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Preparation method and intermediate of chiral diamine compound

A technology of chiral diamines and compounds, applied in the field of preparation of chiral diamine compounds and their intermediates, can solve the problems of lower conversion efficiency, difficult separation of diastereoisomers, harsh reaction conditions, etc., and achieve high yield High, good chiral purity, low safety risk

Inactive Publication Date: 2019-06-21
SHANGHAI SYNCORES TECH INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The above two existing technologies also have the following disadvantages: 1. The conversion from 1F to 1G all adopts NaN 3 Substitution of methanesulfonyl group, the chiral selectivity of this reaction is not good, the diastereoisomers produced are extremely difficult to separate, and the chiral purity is low
2. The conversion yield of 1F to 1G reported in the compound patent is only 30%, which not only has safety risks, but also greatly reduces the conversion efficiency of the entire route, making the production cost high and the discharge of three wastes increasing accordingly
3. The conversion from 1G to 1H requires high-pressure hydrogenation reduction of azide, the reaction conditions are relatively harsh, and there are still safety risks
4. Contains NaN 3 The organic solvents and waste water are not easy to handle, which is not conducive to environmental protection
[0011] Due to pressures such as the aging of the social population, the demand for anticoagulant drugs is increasing, and the shortcomings of the existing technology are not conducive to the industrial production of Edoxaban

Method used

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  • Preparation method and intermediate of chiral diamine compound
  • Preparation method and intermediate of chiral diamine compound
  • Preparation method and intermediate of chiral diamine compound

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Example 1: Preparation of ethyl (1S,3R,4S)-3-(tert-butoxycarbonylamino)-4-(1,3-dioxoisoindoline-2-yl)cyclohexylcarboxylate

[0030]

[0031] In a three-necked flask equipped with mechanical stirring and a thermometer, add 930 mL of anhydrous tetrahydrofuran, ethyl (1S,3R,4R)-3-((tert-butoxycarbonylamino)-4-hydroxycyclohexanecarboxylate (46.5 g, 1.0 eq), phthalimide (28.5g, 1.2eq), triphenylphosphine (51.0g, 1.2eq), N 2 After the replacement, the temperature of the system was lowered to 0-10° C., and diisopropyl azodicarboxylate (42.3 g, 1.5 eq) was slowly added dropwise, and N 2 After replacement, it was raised to room temperature for 2 hours, and further raised to 40-50° C. for 12 hours. TLC monitoring showed that the reaction was complete. After cooling down to room temperature, the tetrahydrofuran was concentrated to dryness, and 280 mL of methyl tert-butyl ether was added for slurry at about 10°C for 2 hours, and an off-white solid was obtained by filtration. T...

Embodiment 2

[0032] Example 2: Preparation of ethyl (1S,3R,4S)-3-(tert-butoxycarbonylamino)-4-(1,3-dioxoisoindoline-2-yl)cyclohexylcarboxylate

[0033] Add 240 mL of anhydrous toluene, ethyl (1S,3R,4R)-3-((tert-butoxycarbonylamino)-4-hydroxycyclohexanecarboxylate (12.0 g, 1.0 eq), phthalimide (12.3g, 2.0eq), triphenylphosphine (21.9g, 2.0eq), N 2 After the replacement, the temperature of the system was lowered to 0-10° C., and diisopropyl azodicarboxylate (21.8 g, 3.0 eq) was slowly added dropwise, and N 2 After the replacement, rise to room temperature and react for 2 hours, and further rise to 70-80° C. for 6 hours. TLC monitoring shows that the reaction is complete. Reduce to about 10°C and beat for 2 hours, filter to obtain off-white solid. Dissolve the solid in 144 mL of dichloromethane, add 72 mL of water and wash once. Separate the organic phase, concentrate the dichloromethane to dryness, add 84mL of ethanol, heat up to 60°C to dissolve, then cool down to 0-10°C to crystallize t...

Embodiment 3

[0034]Example 3: Preparation of (1S,3R,4S)-3-(tert-butoxycarbonylamino)-4-(1,3-dioxoisoindoline-2-yl)cyclohexylcarboxylic acid methyl ester

[0035]

[0036] Add 240 mL of anhydrous methyl tert-butyl ether, (1S,3R,4R)-3-((tert-butoxycarbonylamino)-4-hydroxycyclohexanecarboxylic acid methyl ester into a three-necked flask equipped with mechanical stirring and a thermometer (12.0g, 1.0eq), phthalimide (12.9g, 2.0eq), triphenylphosphine (23.0g, 2.0eq), N 2 After the replacement, the temperature of the system was lowered to 0-10° C., and diethyl azodicarboxylate (22.9 g, 3.0 eq) was slowly added dropwise, and N 2 After replacement, it was raised to room temperature for 2 hours, and further raised to 40-50° C. for 12 hours. TLC monitoring showed that the reaction was complete. Reduce to about 10°C and beat for 2 hours, filter to obtain off-white solid. Dissolve the solid in 144 mL of dichloromethane, add 72 mL of water and wash once. Separate the organic phase, concentrate th...

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Abstract

The present invention relates to a preparation method and an intermediate of a chiral diamine compound, wherein the chiral diamine compound is used for preparing the key intermediate of a small molecule oral anticoagulant edoxaban. According to the present invention, the steps of the preparation method of the chiral diamine compound 2 and the key intermediate 2B are defined in the specification, wherein the group R is preferably selected from methoxy, ethoxy and dimethylamino.

Description

technical field [0001] The invention relates to a preparation method of a chiral diamine compound and an intermediate thereof. The chiral diamine compound is a key intermediate for preparing a small molecule oral anticoagulant edoxaban. Background technique [0002] Edoxaban is a small molecule oral anticoagulant developed by Daiichi Sankyo Co., Ltd. in Japan. It was approved in April 2011 and launched in Japan in July 2011. During the blood coagulation process, activated coagulation factor X (FXa) activates prothrombin (FII) into thrombin (FIIa), which promotes the formation of fibrin, thereby forming thrombus. Therefore, FXa has become the main target of a new generation of anticoagulant drugs . Edoxaban achieves the purpose of inhibiting thrombus formation by selectively and reversibly inhibiting FXa. Clinical studies have verified its good safety, oral absorption and anticoagulant activity. The chemical structure of Edoxaban is shown in the structure in Formula 1. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48C07C269/06C07C271/24
Inventor 栗增翟其松赵鸿斐何先亮张继承黄鲁宁陶安平安建国陈茜顾虹
Owner SHANGHAI SYNCORES TECH INC
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