A kind of synthetic method of S-glycidyl phthalimide

A technology of glycerol phthalimide and potassium phthalimide, applied in the field of medicine and biochemical industry, can solve problems such as unfavorable industrialized production, long reaction time, difficult aftertreatment, etc., and the reaction temperature is not harsh , the effect of high reaction yield and purity, and low production cost

Active Publication Date: 2020-07-17
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • 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 of the poor stability of the epoxy ring, the reaction The optional temperature is low and the reaction time is long; the reaction process of potassium phthalimide and S-epichlorohydrin has an SN2 side reaction of nitrogen anion and methyl chloride, and generates a small amount of R while generating the target product. -Glycidyl phthalimide (possible reaction mechanism described as following synthetic route 4), difficult to purify, unfavorable for industrialized production

Method used

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  • A kind of synthetic method of S-glycidyl phthalimide
  • A kind of synthetic method of S-glycidyl phthalimide
  • A kind of synthetic method of S-glycidyl phthalimide

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Embodiment 1

[0058] Example 1: N-(S-2,2-dimethyl-1,3-dioxolane-4-)methylphthalimide (IV 1 ) preparation

[0059] Add 250 grams of N,N-dimethylformamide (DMF), 37.0 grams (0.20 moles) of potassium phthalimide, 33.3 grams of (0.22 mol) R-2,2-dimethyl-4-chloromethyl-1,3-dioxolane, 0.5 g of potassium iodide, heated, and kept stirring at an internal temperature of 80-85°C for 4 hours. Cool to 20°C, filter, wash the filter cake with 50 g of DMF, and combine the filtrates. DMF was recovered by distillation under reduced pressure, and the residue was recrystallized with 80 g of methyl tert-butyl ether to obtain 49.7 g of N-(S-2,2-dimethyl-1,3-dioxolane-4-)methyl-o- Phthalimide, yield 95.3%, HPLC purity 99.7%.

[0060] The preparation process of embodiment 2-embodiment 5 is the same as embodiment 1, and difference list 1 is as follows:

[0061] Table 1: Example 2-Example 5:

[0062]

Embodiment 6

[0069] Embodiment 6: Preparation of S-glycidylphthalimide (II)

[0070] Add 200 g of 1,2-dichloroethane, 26.5 g (0.10 moles) of N-(S-2,2-dimethyl-1,3-di Oxolane-4-)methylphthalimide, 25 grams of 40% hydrobromic acid, stirred and reacted at 10-15°C for 4 hours. The layers were separated, and the aqueous layer was extracted three times with 1,2-dichloroethane, 20 g each time, the organic phases were combined, and the organic phases were transferred to a constant-pressure low-liquid funnel. In another flask, add 30 g (0.15 moles) of 27% sodium methoxide methanol solution, keep the internal temperature between 0-5°C and add the obtained organic phase dropwise, after dropping, stir and react at 10-15°C for 3 hours. Add 200 grams of ice water, separate layers, extract the water layer twice with 1,2-dichloroethane, 20 grams each time, combine the organic phases, recover 1,2-dichloroethane by distillation, and use 50 grams of methanol to extract the residue. tert-butyl ether was rec...

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Abstract

The invention relates to a low-cost and high-purity S-glycidyl phthalimide synthesis method, which comprises: carrying out a substitution reaction on potassium phthalimide and R-2,2-disubstituted-4-halomethyl-1,3-dioxolane to generate N-(S-2,2-disubstituted-1,3-dioxolane-4-)methylphthalimide, carrying out a ketone (aldehyde) removing ring-opening reaction to produce N-2-S-hydroxy-3-halogenated n-propyl phthalimide, and finally carrying out an elimination reaction to remove hydrogen halide so as to generate S-glycidyl phthalimide, wherein S-glycidyl phthalimide is the key intermediate for the preparation of rivaroxaban. According to the present invention, the synthesis method has advantages of inexpensive and easily-available raw materials, high stability, high reaction selectivity and highproduction efficiency, and the obtained S-glycidyl phthalimide has advantages of low cost and high purity, and is favorable for the industrial production of high-purity rivaroxaban.

Description

technical field [0001] The invention relates to a method for synthesizing 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 that 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. The world's first direct factor Xa inhibitor developed for Bayer was approved by the US Food and Drug Administration (FDA) in 2011. Clinically, it is mainly used to prevent the formation of deep vein thrombosis and pulmonary thrombosis in patients after hip and knee replacement. It can also prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce the recurrence of coronary artery syndrome. risk. Its market sales from 2011 to 2016 reached US$5.56 bil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06
CPCC07D405/06
Inventor 戚聿新钱余锋刘月盛杨嘉民鞠立柱
Owner XINFA PHARMA
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