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Preparation method of (S)-glycidyl phthalimide

A technology of glycerol phthalimide and methanesulfonyloxy group, applied in the field of medicine and biochemical industry, can solve the problem of low solubility of potassium phthalimide, unfavorable environmental protection and industrialized production, and stable epoxy ring. problems such as poor performance, to achieve the effect of easy post-processing, easy control and implementation, and low cost

Active Publication Date: 2020-03-17
XINFA PHARMA
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  • Application Information

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Problems solved by technology

[0020] Although the method product yield is higher, the amount of benzyltriethylammonium chloride used is as high as more than 12% of potassium phthalimide, which is not easy for aftertreatment; in addition, because the stability of the epoxy ring is poor, Optional low temperature reaction
And, although this invention is to react with phthalimide and (S)-epichlorohydrin as raw materials, need to add potassium tert-butoxide, the reaction in this method is actually: phthalimide Amine and potassium tert-butoxide first form potassium phthalimide, and then react with (S)-epichlorohydrin, which is actually the nucleophilic attack of phthalimide anion on epoxy group ; The reaction process of phthalimide potassium and (S)-epichlorohydrin exists the SN of nitrogen negative ion and methyl chloride 2 Side reaction, when generating target product, generates a small amount of (R)-glycidyl phthalimide (reaction mechanism is described as following synthetic route 4), is difficult to purify; And, because phthalimide anion The stronger nucleophilicity, also can generate phthalimide negative ion and final product (S)-glycidyl phthalimide serial reaction by-product in actual reaction; The above-mentioned factors cause target product The highest purity can only reach 92%, and it needs to go through a washing step, resulting in a large amount of waste water, which is not conducive to environmental protection and industrial production
In addition, the potassium phthalimide generated due to its low solubility and low reaction temperature causes a slow reaction rate, the reaction time is 72-140 hours, the production cycle is longer, and the cost is higher

Method used

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  • Preparation method of (S)-glycidyl phthalimide
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  • Preparation method of (S)-glycidyl phthalimide

Examples

Experimental program
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Effect test

Embodiment 1

[0064] Example 1: 2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione (V 1 ) preparation

[0065] Into a 500 ml four-neck flask connected with a stirring, thermometer, and condenser tube, add 160 g of isopropanol, 29.6 g (0.20 mole) of phthalimide (Ⅲ), 27.8 g (0.30 mole) of (S) -1-Chloropropylene oxide (Ⅳ 1 ), 3.22 g (0.01 mole) of tetrabutylammonium bromide, heated, and kept stirring for 12 hours at an internal temperature of 43°C. Isopropanol was recovered by distillation under reduced pressure, 80 g of n-hexane was added to the residue, stirred, stirred at room temperature for 1 hour, filtered, the filter cake was washed with 20 g of n-hexane, and the filtrates were combined. Recover n-hexane and excess (S)-1-chloropropylene oxide by distillation under reduced pressure. After the filter cake was dried, 49.7 grams of crude product 2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione (V 1 ); directly used in Example 2 without further purification.

[0066] figure 1 B...

Embodiment 2

[0071] Embodiment 2: the preparation of (S)-glycidyl phthalimide (II)

[0072] In the 500 milliliter four-necked bottle that is connected with stirring, thermometer, add 200 grams of toluene, 49.7 grams of 2-((S)-3-chloro-2-hydroxypropyl) isoindoline- 1,3-diketone (Ⅴ 1 ), the stirring system is mixed evenly between 20-25°C. 36 grams of 30% sodium methoxide methanol solution was added dropwise thereto, and the addition was completed in 15 minutes. The reaction was stirred at 25°C for 0.5 hours. Filter, add 10 gram ice waters in the filtrate, distill and reclaim toluene, recrystallization of residue with 100 gram ethanols, obtain 34.6 gram (S)-glycidyl phthalimides, yield 85.1% (in the form of phthalimide Formimide is calculated as starting material). Optical purity 99.2% ee.

[0073] image 3 The proton nuclear magnetic spectrum (deuterated CDCl 3 );

[0074] The NMR data of the product are as follows:

[0075] 1 HNMR (400MHz, deuterated CDCl 3 )δ: 2.68(dd, J=4.8, 2....

Embodiment 3

[0079] Example 3: 2-((S)-3-bromo-2-hydroxypropyl)isoindoline-1,3-dione (V 2 ) preparation

[0080] Add 160 g of isopropanol, 29.6 g (0.20 mol) of phthalimide (Ⅲ), 40.8 g (0.30 mol) of (S) -1-Bromopropylene oxide (Ⅳ 2 ), 3.22 grams (0.01 mol) of tetrabutylammonium bromide, heated, and kept stirring for 10 hours at an internal temperature of 43°C. Isopropanol was recovered by distillation under reduced pressure, 80 g of n-hexane was added to the residue, stirred, stirred at room temperature for 1 hour, filtered, the filter cake was washed with 20 g of n-hexane, and the filtrates were combined. Recover n-hexane and excess (S)-1-bromopropylene oxide by distillation under reduced pressure. After the filter cake was dried, 59.8 grams of crude product 2-((S)-3-bromo-2-hydroxypropyl)isoindoline-1,3-dione (V 2 ), was directly used in Example 4 without further purification. 2-((S)-3-bromo-2-hydroxypropyl)isoindoline-1,3-dione (V 2 ) and the (S)-glycidyl phthalimide (II) content of...

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Abstract

The invention provides a preparation method of (S)-glycidyl phthalimide (II). Phthalimide (III) and (S)-1-substituted epoxypropane (IV) which are used as raw materials react under the action of a catalyst to generate 2-((S)-3-substituted-2-hydroxypropyl)isoindoline-1,3-dione (V), and the 2-((S)-3-substituted-2-hydroxypropyl)isoindoline-1,3-dione (V) is subjected to a cyclization reaction to obtainthe (S)-glycidyl phthalimide (II). The method has the advantages of cheap and easily available raw materials, easiness in realization of reaction conditions, low cost, short reaction route, simplicity in operation, simplicity in post-treatment, few side reactions, high yield and high purity of the target product, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of (S)-glycidyl phthalimide, which belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Rivaroxaban, known in English as Rivaroxaban, is a new oral anticoagulant drug; it is absorbed orally and has a long-lasting effect. It is used to prevent and treat venous thrombosis. It has a wide therapeutic range and does not require routine coagulation function monitoring. Rivaroxaban is the world's first direct factor Xa inhibitor developed by Bayer, which was approved by the US Food and Drug Administration (FDA) for marketing in 2011; it is mainly used clinically to prevent hip and knee replacement surgery The formation of deep vein thrombosis and pulmonary thrombosis in patients can also prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce the risk of recurrence of coronary syndrome. From 2011 to 2016, the market...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/06
CPCC07B2200/07C07D405/06C07D413/14
Inventor 刘月盛戚聿新潘秉臣陈军李新发
Owner XINFA PHARMA
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