intermediate (compound 6) of honokiol derivatives is prepared by following reaction scheme

[0070]

[0071] step one:

[0072] Preparation of 3,5'-diallyl-2'-hydroxy-4-(4-methylbenzenesulfonic acid)phenol ester-1,1'-biphenyl (compound 4) (English name 3,5'- Diallyl-2′-hydroxy-[1,1′-biphenyl]-4-yl 4-methylbenzenesulfonate)

[0073] Weigh dichloromethane (160kg) into a 200L reactor, stir to lower the internal temperature to within 10°C, add HOBT (0.744kg), then add DIEA (1.61kg), then add TsCl (0.954kg), react for 30 minutes , TLC detects that TsCl disappears. Weigh honokiol (1.6kg) into the reaction kettle, control the internal temperature to 5±5°C, and continue to stir and react for 6h. Slowly add 1N hydrochloric acid solution (20 L), stir for 30 minutes, let stand, and separate the liquids. Repeat the above pickling once. Add the organic phase to the reaction kettle, add 1N sodium hydroxide solution (20 L), stir, stand still, separate the liquids...

Embodiment 2

[0084] The amino-substituted intermediate (compound 7) of honokiol derivatives was prepared using the following reaction scheme

[0085]

[0086] 3',5-diallyl-3-amino-2,4'-dihydroxy-1,1'-biphenyl (compound 7, English name 3',5-diallyl-3-nitro-[1,1' -biphenyl]-2,4'-diol)

[0087] Anhydrous ethanol (2L) was added into a 10L reaction kettle, and compound 6 (0.248kg) was added with stirring. Weigh tin protochloride (0.629kg) and add to the reactor, reflux for 2 hours, and TLC detects that the reaction is complete. Cool down to room temperature, concentrate under reduced pressure, add 5 L of ethyl acetate to the residue, stir, slowly add saturated sodium bicarbonate dropwise to pH = 8, a large amount of solids are produced, filter, separate liquids, collect the organic phase, and filter the cake with ethyl acetate 5LX3 washed, combined organic phases, and concentrated under reduced pressure to obtain khaki solid compound 7 (0.179kg), with a purity of 96% and a yield of 80%.

...

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Abstract

The invention provides a preparation of a water-soluble magnolol derivative, a honokiol derivative and an intermediate of the magnolol derivative and the honokiol derivative and a related monohydroxylprotection intermediate. The nitration intermediate has a structure as shown in a formula I which is described in the specification, wherein in the formula I, R2 is hydroxyl, and R3 is H; or R2 is H,and R3 is hydroxyl; and R1 and R4 are respectively and independently selected from electron donating groups of C1-C12. The preparation method comprises the steps of carrying out monohydroxyl protection on a compound A and a hydroxyl protection reagent in the presence of an acid-binding agent to form a monohydroxyl protection compound, wherein R1, R2, R3 and R4 in the compound A have the same definition as the former, and the hydroxyl protection reagent is p-toluenesulfonyl chloride and 1-hydroxybenzotriazole; and sequentially carrying out nitration reaction and deprotection reaction on the monohydroxyl protection compound to obtain a nitration intermediate. The synthesis efficiency of the water-soluble magnolol derivative and the honokiol derivative is effectively improved.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing water-soluble magnolol derivatives, honokiol derivatives and intermediates thereof, and related monohydroxyl protected intermediates. Background technique [0002] Magnolol and honokiol are the main active ingredients of traditional Chinese medicine magnolol, and the chemical structural formulas of magnolol and honokiol are as follows: [0003] [0004] In 1930, Japanese Sugii first isolated magnolol from the bark of Magnolia officinalis in China (Chinese herbal medicine; 2005, 36, 10, 1591-1594). In 1989, Meng Lizhen and others in China also isolated honokiol from magnolia bark (Chinese patent medicine: 1989, 11 (8): 223.). [0005] Magnolol and honokiol have a wide range of pharmacological effects such as antibacterial, anti-inflammatory, anti-tumor, muscle relaxation, cholesterol-lowering and anti-aging (Chinese herbal medicine; 2005, 36, 1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C201/12C07C205/23C07C303/30C07C309/75C07C303/28C07C213/02C07C215/78C07C231/12C07C237/08C07C269/06C07C271/22
CPCC07C201/12C07C303/30C07C303/28C07C213/02C07C231/12C07C269/06C07C309/75C07C205/23C07C215/78C07C237/08C07C271/22Y02P20/55C07C309/73C07C205/22C07C237/04
Inventor 张平平刘晔于国坤赵强峰
Owner BEIJING HONGHUI MEDITECH CO LTD
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