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Preparation method of argatroban intermediate

A compound, -quinolinesulfonyl technology, applied in the direction of peptides, etc., can solve problems such as large-scale production of difficult argatroban

Inactive Publication Date: 2015-12-23
CHONGQING CHANGJIE MEDICINE CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, reagents such as diphenyl phosphate azide are active in chemical properties, decompose and change color when exposed to light and moisture, and are difficult to be used in large-scale production of argatroban

Method used

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  • Preparation method of argatroban intermediate
  • Preparation method of argatroban intermediate
  • Preparation method of argatroban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 42.4g (0.10mol) of compound IV, 13.5g (0.10mol) of 1-hydroxybenzotriazole, 26mL (0.15mol) of diisopropylethylamine, 550mL of dichloromethane and 35mL of DMF in a 1000ml three-necked flask , stirred and dissolved, cooled to 0°C-5°C with ice water, added 18.8g (0.11mol) of compound V and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid ( TBTU) 32.1g (0.10mol), stirred and reacted at 0°C to 10°C for 30 minutes. Transfer to a separatory funnel, add 240 ml of water, shake and let stand to separate layers, take the organic phase, add 200 mL of dichloromethane to the water phase for extraction, combine the organic phases, dry with anhydrous magnesium sulfate, filter, and concentrate under reduced pressure , add 150 ml of diethyl ether, stir and crystallize at 0°C~-5°C for 1h. 54.9 g of the off-white solid of the target object was obtained by filtration, the yield was 95.0%, and the content was 97.6% (HPLC normalization method).

Embodiment 2

[0022] Add 21.2g (0.05mol) of compound IV, 6.8g (0.05mol) of 1-hydroxybenzotriazole, 17.5mL (0.10mol) of diisopropylethylamine, and 320mL of tetrahydrofuran into a 500ml three-necked flask, and stir to dissolve , cooled to 0°C to 5°C with ice water, added 10.3g (0.06mol) of compound V and 19.0g (HBTU) of benzotriazole-N,N,N',N'-tetramethylurea hexafluorophosphate (HBTU) ( 0.05mol), stirred and reacted at 0°C to 10°C for 60 minutes. Transfer to a separatory funnel, add 160 ml of saturated saline, shake and let stand to separate layers, take the upper organic phase, dry it with anhydrous magnesium sulfate, filter, concentrate under reduced pressure, add 80 ml of diethyl ether, and store at 0 ° C ~ -5 After stirring and crystallizing at ℃ for 40 minutes, 24.9 g of the off-white solid of the target object was obtained by filtration, with a yield of 86.1% and a content of 97.3% (HPLC normalization method).

Embodiment 3

[0024] Add 21.2g (0.05mol) of compound IV, 6.8g (0.05mol) of 1-hydroxybenzotriazole, 14.0mL (0.10mol) of triethylamine, 300mL of acetonitrile into a 500ml three-necked flask, stir to dissolve, and dissolve in ice water Cool to 0°C-5°C, add 10.3g (0.06mol) of compound V and 26.0g (0.05mol) of benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate (PyBOP), Stir the reaction at 10°C for 60 minutes, concentrate under reduced pressure, add 200 mL of dichloromethane and transfer it to a separatory funnel, then add 160 mL of saturated saline, shake and leave to separate layers, take the lower layer of dichloromethane and wash with anhydrous sulfuric acid Dry magnesium, filter, concentrate under reduced pressure at 35 ° C, add 80 ml of ether, stir and crystallize at 0 ° C ~ -5 ° C for 40 minutes, filter to obtain 25.6 g of off-white solid of the target object, the yield is 88.6%, and the content is 97.5%. (HPLC normalization method).

[0025] With PyBOP as condensing agent...

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Abstract

The invention relates to a preparation method of an argatroban intermediate (2R,4R)-1-[NG-nitro-N2-(3-methyl-8-quinolinyl sulfonyl)-L-arginyl]-4-methylpiperidine-2-ethyl formate (shown in the figure described in the description). Starting materials N2-(3-methyl-8-quinolinyl sulfonyl)-NG-nitro-L-arginine and (2R,4R)-4-methylpiperidine-2-ethyl formate are dissolved in an organic solvent, a condensation promoter and a condensation agent are added, an amidation reaction is completed to obtain the target product. The adopted condensation promoter is composed of 1-hydroxybenzotriazole and a tertiary amine, the condensation agent is O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), or O-benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophospate (HBTU), or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP). The method makes the feeding capacity of the chiral raw material (2R,4R)-4-methylpiperidine-2-ethyl formate reduced, reduces the cost, is fast in reaction rate and simple to operate, increases the yield, and is beneficial for industrialized production.

Description

technical field [0001] A method for preparing an intermediate of argatroban (Argatroban), the product of the method can be used in the synthesis of the anti-cerebrothrombotic drug Argatroban. Background technique [0002] Argatroban (Argatroban) is a non-protein thrombin inhibitor jointly developed and launched by Mitsubishi Pharmaceuticals and Daiichi Sankyo Co., Ltd. The product was first launched in Japan in 1990, in the United States in November 2000, and later in Germany and other European countries for the treatment of thromboembolism and acute cerebral thrombosis caused by chronic arterial obstruction, heparin-induced thrombocytopenia (Heparin -inducedthrombocytopenia, HIT), and prevention of thrombosis in patients receiving percutaneous coronary intervention (PCI) with or potential HIT risk. [0003] The chemical name of argatroban is: (2R,4R)-1-[N 2 -((R,S)-3-Methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-4-methylpiperidine-2-carboxylic acid- Hydrate. ...

Claims

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Application Information

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IPC IPC(8): C07K5/068
Inventor 李能刚
Owner CHONGQING CHANGJIE MEDICINE CHEM
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