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Method for synthesizing diastereoisomer of Doranidazole intermediate

A technology of diastereoisomers and synthetic methods, which is applied in the direction of organic chemistry, can solve the problems of easy explosion, unsatisfactory operation yield and purity, instability, etc., and achieve the safety of raw materials and reagents, easy operation and large-scale production , to avoid the effect of hydrolysis

Inactive Publication Date: 2010-08-18
深圳万乐药业有限公司
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Problems solved by technology

[0011] EP0632028 discloses the method for synthesizing (4R, 5R)-4,5-bis(acetoxymethyl)-1,3-dioxolane by D-diethyl tartrate through four-part reaction, wherein the ring-forming reaction needs two The first step is completed, using dimethoxymethane (also called methylal) and phosphorus pentoxide, dimethoxymethane has a low boiling point, is unstable, and is prone to explosion, and phosphorus pentoxide is violently exothermic when it meets water, so this method Not convenient for industrial enlargement operation
[0012] JP2001-158782 discloses the synthesis of 4,5-bis(benzoyloxymethyl)-1,3-dioxolane by cyclization reaction of 1,4-dibenzoyloxybutanetetraol and paraformaldehyde The method of alkane, European Patent EP72027 discloses the method for synthesizing 4,5-bis(benzoyloxymethyl)-1,3-dioxolane by 1,4-dichloro-2,3-butanediol , Japanese Patent Laid-Open No. 10-287657 discloses the synthesis of (4RS, 5SR)-4,5-bis(benzoyloxymethyl) by (2RS, 3SR)-1,4-dibenzoyloxybutanetetraol -1, the method for 3-dioxolane, but the corresponding optically active starting material required for the compounds shown in the synthetic formula II and formula III by these methods is not easy to buy and obtain, and the actual operation yield and purity are not ideal

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  • Method for synthesizing diastereoisomer of Doranidazole intermediate
  • Method for synthesizing diastereoisomer of Doranidazole intermediate
  • Method for synthesizing diastereoisomer of Doranidazole intermediate

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Embodiment 1

[0024] Synthesis of (4R, 5R)-4,5-bis(benzoyloxymethyl)-1,3-dioxolane a) (4R,5R)-4,5-bis(ethoxy Preparation of carbonyl)-1,3-dioxolane

[0025] Add 100g of L-diethyl tartrate, 100g of anhydrous calcium chloride, 50g of paraformaldehyde into the reactor, add 1000ml of toluene, then add 50ml of boron trifluoride ether, heat and stir, stir at 78-82°C for 3 hours, cool To 0-10°C, add triethylamine dropwise to the reaction solution until the pH is 9, filter, and concentrate the filtrate to obtain an oily substance. Purification by silica gel column chromatography (elution with ethyl acetate / petroleum ether 1:20) gave 30.1 g of the product.

[0026] b) Preparation of (4R, 5R)-4,5-bis(hydroxymethyl)-1,3-dioxolane

[0027] Add 5.94 g of lithium aluminum hydride into 70 ml of THF in portions, and dissolve 30.1 g of (4R,5R)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane obtained in a) in 23 ml of THF, And dropwise added to the aforementioned mixture of lithium aluminum hydride and THF, first s...

Embodiment 2

[0036] Embodiment 2 (4S, 5S)-4, the synthesis of 5-bis(benzoyloxymethyl)-1,3-dioxolane

[0037] a) Preparation of (4S, 5S)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane

[0038] Add 100g of D-diethyl tartrate, 100g of anhydrous calcium chloride, and 50g of paraformaldehyde into the reactor, add 1000ml of benzene, then add 50ml of boron trifluoride ether, heat and stir, and react with stirring at 78-82°C for 3 hours. Cool to 0-10°C, add triethylamine dropwise to the reaction solution until the pH is 9, filter, and concentrate the filtrate to obtain an oil. Purification by silica gel column chromatography (elution with ethyl acetate / petroleum ether 1:20) gave 30 g of the product.

[0039] b) Preparation of (4S, 5S)-4,5-bis(hydroxymethyl)-1,3-dioxolane

[0040]Add 5.92 g of lithium aluminum hydride into 70 ml of THF in portions, and dissolve 30 g of (4S, 5S)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane obtained in the above a) in 23 ml of THF, And dropwise added to the above-mentioned mixtur...

Embodiment 3

[0049] Embodiment 3 (4S, 5S)-4, the synthesis of 5-bis(benzoyloxymethyl)-1,3-dioxolane

[0050] a) Preparation of (4S, 5S)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane

[0051] Add 100g of D-diethyl tartrate, 100g of anhydrous calcium chloride, and 50g of paraformaldehyde into the reactor, add 1000ml of toluene, then add 50ml of boron trifluoride ether, heat and stir, and react with stirring at 78-82°C for 2 hours, Cool to 0-10°C, add triethylamine dropwise to the reaction solution until the pH is 9, filter, and concentrate the filtrate to obtain an oil. Purification by silica gel column chromatography (elution with ethyl acetate / petroleum ether 1:20) yielded 31.2 g of the product.

[0052] b) Preparation of (4S, 5S)-4,5-bis(hydroxymethyl)-1,3-dioxolane

[0053] Add 6.00 g of lithium aluminum hydride into 70 ml of THF in portions, and dissolve 31.2 g of (4S, 5S)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane obtained in a) in 25 ml of THF, And dropwise added to the above-mentioned mixture ...

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Abstract

The invention discloses a method for synthesizing diastereoisomer of Doranidazole intermediate [(4RS,5SR)-4,5-di(benzoyl oxido-methyl)-1,3-dioxolane]. The method is realized in the following steps: using L-diethyl tartrate or D-diethyl tartrate as the initial raw material, cyclizing, reducing and acidylating to obtain the diastereoisomer [(4R,5R)-4,5-di(benzoyl oxido-methyl)-1,3-dioxolane or (4S,5S)-4,5-di(benzoyl oxido-methyl)-1,3-dioxolane]. The invention has the advantages that the initial raw material with optical activity is easy to purchase, the raw material and the reagents are safe and stable, and the method is convenient for operation and amplified production.

Description

technical field [0001] The invention relates to the field of organic chemistry, and further relates to a method for synthesizing diastereoisomers of Doranidazole intermediates. Background technique [0002] (4RS,5SR)-4,5-bis(benzoyloxymethyl)-1,3-dioxolane has the structure of formula I: [0003] [0004] Formula I [0005] This compound can be used as an intermediate for preparing radiosensitizer anticancer drug Doranidazole. EP0632028 discloses a method for synthesizing Doranidazole from 4,5-bisacyloxymethyl-1,3-dioxolane. The reaction formula is as follows: [0006] [0007] The compound of formula I exists as two diastereoisomers of dioxolane, namely (4R,5R)-4,5-bis(benzoyloxymethyl)-1,3-dioxolane And (48,55)-4,5-bis(benzoyloxymethyl)-1,3-dioxolane, as shown in formula II and formula III: [0008] [0009] Formula II Formula III [0010] The diastereoisomers can be used as reference substances in the quality research of Doranidazole bulk drug, and can also b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/24
Inventor 钱建彬张广明刘飞键陈轶之吴祖望
Owner 深圳万乐药业有限公司
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