Sarpogrelate intermediate and preparation method thereof

A technology for sarcogrelate and intermediates, which is applied in the field of sarcogrelate intermediates and its preparation, can solve the problems of not being able to meet the needs of large-scale production, high requirements for reaction temperature, difficult sarcogrelate hydrochloride, etc., and achieve low pollution and raw materials The effect of low cost and high purity

Active Publication Date: 2015-05-20
NEW FOUNDER HLDG DEV LLC +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The inventors have found through experiments that although this method also avoids the production of triphenylphosphine oxide, the reduction step in the process has high requirements on the reaction temperature. After the reaction is completed under high temperature conditions, the resulting product has more impurities , it is difficult to finally obtain high-purity sargrel hydrochloride
In addition, high temperature reaction conditions lead to high industrial energy consumption, which cannot meet the needs of large-scale production

Method used

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  • Sarpogrelate intermediate and preparation method thereof
  • Sarpogrelate intermediate and preparation method thereof
  • Sarpogrelate intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Embodiment 1: the preparation of 3-methoxybenzyl alcohol (II):

[0071] Add 447.6g (3.29mol) of 3-methoxybenzaldehyde, 170ml of methanol and 2g of sodium hydroxide into the reaction flask, cool down to about 0°C in an ice bath, and add 34.3g of sodium borohydride powder in batches under mechanical stirring (0.91mol), control the rate of addition, keep the temperature below 50°C, after the addition is complete, place it at 25°C for 4 hours, TLC (ethyl ethyl ester: n-hexane = 1: 8) reacts completely, and then in an ice bath Next, add glacial acetic acid to the yellow reaction solution to adjust the pH value to 4 to 5; evaporate methanol under reduced pressure, add 300ml of water, separate the layers, and extract the water layer twice with 300ml of ethyl acetate. The combined organic layers were washed twice with 200 ml of saturated aqueous sodium carbonate solution, separated, dried over anhydrous sodium sulfate, filtered, and evaporated to remove the solvent under reduce...

Embodiment 2

[0072] Embodiment 2: Preparation of 3-methoxybenzyl chloride (III):

[0073] 440.6g (3.19mol) of intermediate II was added to a 1000ml reaction flask, the ice bath was lowered to 0°C, and 420ml of concentrated hydrochloric acid (37%) was added under vigorous stirring, and the reaction was completed at 30°C for 2 hours, then the temperature was raised to Reaction was carried out at 50°C for 7 hours, and TLC (ethyl ethyl ester:n-hexane=1:8) showed that the reaction was complete. Cool in an ice-water bath again to 0°C, add 400ml of water to the reaction solution, stir for 30 minutes, separate the layers, save the lower orange organic layer, extract the water layer twice with 350ml ethyl acetate, and save the organic layer with the orange separated from the previous step Combined, washed twice with 400ml saturated aqueous sodium bicarbonate solution, separated, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to obtain a light yellow liqu...

Embodiment 3

[0074] Embodiment 3: Preparation of 3-methoxybenzyl bromide (III):

[0075] Add 440.6g (3.19mol) of intermediate II to a 2000ml reaction flask, drop the ice bath to 0°C, add 700ml of hydrobromic acid (40%) under vigorous stirring, complete the addition, react at 30°C for 2 hours, then raise the temperature Reaction was carried out at 45°C for 6 hours, and TLC (ethyl ethyl ester:n-hexane=1:8) showed that the reaction was complete. Cool in an ice-water bath again to 0°C, add 400ml of water to the reaction solution, stir for 30 minutes, separate the layers, save the lower orange organic layer, extract the water layer twice with 350ml ethyl acetate, and save the organic layer with the orange separated from the previous step Combined, washed twice with 400ml of saturated aqueous sodium bicarbonate solution, separated, dried over anhydrous sodium sulfate, stored in the dark, filtered, and evaporated to dryness under reduced pressure to obtain a pale yellow liquid, decompressed by an...

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Abstract

The invention provides a sarpogrelate intermediate and a preparation method thereof. The sarpogrelate intermediate is a compound shown as formula VI. The preparation method of the intermediate comprises a Grignard reaction of salicylic aldehyde with phenolic groups protected and a Grignard reagent. The method is mild in reaction conditions, low in energy consumption and small in pollutions, and has relatively high conversion rate and low cost of the raw materials. The obtained sarpogrelate hydrochloride has high purity with the detection purity of HPLC higher than 99%. The method is suitable for large-scale production conversion.

Description

technical field [0001] The invention belongs to the field of chemical synthesis of medicines, and in particular relates to a sagrelate intermediate and a preparation method thereof. Background technique [0002] Sarpogrelate Hydrochloride (Sarpogrelate Hydrochloride, its chemical structural formula is shown in I), chemical name is: succinic acid mono[2-(dimethylamino)-1-[[2-[2-(3-methoxy Phenyl)ethyl]phenoxy]methyl]ethyl]ester hydrochloride, CAS number: 135159-51-2. This drug is a 5-HT2 receptor antagonist and platelet aggregation antagonist developed by Mitsubishi Tanabe Pharma in Japan. It was first launched in Japan in 1993. It is mainly used clinically to improve chronic thrombotic occlusive vessels with ulcers, pain and cold sensation. inflammation and other ischemic symptoms. [0003] [0004] Existing documents about sarcogrelate hydrochloride mainly include: 1) U.S. Patent US4485258; 2) Chinese patent application publication CN101239920A; 3) Chinese patent appli...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C43/23C07C41/30C07C41/26C07C219/06C07C213/06
Inventor 王威马芳
Owner NEW FOUNDER HLDG DEV LLC
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