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Preparation method of eptifibatide key raw material L-higher arginine

A technology of eptifibatide and arginine, which is applied in the field of preparation of unnatural amino acids, can solve the problems of high cost, low yield, and complicated purification, and achieve the effect of low route cost

Inactive Publication Date: 2021-02-19
宁夏蓝博思化学技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the technical problems of purification complexity, low yield and high cost in the original process, and provide a kind of (S)-11-(tert-butoxycarbonylamino)-1-(9H-fluoren-9-yl )-15,15-Dimethyl-3,13-dioxa-2,14-dioxa-4,10,12-triazahexadecyl-11-ene-5-carboxylic acid and subsequent N-(9-fluorenylmethoxycarbonyl)-2,2,4,6,7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine, a key intermediate in the synthesis of eptifibatide preparation method

Method used

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  • Preparation method of eptifibatide key raw material L-higher arginine
  • Preparation method of eptifibatide key raw material L-higher arginine
  • Preparation method of eptifibatide key raw material L-higher arginine

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Experimental program
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Effect test

Embodiment 1

[0030] (S)-11-(tert-butoxycarbonylamino)-1-(9H-fluoren-9-yl)-15,15-dimethyl-3,13-dioxa-2,14-dioxa- Synthesis of 4,10,12-Triazahexadecyl-11-ene-5-carboxylic Acid

[0031]

[0032] 2L tetrahydrofuran was added to a 5L reactor, and 680g (2.622mol, 1eq) of 1,3-di(tert-butoxycarbonyl)guanidine and 291g (2.884mol, 1.2eq) of triethylamine were added under stirring. After the addition was complete, Stir to dissolve, then add 500g (2.623mol, 1eq) of tetrahydrofuran solution of p-toluenesulfonyl chloride dropwise. After extracting with methane and concentrating dichloromethane, a large amount of solids precipitated out, filtered, the filter cake was washed with 500 mL of water, and dried to obtain 950 g of the product. The yield is 87.6%, and the liquid phase content is 99.61%.

[0033]

[0034] In the reaction kettle, add 75Kg DMF, add 7.5Kg (16mol, 1eq) N-fluorenylmethoxycarbonyl-N'-tert-butoxycarbonyl-L-lysine under stirring, after the addition is complete, stir to dissolve, ...

Embodiment 2

[0036] (S)-11-(tert-butoxycarbonylamino)-1-(9H-fluoren-9-yl)-15,15-dimethyl-3,13-dioxa-2,14-dioxa- Synthesis of 4,10,12-Triazahexadecyl-11-ene-5-carboxylic Acid

[0037]

[0038] Add 3.4L dichloromethane in 5L reactor, add 680g (2.622mol, 1eq) 1,3-bis (tert-butoxycarbonyl) guanidine and 372.8g (2.884mol, 1.2eq) diisopropyl under stirring After the addition of ethylamine, stir to dissolve, then dropwise add 0.5L dichloromethane solution containing 500g (2.623mol, 1eq) p-toluenesulfonyl chloride, control the temperature at 15-20°C, stir and react for 2 hours, take a sample for TLC It was detected that there was no raw material remaining, the solvent was concentrated under reduced pressure and then extracted with dichloromethane. After concentrating the dichloromethane, a large amount of solids precipitated, filtered, the filter cake was washed with 500mL of water, and 1020.2g of the product was obtained after drying. The yield is 94.1%, and the liquid phase UPLC content is 9...

Embodiment 3

[0042] Synthesis of N-(9-fluorenylmethoxycarbonyl)-2,2,4,6,7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine

[0043]

[0044] In the reaction kettle, add 3Kg ethyl acetate, add 500g (0.819mol, 1eq) Fmoc-hArg(Boc2)-OH under stirring, after the addition is complete, stir to dissolve, then cool down to 0°C, add dropwise 4mol / L ethyl acetate Ester hydrochloric acid solution 620mL, control the temperature at 20-25°C, stir and react for 2 hours, concentrate ethyl acetate under vacuum until no liquid, add 1Kg acetone to solidify to obtain 395g wet product of Fmoc-L-arginine hydrochloride (LOD10 %), put 395g wet product Fmoc-L-arginine hydrochloride into the kettle, add 3L acetone, cool to 0°C, add dropwise 8% sodium bicarbonate aqueous solution to adjust pH=7-7.5, add 147.6g (1.142 mol, 1.5eq) DIPEA, add 241.4g (0.836mol, 1.1eq) Pbf-Cl in batches, after the addition is complete, raise the temperature to 20-25°C and react for 3 hours, the raw material is detected by HPLC < 0.2%, a...

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Abstract

The invention discloses a preparation method of an eptifibatide key raw material L-higher arginine, and belongs to the field of synthesis of medical intermediates. The preparation method comprises thefollowing steps: reacting 1,3-bis(tert-butyloxycarbonyl)guanidine with p-toluenesulfonyl chloride to obtain 1,3-bis-Boc-2-(p-toluenesulfonyl)guanidine, then reacting the 1,3-bis-Boc-2-(p-toluenesulfonyl)guanidine with N-fluorenylmethoxycarbonyl-N'-tert-butyloxycarbonyl-L-lysine Fmoc-hArg(Boc2)-OH, removing Boc protection, and feeding Pbf-Cl to obtain N-(9-fluorenylmethoxycarbonyl)-2,2,4,6,7-pentamethyl-2H-benzofuran-5-sulfonyl-L-arginine. According to the invention, a p-toluenesulfonyl polypeptide guanidinylating agent is adopted in the route, so that ultralow-temperature reaction and the useof trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride with high corrosivity are avoided, and a simple and efficient way is provided for the synthesis of the intermediate.

Description

technical field [0001] The present invention relates to a preparation method of an unnatural amino acid, in particular to a (S)-11-(tert-butoxycarbonylamino)-1-(9H-fluoren-9-yl)-15,15-dimethyl- 3,13-Dioxa-2,14-dioxa-4,10,12-triazahexadecyl-11-ene-5-carboxylic acid. Background technique [0002] Eptifibatide, alias Eptifibatide, English name Eptifibatide, CAS: 188627-80-7. It was first developed by COR Therapeuties in the United States, and it was first listed in the United States under the trade name of Integrelin in July 1998. [0003] Eptifibatide is a synthetic cyclic peptide containing one mercaptopropionic acid and six amino acid residues. It is a specific antagonist of platelet glycoprotein GP IIb / IIIa receptors, and selectively and reversibly inhibits the final process of platelet aggregation. The common pathway (plasma coagulation due to the combination of coagulation factor I and GP IIb / IIIa) can reverse the ischemic state caused by thrombosis. Clinically, it is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/79C07C279/24C07C277/08C07C303/38C07C311/64C07C269/06C07C271/22
CPCC07B2200/07C07C269/06C07C277/08C07C303/38C07D307/79C07C2603/18C07C279/24C07C311/64C07C271/22
Inventor 杨文茂王勇余翔唐磊马龙王玉莹何伦云
Owner 宁夏蓝博思化学技术有限公司
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