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A kind of preparation method of rivaroxaban intermediate and new synthesis method of rivaroxaban

A compound and reaction time technology, applied in the direction of organic chemistry, can solve the problems of unstable toxicity, low optical purity, product racemization, etc., and achieve the effect of high safety, high optical purity and simple operation

Active Publication Date: 2015-09-09
JIANGXI SYNERGY PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] This method requires a large amount of irritating, volatile, unstable and highly toxic (S)-epichlorohydrin; and in the post-treatment, water needs to be added, and the reaction system becomes strongly alkaline, resulting in partial racemization of the product. Optical purity is only 98% or less

Method used

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  • A kind of preparation method of rivaroxaban intermediate and new synthesis method of rivaroxaban
  • A kind of preparation method of rivaroxaban intermediate and new synthesis method of rivaroxaban
  • A kind of preparation method of rivaroxaban intermediate and new synthesis method of rivaroxaban

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Embodiment 1: the preparation of (S)-N-glycidyl phthalimide

[0054] I. Synthesis of (S)-N-2,3-dihydroxypropylphthalimide

[0055] Under nitrogen protection, in a 250ml reaction flask, (R)-3-chloro-1,2-propanediol (5.0g, 45.2mmol) and phthalimide potassium salt (10.0g, 54.0mmol) were mixed in In 100ml of absolute ethanol, the temperature was raised to 78°C, and the reaction was refluxed for 12 hours. After completion of the reaction, filter, and concentrate the filtrate to dryness under reduced pressure, add 100ml of ethyl acetate and 100ml of water, extract and separate layers, wash the organic layer with 50ml of saturated brine, and concentrate to dryness under reduced pressure to obtain (S)-N-2, 3-Dihydroxypropylphthalimide (9.0 g), yield: 90%, optical purity: 99.5%.

[0056] II. Preparation of (S)-N-glycidylphthalimide

[0057] Under nitrogen protection, in a 250ml reaction flask, (S)-N-2,3-dihydroxypropylphthalimide (5.0g, 22.6mmol) prepared in step I was mixed wi...

Embodiment 2

[0066] Embodiment 2: the preparation of (S)-N-glycidyl phthalimide

[0067] I. Synthesis of (S)-N-2,3-dihydroxypropylphthalimide

[0068] Under nitrogen protection, in a 250ml reaction flask, (R)-3-bromo-1,2-propanediol (5.0g, 32.3mmol) and phthalimide potassium salt (9g, 48.6mmol) were dissolved in 100ml The temperature was raised to 78° C. in absolute ethanol, and the reaction was refluxed for 14 hours. After the reaction was completed, the filtrate was concentrated to dryness under reduced pressure, 100ml of ethyl acetate and 100ml of water were added, the layers were extracted, the organic layer was washed with 50ml of saturated brine, and then concentrated to dryness under reduced pressure to obtain (S)-N-2,3 - Dihydroxypropylphthalimide (6.6 g), yield: 92%, optical purity: 99.5%.

[0069] II. Preparation of (S)-N-glycidylphthalimide

[0070] Under nitrogen protection, in a 250ml reaction flask, the (S)-N-2,3-dihydroxypropylphthalimide (5.0g, 22.6mmol) obtained in step...

Embodiment 3

[0071] Embodiment 3: the preparation of (S)-N-glycidyl phthalimide

[0072] I. Synthesis of (S)-N-2,3-dihydroxypropylphthalimide

[0073] Under nitrogen protection, in a 250ml reaction flask, (R)-3-iodo-1,2-propanediol (5.0g, 24.8mmol) and phthalimide sodium salt (4.2g, 24.8mmol) were mixed in Heat up to 82°C in 100ml of isopropanol, and reflux for 8 hours. After the reaction was completed, the filtrate was concentrated to dryness under reduced pressure, 100ml of ethyl acetate and 100ml of water were added, the layers were extracted, the organic layer was washed with 50ml of saturated brine, and then concentrated to dryness under reduced pressure to obtain (S)-N-2,3 - Dihydroxypropylphthalimide (4.9 g), yield: 89%, optical purity: 99.4%.

[0074] II. Preparation of (S)-N-glycidylphthalimide

[0075] Under nitrogen protection, in a 250ml reaction flask, the (S)-N-2,3-dihydroxypropylphthalimide (4.5g, 20mmol) prepared in step I and pyridine (3.5g, 44mmol ) was dissolved in 1...

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Abstract

The invention discloses a preparation method of (S)-N-glycidol phthalimide in a structural formula 1. The method comprises the following steps of: I, phthalimide salt of a structural formula 9 and a compound of a structural formula 10 are subjected to heating reflux for reaction in an alcohols solvent to obtain the compound of a structural formula 11; II, the compound of the structural formula 11 obtained form the step I is reacted with the compound of a structural formula 12 in an aprotic solvent under the action of alkaline to obtain a (S)-N-glycidol phthalimide crude product of the structural formula 1; and III, the (S)-N-glycidol phthalimide crude product of the structural formula 1 obtained from the step II is refined by ethanol to obtain the (S)-N-glycidol phthalimide with the optical purity larger than or equal to 99.0%. The preparation method is simple to operate and good in safety, the optical purity of the obtained product is high (larger than or equal to 99.0%), and the preparation method is suitable for industrial production. The invention also discloses a novel synthetic method of Rivaroxaban.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a method for preparing a rivaroxaban intermediate: (S)-N-glycidyl phthalimide and a new method for synthesizing rivaroxaban by using the method. technical background [0002] Rivaroxaban (Rivaroxaban), chemical name: 5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl) -1,3-oxazolin-5-yl)methyl)thiophene-2-carboxamide, CAS number: 366789-02-8, the structural formula is shown in 2. [0003] [0004] Rivaroxaban is the world's first oral direct inhibitor of coagulation factor Xa. It has definite anticoagulant effect and is mainly used clinically to prevent deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients after hip and knee replacement. ) formation; it can also be used to prevent stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation, and reduce the risk of recurrence of coronary syndrome. It is current...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/06C07D413/14
Inventor 蒋慧纲徐烘材黄伟平黄国军
Owner JIANGXI SYNERGY PHARMA
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