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A kind of 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: 2021-08-13
南京恩泰医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

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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  • A kind of preparation method of edoxaban tosylate intermediate and intermediate compound
  • A kind of preparation method of edoxaban tosylate intermediate and intermediate compound
  • A kind of preparation method of edoxaban tosylate intermediate and intermediate compound

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Example 1: Preparation of toluenesulfonic acid or Salase intermediate, including the following steps,

[0022] Step S1: (1S, 4S, 5S) -4-bromo-6-oxine diaphragm [3.2.1] Hull-7-ketone preparation, reaction formula as follows:

[0023]

[0024] Specific steps: 887.7 GN-bromine succinimide was added to a 10 L reaction bottle, and 1 l-dichloromethane was added, and the mixture was stirred. 23.44 g of calcium oxide was added. Continue to stir. The control temperature was about 25 ° C, and 600 g of S-cyclohexhene is diluted with 5 L dichloromethane to add the reaction system. Dip added, at this temperature until the end. The filter cake was washed with dichloromethane by filtration. The filtrate was combined and concentrated under reduced pressure to dry. 3 L in advance preheating 35-40 ° C Distilled water was added to the residue, stirred, filtered, and hot water. Repeat hot water is pulled once. Collect solids. The resulting white solid was dried at 35-40 ° C under vacuum. (1S...

Embodiment 2

[0031] Example 2: Preparation of the toluenesulfonic acid stated sandsess intermediate, the difference from Example 1 is that in step S3, the product of the product is 48.7 g (0.17 mol) and triphenyl phosphorus 44.6 g (0.17 mol) N- (tert-butoxycarbonyl) dissolved 51.4 g (0.17 mol) of nitrobenzenesulfonamide into 5 l of toluene, and the reaction liquid was cooled to 0 ° C, slowly add azo dihalate 296 g (1.7 mol), At this temperature, the solvent was reacted at this temperature, and the solvent was concentrated under reduced pressure, and the residue was added to the residue, cooled to 0-5 ° C, stirred, filtered, to give a white powder solid, (1S, 3R, 4S) -3- [(Tert-butoxycarbonyl) amino group] -4- [N- (tert-butoxycarbonyl) to nitrobenzenesulfonamide] -N, N-dimethylcycloxane is 79.8 g. Yield: 82.2%.

Embodiment 3

[0032] Example 3, the preparation of the toluenesulfonic agent sandseng intermediate, and the difference from Example 1 is that in step S3, (1s, 3r, 4S) -3-[(tert-butoxycarbonyl) amino] -4 - [N- (tert-butoxycarbonyl) on methylbenzenesulfonamide] -N, N-dimethylcyclohexane is prepared, and the reaction formula is as follows:

[0033]

[0034] Specific step: 23.4 g (0.082 mol) of the product of step S2 and 21.5 g (0.082 mol) of triphenyl phosphorus, N- (tert-butoxycarbonyl) were dissolved to 450 ml of toluene (0.082 mol) of methylbenzenesulfonamide. In the middle, the reaction solution was cooled to -20 ° C, and the diazethylene dikaroxide 14.3 g (0.082 mol) was slowly added, and the solvent was removed at this temperature, and the solvent was concentrated under reduced pressure, and 300 ml of ethyl acetate was added. Cooling to 0-5 ° C, stirring alfing, filtration, to give a white powder solid, (1S, 3R, 4R) -3 - [(tert-butoxycarbonyl) amino] -4- [N- (tert-butoxycarbonyl) pair Meth...

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Abstract

The present invention proposes a preparation method of edoxaban tosylate intermediate: obtained through the following reaction steps: the specific steps are: step a: under certain temperature conditions, use diformamide-substituted cyclohexylaminoalcohol, triphenyl Phosphine (PPh 3 ), diethyl azodicarboxylate (DEAD) in a solvent, then add N-(tert-butoxycarbonyl) p-nitrobenzenesulfonamide or N-(tert-butoxycarbonyl)-p-toluenesulfonamide to react to obtain hand Compound 2 after sex reversal; step b: remove Boc under strongly acidic conditions to obtain compound 1. The present invention also proposes intermediate compounds in the preparation of edoxaban tosylate intermediates: compounds and compounds. Sodium is beneficial to improve process safety and increase production yield.

Description

Technical field [0001] The present invention relates to a toluenesulfonic acid binding sandseng intermediate, which belongs to the technical field of drug preparation. Background technique [0002] EDOXABAN, trade name lixiana, is a coagulation factor XA inhibitor developed by Japan's First Three Communist Corporation, which is approved by the US FDA on January 8, 2015 to reduce non-heart valve problems. Stroke and hazardous thrombosis (systemic embolism) of patients with atrial fibrillation. During the coagulation process, activated coagulation factor X (FXA) activates thrombin (FII) into thrombin (FIIA), which causes fibrin to form, thereby forming a thrombus, so FXA has become the main one-generation anticoagulant Target. Deactivated sandsets by selective, reversible and directly inhibiting FXA to reach an oral anticoagulant drug inhibiting thrombosis, which is 104 times higher than FXA. Japan's domestic and foreign clinical trials have confirmed this product to effectively in...

Claims

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Application Information

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Patent Type & Authority Patents(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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