Chiral amino compound, preparation method and application thereof, and preparation method for preparing edoxaban intermediate from chiral amino compound

A technology of amino compounds and edoxaban, which is applied in the preparation of organic compounds, preparation of carbamic acid derivatives, chemical instruments and methods, etc., can solve the problems of high price and increased production cost, and achieve low cost, easy operation, The effect of mild reaction conditions

Active Publication Date: 2020-10-13
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In the above-mentioned route, the raw material chiral (S)-cyclohexene-1-carboxylic acid is expensive, and additional amino groups need to be introduced, which increases the production cost

Method used

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  • Chiral amino compound, preparation method and application thereof, and preparation method for preparing edoxaban intermediate from chiral amino compound
  • Chiral amino compound, preparation method and application thereof, and preparation method for preparing edoxaban intermediate from chiral amino compound
  • Chiral amino compound, preparation method and application thereof, and preparation method for preparing edoxaban intermediate from chiral amino compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] This example provides The synthesis method is as follows:

[0075] Provide a 5mL sealed tube, add nitroene sequentially (1 mmol), catalyst (20 mol%), add 2 mL of 1,4-dioxane and a stir bar, acetaldehyde (10 mmol). The reaction was detected by TLC until the nitroalkene raw material disappeared. Spin to dry, column chromatography (petroleum ether / ethyl acetate=4:1) to get the product. Yield 86%.

[0076] Optical purity values ​​determined by chiral HPLC column, ee: 95%.

[0077] NMR analysis: 1 H NMR (400MHz, CDCl 3 )δ:9.74(s,1H),7.84(dd,J=5.5,3.1Hz,2H),7.74(dd,J=5.5,3.1Hz,2H),5.57-5.44(m,1H),5.07(dd ,J=13.2,9.6Hz,1H),4.77(dd,J=13.2,4.6Hz,1H),3.24(qd,J=18.6,7.2Hz,2H). 13 C NMR (101MHz, CDCl 3 )δ: 197.2, 167.4, 134.6, 131.3, 123.8, 74.5, 43.3, 43.1.

Embodiment 2

[0079] This example provides The specific method is as follows:

[0080] The product of Example 1 was dissolved in tetrahydrofuran as a reactant (1mmol), and 2-diethoxyoxyphosphonic acid ethyl ester (1.5mmol) and sodium carbonate (2mmol) were added at 0°C, and then reacted at 0°C, TLC monitors the reaction until the reaction is complete, the reaction is quenched with saturated ammonium chloride solution, extracted three times with dichloromethane, the organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent is evaporated under reduced pressure, column chromatography (eluent: Petroleum ether / ethyl acetate=4:1) to obtain the product. Yield 40%.

[0081] The ratio of diastereoisomers was determined by proton NMR, dr=20:1.

[0082] NMR analysis: 1 H NMR (400MHz, CDCl 3 )δ7.83(dd, J=5.4,3.1Hz,2H),7.73(dd,J=5.4,3.1Hz,2H),6.99-6.93(m,1H),5.65(td,J=11.2,5.7Hz ,1H),4.93(td,J=11.2,6.2Hz,1H),4.23(q,J=7.1Hz,2H),3.31(dd,J=17.1,5.4Hz,1H...

Embodiment 3

[0084] This example provides Synthesis.

[0085] Method 1: Provide 5mL sealed tubes, add nitroolefins sequentially (1 mmol), catalyst (20mol%), add 2mL of methanol and a stir bar, acetaldehyde (10mmol). The reaction was detected by TLC until the nitroenamine raw material disappeared. Spin to dry, column chromatography (petroleum ether / ethyl acetate=4:1) to get the product. Yield 56%.

[0086] Optical purity values ​​determined by chiral HPLC column, ee = 50%.

[0087] NMR analysis: 1 H NMR (400MHz, CDCl 3 )δ:9.74(s,1H),5.20(d,J=7.3Hz,1H),4.74(dd,J=13.6,7.0Hz,1H),4.64-4.52(m,2H),2.93(dd,J =10.3,5.8Hz,2H),1.42(s,9H). 13 CNMR (101 MHz, CDCl 3 )δ: 199.0, 154.8, 80.67, 44.9, 44.3, 28.2.

[0088] Method 2:

[0089] Its synthetic route is as follows:

[0090]

[0091] Compound 1 (the product of Example 1) was dissolved in dichloromethane: isopropanol: water (1:6:1 by volume) solution, then added 7 equivalents of sodium borohydride, stirred at room temperature for r...

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Abstract

The invention provides a chiral amino compound, a preparation method and application thereof, and a preparation method for preparing an edoxaban intermediate from the chiral amino compound. The structure of the chiral amino compound is shown as a formula (III); the structure of the edoxaban intermediate prepared by the formula (III) is as shown in the formula (I). The R1 and R2 are independently aprotecting group of nitrogen or hydrogen; wherein R is a C1-6 alkoxy group, an N, N-dimethylamino group, an N-methylamino group or a benzylamino group. The compound shown in the formula (III) can beprepared on a large scale with high optical purity only through one-step reaction without a chiral resolution process, and the preparation process is simple, efficient and low in cost; according to the present invention, the edoxaban intermediate represented by the formula (I) can be prepared by using the compound represented by the formula (III) as the raw material through the one-step reaction,wherein the expensive (S)-3-cyclohexene-1-formic acid does not need to be used as the starting material, and the chiral resolution is not required, the route is short, and the use of sodium azide canbe effectively avoided; therefore, the reaction condition is mild, the yield is high, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the preparation and application of an intermediate compound of an anticoagulant drug edoxaban. Background technique [0002] With the aging population and changes in living environment and eating habits, thrombosis is gradually becoming an important disease that threatens human health. Thromboembolic diseases, such as myocardial infarction, stroke, and deep vein thrombosis, have become one of the diseases with the highest morbidity and mortality rates in the world. At present, antithrombotic drugs are divided into three categories: antiplatelet aggregation drugs, thrombolytic drugs and anticoagulant drugs. Anticoagulant drugs mainly include traditional anticoagulant heparin, vitamin K inhibitors, thrombin inhibitors, and coagulation factor Xa inhibitors. Direct coagulation factor Xa inhibitor Shaban drugs are new anticoagulant drugs with high selectivity, good anticoagulant e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/18C07C271/64C07C233/76C07D209/48C07C271/24C07C233/81C07D513/04C07C269/06C07C231/12C07C269/04C07C303/38C07C311/20
CPCC07C231/12C07C233/76C07C233/81C07C269/04C07C269/06C07C271/18C07C271/24C07C271/64C07C303/38C07D209/48C07D513/04C07C2601/16C07C311/20Y02P20/55
Inventor 翁江庞孟柯鲁桂李卓明
Owner SUN YAT SEN UNIV
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