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Preparation method of Edoxaban tosylate intermediate and intermediate compound

A technology for edoxaban toluenesulfonate and intermediates, which is applied in the field of pharmaceutical preparation, can solve the problems of increased risk, low reaction yield, and lengthy steps, etc., and achieves improved process safety, simple introduction process, and increased production yield. rate effect

Active Publication Date: 2019-06-04
南京恩泰医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The Chinese invention patent with the authorized notification number CN1826333B discloses the synthesis process of cyclohexylamino alcohol to obtain compound A through methanesulfonate esterification, sodium azide substitution, hydrolysis, amidation, and hydrogenation amination. The reaction yield in the process of ester azidation is not high, about 30%, and the diastereoselectivity is not high. In addition, in order to obtain the diformamide functional group, ethyl ester hydrolysis, condensation, and amidation procedures are required. The steps are relatively lengthy, the yield is low, the cost is high, and the dangerous chemical sodium azide needs to be used in the production, which increases the risk in the process

Method used

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  • Preparation method of Edoxaban tosylate intermediate and intermediate compound
  • Preparation method of Edoxaban tosylate intermediate and intermediate compound
  • Preparation method of Edoxaban tosylate intermediate and intermediate compound

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Embodiment 1: the preparation of edoxaban tosylate intermediate comprises the following steps,

[0022] Step S1: Preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]oct-7-one, the reaction formula is as follows:

[0023]

[0024] Specific steps: Add 887.7g of N-bromosuccinimide into a 10L reaction flask, add 1L of dichloromethane, and stir to dissolve. 23.44 g of calcium oxide were added. Continue to stir. Control the temperature at about 25°C, dilute 600g of S-cyclohexenecarboxylic acid with 5L of dichloromethane and add to the reaction system. The dropwise addition was completed, and the reaction was completed at this temperature. Filter through celite and wash the filter cake with dichloromethane. The combined filtrates were concentrated to dryness under reduced pressure. Add 3L of distilled water preheated at 35-40°C to the residue, stir to disperse, filter, and rinse with hot water. Repeat hot water beating once. Collect solids. The resulting white soli...

Embodiment 2

[0031] Embodiment 2: the preparation of edoxaban tosylate intermediate, the difference with embodiment 1 is, in step S3, get the product 48.7g (0.17mol) of step S2 and triphenylphosphine 44.6g (0.17mol ), N-(tert-butoxycarbonyl) p-nitrobenzenesulfonamide 51.4g (0.17mol) was dissolved in 5L of toluene, the reaction solution was cooled to 0°C, and 296g (1.7mol) of diethyl azodicarboxylate was slowly added, React at this temperature for 6 hours, concentrate under reduced pressure to remove the solvent, add 300ml ethyl acetate to the residue, cool down to 0-5°C, stir and crystallize, filter to obtain a white powder solid, (1S,3R,4S)-3- [(tert-butoxycarbonyl)amino]-4-[N-(tert-butoxycarbonyl)p-nitrobenzenesulfonamide]-N,N-dimethylcyclohexanecarboxamide 79.8 g. Yield: 82.2%.

Embodiment 3

[0032] Example 3, the preparation of edoxaban tosylate intermediate, differs from Example 1 in that in step S3, (1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4 -[N-(tert-butoxycarbonyl) p-toluenesulfonamide]-N, the preparation of N-dimethylcyclohexanecarboxamide, the reaction formula is as follows:

[0033]

[0034] Concrete steps: Take 23.4g (0.082mol) of the product of step S2, 21.5g (0.082mol) of triphenylphosphine, and 22.2g (0.082mol) of N-(tert-butoxycarbonyl) p-toluenesulfonamide into 450ml of toluene , the reaction solution was cooled to -20°C, and 14.3 g (0.082 mol) of diethyl azodicarboxylate was slowly added, reacted at this temperature for 6h-8h, concentrated under reduced pressure to remove the solvent, and 300ml of ethyl acetate was added to the residue. Cool down to 0-5°C, stir and crystallize, and filter to obtain a white powder solid, (1S,3R,4R)-3-[(tert-butoxycarbonyl)amino]-4-[N-(tert-butoxycarbonyl) Toluenesulfonamide]-N,N-dimethylcyclohexanecarboxamide 30....

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Abstract

The invention provides a preparation method of an Edoxaban tosylate intermediate, the method comprises the following reaction steps: step a, under a certain temperature condition, adding dimethylformamide substituted cyclohexane, triphenylphosphine (PPh3)) and diethyl azodicarboxylate (DEAD) in a solvent, and then adding N-(t-butyloxycarboryl) p-nitrobenzenesulfonamide or N-(t-butyloxycarboryl) p-toluene sulfonamide for reacting to obtain a chirally-turned compound 2; and step b, removing Boc under a strong acid condition so as to obtain a compound 1; the invention further provides intermediate compounds of the compound 1 and the compound 2 in the preparation of the Edoxaban tosylate intermediate; the amino introduction process in the preparation method is simple, the reaction conversion rate is relatively high, and industrialization is easy to realize, so that the use of hazardous chemical sodium azide is avoided, the process safety is improved, and the production yield is improved.

Description

technical field [0001] The invention relates to an intermediate of edoxaban tosylate, which belongs to the technical field of medicine preparation. Background technique [0002] Edoxaban, trade name Lixiana, is a coagulation factor Xa inhibitor developed by Daiichi Sankyo Co., Ltd., which was approved by the U.S. FDA on January 8, 2015 to reduce the risk of non-cardiac valve problems. Risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation. In the process of coagulation, activated coagulation factor X (FXa) activates prothrombin (FII) into thrombin (FIIa), which promotes the formation of fibrin and thus forms thrombus. Therefore, FXa has become the main factor for the development of a new generation of anticoagulant drugs. target. Edoxaban is an oral anticoagulant drug that inhibits thrombus formation through selective, reversible and direct inhibition of FXa, and its selectivity for FXa is 104 times higher than that of FIIa. Clin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C303/40C07C311/20
CPCY02P20/55
Inventor 夏季红孙冲于慧
Owner 南京恩泰医药科技有限公司
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