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A technology of edoxaban and free state, which is applied in the field of compound synthesis, can solve the problems of unfavorable process preparation in purification methods, solidification of reaction liquid, and easy inclusion of impurities, etc., and achieve the effect of improved crystallization method, mild reaction conditions, and easy purification
Active Publication Date: 2016-07-13
LEPU PHARMACEUTICAL CO LTD
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[0004] Existing preparations of free edoxaban include: US7365205, CN102348688A, CN200680033991.7, CN201310069698.8, CN104761571A. In most of the previous patents, there are shortcoming of long synthetic route and unfavorable purification method f
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[0021] A preparation method of free edoxaban, the synthetic route is as follows:
[0022]
[0023] 1. Preparation of Intermediate 1:
[0024]
Embodiment 1
[0025] Example 1: Suspend raw material B (25.5g, 0.096mol) in acetonitrile (300mL), add the first amount of triethylamine (9.6g, 0.096mol) dropwise at 10°C±2°C, and then add raw material A (30g, 0.0810mol), add dropwise the second amount of triethylamine (39g, 0.384mol), raise the temperature to 60°C±5°C, stir at 60°C±5°C for 6-8 hours, then cool down to room temperature, add the first A certain amount of water (300mL) was used to quench the reaction; after stirring for 1-1.5 hours at 10°C±2°C, a second amount of water (600ml) was added, filtered, and the resulting solid was washed and purified to obtain the compound intermediate 1 (34.8 g, yield 93%, product purity > 95%);
Embodiment 2
[0026] Example 2: Suspend raw material B (25.5g, 0.096mol) in acetonitrile (300mL), add the first amount of triethylamine (9.6g, 0.096mol) dropwise at 10°C±2°C, and then add raw material A (30g, 0.0810mol), drop the second amount of triethylamine (39g, 0.384mol), raise the temperature to 60℃±5℃, and stir at this temperature for 6-8 hours, then cool down to room temperature, add water (900mL ) to quench the reaction; after stirring for 1-1.5 hours at 10°C ± 2°C, filter, and the obtained solid was washed and purified, and the spot plate showed that raw material B was included, and recrystallization and purification made the preparation process cumbersome, and intermediate 1 (30g , Yield 80%), the yield decreases.
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Abstract
The invention discloses a preparation method for free-state edoxaban.The synthetic route is shown in the description.According to the preparation method, the charging sequence is changed, and a curing problem caused by a traditional method is reduced; according to an existing method, a starting material A and triethylamine are added at first, a starting material B is added, a large amount of solid will appear in the temperature increasing process, and the stirring uniformity is greatly affected, so that the yield is greatly lowered, and the method is adopted for greatly solving the problem and improving the yield; when the compound free-state edoxaban is synthetized, a first amount of a saturated sodium bicarbonate water solution is added at first, the phenomenon that a product is rapidly separated out and impurities are included due to the fact that the added saturated sodium bicarbonate water solution is excessive is avoided, and meanwhile introduction of genotoxicity impurity methanesulfonate is effectively avoided; after the impurities are completely hydrolyzed, a second amount of the saturated sodium bicarbonate water solution is added so that the product can be separated out thoroughly; the method improves the crystallization way, the yield is improved, and generation of impurities is reduced.
Description
technical field [0001] The invention belongs to the technical field of compound synthesis, and in particular relates to a preparation method of free edoxaban. Background technique [0002] Edoxaban in free form, chemically expressed as: N-(5-chloropyridin-2-yl)-N ， -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c ]pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide, the molecular formula is: C 24 h 30 ClN 7 o 4 S, its p-toluenesulfonate monohydrate is the main component of antithrombotic preparations. [0003] Edoxaban is a small molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd., which is a factor X (FXa) blocker. Edoxaban clinical trials were conducted on patients undergoing total knee arthroplasty (TKA), total hip arthroplasty (THA), and hip fracture surgery (HFS) in Japan and Taiwan, and each group of edoxaban inhibited the occurrence of VTE. The effects were significantly better than the placebo group and compa...
Claims
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