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Synthesis method of Beraprost sodium intermediate

A synthesis method and compound technology, applied in organic chemistry methods, chemical instruments and methods, organic chemistry, etc., can solve problems such as hidden dangers of industrial production safety, equipment is difficult to meet requirements, and the reaction environment is unfriendly, and the reaction time can be shortened, It is convenient for safe operation and industrial production, and the effect of saving operation steps

Inactive Publication Date: 2019-11-15
JINAN KANGHE MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0018] The preparation route of literature Synlett, 1998, 930-932 synthesizes 3a, 8b-cis-dihydro-3H-5,7-dibromocyclopentadiene [b] benzofuran to (1S, 4R)-4- Acetoxy-cyclopenten-1-alcohol is used as raw material to obtain (1R)-4-phenoxy-1-(2-bromophenoxy)-cyclopentene through three-step reaction, and then through n-butyllithium Reaction with bromine and metal zinc reaction to obtain 3a, 8b-cis-dihydro-3H-5,7-dibromocyclopentadiene [b] benzofuran, the synthetic route is as follows; the route steps are long, and two This is the first time to use Mitsunobu reaction, which is not friendly to the environment and has potential safety hazards; in addition to using bromine, the reaction uses n-butyllithium to react at ultra-low temperature -78°C, and it is difficult for the equipment to meet the requirements in scale-up production
In addition, the use of a large amount of metal zinc (40 equivalents) will bring safety hazards to future industrial production

Method used

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  • Synthesis method of Beraprost sodium intermediate
  • Synthesis method of Beraprost sodium intermediate
  • Synthesis method of Beraprost sodium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Embodiment one: the synthesis of compound I

[0057]

[0058] Add cyclopentene, carbon tetrachloride, NBS, benzoyl peroxide (BPO), cyclopentene and carbon tetrachloride in a mass / volume ratio of 1:10 g / mL, cyclopentene and NBS molar The ratio is 1:1.8, the molar ratio of cyclopentene and benzoyl peroxide (BPO) is 1:0.01, the system is under nitrogen atmosphere, at 60-70°C, react for 0.5-1 hour, cool down to 0-5°C and stir At least half an hour. Then filter, collect the filtrate, and directly carry out the next reaction.

[0059] In another reaction flask, add ethylene glycol dimethyl ether, add 60% NaH, the molar ratio of cyclopentene and NaH is 1:1.8, cool down to -10~0°C, add 2,4,6-tribromophenol Ethylene glycol dimethyl ether solution, the molar ratio of cyclopentene and tribromophenol is 1:1.8, stir at -5~0°C for at least 1 hour, and add the previously prepared dibromide solution at -5~0°C , add 18-crown-6, rise to room temperature, and stir the reaction at ro...

Embodiment 2

[0064] Embodiment two: the synthesis of compound I

[0065] Add cyclopentene, carbon tetrachloride, NBS, benzoyl peroxide (BPO), cyclopentene and carbon tetrachloride in a mass / volume ratio of 1:10 g / mL, cyclopentene and NBS molar The ratio is 1:1.8, the molar ratio of cyclopentene and benzoyl peroxide (BPO) is 1:0.03, the system is under nitrogen atmosphere, at 70-76°C, reacted for 0.5-1 hour, cooled to 0-5°C, Stir for at least half an hour. Then filter, collect the filtrate, and directly carry out the next reaction.

[0066] In another reaction flask, add ethylene glycol dimethyl ether, add 60% NaH, the molar ratio of cyclopentene and NaH is 1:1.8, cool down to -10~0°C, add 2,4,6-tribromophenol Ethylene glycol dimethyl ether solution, the molar ratio of cyclopentene and tribromophenol is 1:1.8, stir at -5~0°C for at least 1 hour, and add the previously prepared dibromide solution at -5~0°C , add 18-crown-6, rise to room temperature, and stir the reaction at room temperatu...

Embodiment 3

[0067] Embodiment three: the synthesis of compound I

[0068] Add cyclopentene, carbon tetrachloride, NBS, benzoyl peroxide (BPO), cyclopentene and carbon tetrachloride in a mass / volume ratio of 1:20 g / mL, cyclopentene and NBS molar The ratio is 1:1.8, the molar ratio of cyclopentene and benzoyl peroxide (BPO) is 1:0.01, the system is under nitrogen atmosphere, at 76-80°C, react for 0.5-1 hour, cool down to 0-5°C and stir At least half an hour. Then filter, collect the filtrate, and directly carry out the next reaction.

[0069]In another reaction flask, add ethylene glycol dimethyl ether, add 60% NaH, the molar ratio of cyclopentene and NaH is 1:2.0, cool down to -10~0°C, add 2,4,6-tribromophenol Ethylene glycol dimethyl ether solution, the molar ratio of cyclopentene and tribromophenol is 1:2.0, stir at -5~0°C for at least 1 hour, and add the previously prepared dibromide solution at -5~0°C , add 18-crown-6, rise to room temperature, and stir the reaction at room temperat...

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Abstract

The invention relates to a synthesis method of a Beraprost sodium intermediate (III). Cyclopentene and N-bromo-succinimide (NBS) carry out free radical reaction to obtain dibromocyclopentene; and dibromocyclopentene reacts with 2,4,6-tribromophenol to directly generate 3,5-bis(2,4,6-tribromophenoxyl) cyclopentene (compound I) through a one-pot method. Then through Grignard reactions, a compound (I) and a compound (II) are obtained. N-bromo-succinimide and a commercial product namely cyclopentene are taken as the raw materials to synthesize dibromocyclopentene, 170 DEG C cracking and ultralow temperature reactions (-40 to -30 DEG C) are avoided, the using of bromine is also avoided, the reaction conditions are milder, and the synthesis method is more environmentally friendly and is convenient for industrial production.

Description

technical field [0001] This field belongs to the field of compound preparation, and specifically relates to a synthetic method of a key intermediate of beraprost sodium. Background technique [0002] Beraprost sodium (trade name Dorner) belongs to prostacyclin derivatives and is an antiplatelet drug developed by Japan Toray Co., Ltd. (Toray). Beraprost (Beraprost) was approved in Japan in 1992 as a drug for chronic arterial occlusion. Beraprost in the form of racemate for the treatment of pulmonary arterial hypertension (PAH) has been approved by the U.S. FDA to enter phase II clinical trials. In 2007, Toray and Astellas (formerly Yamanouchi) )’s Beraprost Sodium Sustained Release Tablets (Careload LA) was approved in Japan for the treatment of PAH, becoming the first sustained release agent among prostacyclins. At present, this variety has not yet been listed in the United States and the European Union. [0003] At present, the domestic beraprost sodium preparations are ...

Claims

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Application Information

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IPC IPC(8): C07C41/16C07C43/247C07D307/91
CPCC07D307/91C07C41/16C07C43/247C07C17/10C07C2601/10C07B2200/07C07C23/08
Inventor 侯云艳艾雷锋邓超张颖胡金山
Owner JINAN KANGHE MEDICAL TECH
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