A kind of preparation method of rivaroxaban intermediate

A technology for rivaroxaban and intermediates, applied in the field of preparation of rivaroxaban intermediate S-N-glycidyl phthalimide, which can solve the problems of difficult purification of mixtures, difficult industrialization, and harsh reaction conditions , to achieve the effect of avoiding special requirements of equipment, reducing production cost and low cost

Active Publication Date: 2020-02-21
ZHEJIANG YONGTAI TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0032] This technical route obtains the mixture that is difficult to purify and the yield is low, and only the target product with a chiral purity of about 95% is obtained
[0033] In summary, the current process for synthesizing S-N-glycidyl phthalimide generally has problems such as harsh reaction conditions, low yield, high cost, poor quality, and difficult industrialization.

Method used

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  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Preparation of 2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione (Compound I)

[0063]

[0064] Put phthalimide (100.0 g 0.68 mol), 1.0 g of basic alumina, 1.0 g of TMBAC, 300 g of isopropanol, and 23.0 g of S-epichlorohydrin into a four-necked flask, and stir. Control the inner temperature at 20-25°C and keep it warm for 12 hours, take samples and control it until the residue of phthalimide in the reaction solution is ≤1.0%, and the reaction ends. Concentrate to remove isopropanol, add 400g of toluene to dissolve and filter to recover alumina for use; the filtrate is washed with 2×100g of water, concentrated, and 450g of n-heptane is added to crystallize to obtain 150g of compound I (yield 92.1%).

Embodiment 2

[0065] Example 2: Preparation of 2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione (Compound I)

[0066]

[0067] Put phthalimide (100.0g 0.8mol), basic aluminum oxide (recovered from Example 1) 1.0g, TMBAC1.0g, isopropanol 300g, S-epichlorohydrin 23.0g into four ports bottle, stir. Control the inner temperature at 20-25°C and keep it warm for 12 hours, take samples and control it until the residue of phthalimide in the reaction solution is ≤1.0%, and the reaction ends. Concentrate to remove isopropanol, add 400g of toluene to dissolve and filter to recover alumina for use; the filtrate is washed with 2×100g of water, concentrated, and 450g of n-heptane is added to crystallize to obtain 149.4g of compound I (91.7% yield).

Embodiment 3

[0068] Example 3: Preparation of 2-((S)-3-chloro-2-hydroxypropyl)isoindoline-1,3-dione (Compound I)

[0069]

[0070] Put phthalimide (100.0g 0.8mol), basic aluminum oxide (recovered from Example 2) 1.0g, TMBAC1.0g, isopropanol 300g, S-epichlorohydrin 23.0g into four ports bottle, stir. Control the inner temperature at 20-25°C and keep it warm for 12 hours, take samples and control it until the residue of phthalimide in the reaction solution is ≤1.0%, and the reaction ends. Concentrate to remove isopropanol, add 400g of toluene to dissolve and filter to recover alumina for use; the filtrate is washed with 2×100g of water, concentrated, and 450g of n-heptane is added to crystallize to obtain 149.0g of compound I (yield 91.5%).

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Abstract

The invention relates to a preparation method of rivaroxaban intermediate S-N-glycidyl phthalimide. According to the method, catalytic reaction is carried out by using recoverable aluminum oxide in apreparation process of S-N-glycidyl phthalimide, so that the production cost is reduced, the emission requirement is reduced, the problem that the product quality is affected by a phase transfer catalyst difficultly eliminated is solved, the reaction time is further shortened, the special requirement on equipment caused by the use of potassium tert-butanolate is avoided, the production cost is reduced, and therefore, the preparation method is particularly suitable for industrial production.

Description

technical field [0001] The invention relates to the field of organic synthetic medicinal chemistry, and more specifically, relates to a preparation method of S-N-glycidyl phthalimide, an intermediate of rivaroxaban. Background technique [0002] Rivaroxaban is currently the most promising antithrombotic drug. The essential difference from the traditional antithrombotic drug heparin is that it does not require the participation of antithrombin III and can directly antagonize free and bound factor Xa. Heparin requires antithrombin III to function, and factor Xa in the prothrombin complex is ineffective. These two new oral anticoagulant drugs are hailed by the medical community as a major advance in the field of anticoagulant therapy and the prevention of potentially fatal thrombosis, and will become new milestones in the history of cardiovascular drug development. Rivaroxaban was jointly developed by Bayer Pharmaceuticals of Germany and Johnson & Johnson of the United States....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/48C07D405/06
CPCC07B2200/07C07D209/48C07D405/06
Inventor 王学进甘立新周国斌徐旭炳杨家乐张冲
Owner ZHEJIANG YONGTAI TECH CO LTD
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