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Method for preparing edoxaban chiral amine intermediate

A technology of intermediates and compounds, applied in the field of medicinal chemistry, can solve problems such as unfavorable production safety, achieve cost reduction, reduce the risk of residual nitrosamine carcinogenic compounds, and reduce the possible effects of nitrosamine compounds

Active Publication Date: 2020-09-01
内蒙古京东药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route requires the use of extremely explosive and highly dangerous metal azide salts, which have high risks in terms of storage, use, and subsequent disposal of the raw material metal azide salts; for the above reasons, This route is very unfavorable for the control of production safety

Method used

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  • Method for preparing edoxaban chiral amine intermediate
  • Method for preparing edoxaban chiral amine intermediate
  • Method for preparing edoxaban chiral amine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Synthesis of N-[(1R, 2R, 5S)-5-[(dimethylamino)carbonyl]-2-hydroxycyclohexyl]carbamate tert-butyl ester

[0044]

[0045]Add 109B4-01 (1200g; 7.091mol) to the reaction flask, add concentrated ammonia water (6000g), heat to 40°C and react for 8-10hrs. Concentrate under reduced pressure until about 2000-2500 g remains in the reaction flask. Add pre-prepared and cooled to room temperature sodium hydroxide aqueous solution (a solution of 600g sodium hydroxide and 5400g water), keep warm at about 40°C, add Boc-anhydride (1920g; 8.797mol) in batches; after adding, keep warm at React at 40-50°C for 2-3 hours. After cooling, dichloromethane (4800g) was added for extraction, and the aqueous phase was extracted with dichloromethane (1200g×2). Combine the organic phases; dry with anhydrous sodium sulfate, filter, and concentrate the filtrate; add 6000 g of toluene to the obtained residue, heat and stir to disperse for 1 to 2 hours, and cool to crystallize. The soli...

Embodiment 2

[0046] Example 2 Synthesis of N-[(1R, 2S, 5S)-2-azido-5-[(dimethylamino)carbonyl]cyclohexyl]carbamate tert-butyl ester

[0047]

[0048] Add toluene (3000g) to the reaction flask, then add 109B6-01 (600g; 2.095mol), add DBU (420g; 2.759mol), add diphenylphosphoryl azide (DPPA) (750g; 2.725mol). Heat to 45-50°C for 2-3hrs, then add anhydrous potassium carbonate (500g; 3.618mol), continue to heat up to 100-105°C, and stir for 36-40hrs.

[0049] After the reaction is completed, cool to 40-50°C, add water (3000g) to the reaction system, keep warm at 40-45°C, stir and extract, keep the water phase at 40-45°C, and extract with toluene three times (1200g+600g× 2); combine the organic phases; dry with anhydrous sodium sulfate, filter, collect the filtrate, concentrate toluene under reduced pressure to obtain a residue; add ethyl acetate and n-heptane (1:3, w / w) to the residue , stirred and crystallized at room temperature; filtered, collected the solid, and dried to obtain 109B8-0...

Embodiment 3

[0050] Example 3 Synthesis of N-[(1R, 2R, 5S)-5-[(dimethylamino)carbonyl]-2-[(diphenoxyphosphoryl)oxy]cyclohexyl]carbamate tert-butyl ester

[0051]

[0052] Add toluene (800g) to the reaction flask, then add 109B6-01 (100g; 349.2mmol), add DBU (75g; 492.6mmol), add diphenylphosphoryl azide (DPPA) (150g; 545.1mmol). Heat to 45-50°C, keep warm for 4 hours, cool to room temperature, stir and crystallize; filter, collect the solid, and dry to obtain 109B7-P1 with a dry weight of about 157g. Yield: 86.7% (theoretical amount: 181.08 g).

[0053] Take part of the solid obtained above, heat beating and refining with toluene to obtain purified 109B7-P1, and its nuclear magnetic spectrum data are as follows:

[0054] 1 H-NMR (500MHz, CDCl 3 ): 1.40ppm(s, 9H); 1.52~2.19ppm(m, 2H+2H+2H); 2.78ppm(m, 1H); 2.92ppm, 3.00ppm(d, 3H+3H); 4.10~4.12ppm( m, 1H); 4.66 ~ 4.67ppm (m, 1H); 5.67pm (br, 1H); 7.16 ~ 7.18ppm (t, 2H); 7.21 ~ 7.25ppm (m, 4H); 4H).

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Abstract

The invention provides a safe, simple and convenient method which is more suitable for industrial large-scale production and preparation of N-[(1R, 2S, 5S)-2-amino-5-[(dimethylamino) carbonyl] cyclohexyl] tert-butyl carbamate. A compound N-[(1R, 2R, 5S)-5-[(dimethylamino) carbonyl]-2-hydroxycyclohexyl] tert-butyl carbamate is used as a raw material; toluene, n-heptane and other hydrocarbons are used as reaction solvents; in presence of DBU, reacting with diphenylphosphoryl azide to obtain a mixture of N-[(1R, 2R, 5S)-5-[(dimethylamino) carbonyl]-2-[(diphenoxy phosphoryl) oxy] cyclohexyl] tert-butyl carbamate and DBU azide acid salt; adding a proper amount of an alkali, and replacing phosphate with azide generated in the system to obtain corresponding azide N-[(1R, 2S, 5S)-2-azide-5-[(dimethylamino) carbonyl] cyclohexyl] tert-butyl carbamate; and reducing the azido group to obtain the corresponding amino compound N-[(1R, 2S, 5S)-2-amino-5-[(dimethylamino) carbonyl] cyclohexyl] tert-butyl carbamate.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new method for preparing edoxaban p-toluenesulfonic acid hydrate and its key intermediate. Part of the edoxaban p-toluenesulfonate hydrate intermediate structure involved in the present invention is as follows: [0002] Background technique [0003] Edoxaban p-toluenesulfonate Hydrate developed by Daiichi Sankyo Co., Ltd. was approved for marketing by Japan Pharmaceuticals and Medical Devices Agency (PMDA) on April 22, 2011; The U.S. Food and Drug Administration (FDA) approved for marketing; on June 19, 2015, it was approved for marketing by the European Medicines Agency (EMA). It is marketed and sold in Japan by Daiichi Sankyo Co., Ltd. under the trade name It is a direct anticoagulant factor Xa inhibitor. For the treatment of venous thromboembolism in patients following total knee replacement, total hip replacement, or hip fracture surgery. [0004] The main routes ...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/24
CPCC07C269/06C07C269/04C07C231/12C07B2200/07C07C2601/14C07C271/24C07C237/24Y02P20/55
Inventor 吕关锋肖江郭荣耀
Owner 内蒙古京东药业有限公司
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