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Eptifibatide preparing method

A technology of efibactide and efibactide, which is applied in the field of drug synthesis, can solve the problems of easy generation of impurities, complicated process, harsh acid hydrolysis conditions, etc., and achieve the effect of avoiding the generation of impurities

Inactive Publication Date: 2016-01-06
叶仲林
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Chinese patent CN1500805A, the raw material has used Mpr (Bzl) and Fmoc-Harg (Pbf)-OH, because the group Bzl acid hydrolysis condition on Mpr (Bzl) is harsh, efbate resin must adopt acid hydrolysis reagent (TFA / HBr / HAc / TIS / EDT), it is easy to produce impurities, and the price of Fmoc-Harg(Pbf)-OH is more expensive at the same time; Chinese patent CN1858060A, the raw material uses fragment Mpr(Trt)-Harg(Boc 2 )-OH, but the fragment Mpr(Trt)-Harg(Boc 2 )-OH preparation is more cumbersome
Chinese patent CN102584944A raw material adopts two fragments Mpr(TrtorAcm)-Harg-OH and Fmoc-Gly-Asp(OtBu)-OH, the process is complex

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0051] Example 1: Synthesis of Mpr(Mmt)-Harg-OH.HCl

[0052] Dissolve 200g 3-mercaptopropionic acid (Mpr) with 2.5LN,N-dimethylformamide (DMF), cool in ice water, and slowly add 582g 4-methoxytriphenylchloromethane (Mmt-Cl) under stirring, add After 4-methoxytriphenylchloromethane, the reaction was stirred for another 8 hours. Add 5L of water to the reaction solution under stirring to separate out solids. Wash the solids with water 5 times (2L each time), filter, and then wash with ethyl acetate 3 times (2L each time), filter, and dry at 60°C to obtain 611g product Mpr(Mmt) -OH (85.7% yield).

[0053] Dissolve 600gMpr(Mmt)-OH and 201gHOSu with 3L tetrahydrofuran (THF), cool in ice water, and slowly add 327gN,N'-dicyclohexylcarbodiimide (DCC) with stirring, naturally warm to room temperature, and react at room temperature for 15 hour. Filter, wash the solid with THF 3 times (0.5L each time), combine the filtrate and washing liquid, concentrate at least the amount in vacuum at 40°...

Embodiment 2

[0055] Example 2: Synthesis of Fmoc-Cys(Mmt)-OH

[0056] 200g cysteine ​​hydrochloride (Cys.HCl) add 1.5LN,N-dimethylformamide (DMF) to dissolve, slowly add 392g 4-methoxytriphenylchloromethane (Mmt-Cl) under stirring, After 4-methoxytriphenylchloromethane was added, the reaction was stirred at room temperature for 12 hours. Add 3L of water to the reaction solution under stirring, then add sodium carbonate (Na 2 CO 3 ) Adjust PH=6~7, precipitate solid, wash the solid with water 3 times (1.5L each time), filter, and then wash 3 times with ethyl acetate (1.5L each time), filter, and dry at 45°C to obtain 412g product Cys(Mmt ) (Yield 82.5%).

[0057] 400gCys(Mmt) plus 1L water (H 2 O), 0.5L tetrahydrofuran (THF) dissolved, add sodium carbonate (Na 2 CO 3 ) Adjust PH=7~9, add 342g Fmoc-OSu, stir and react for 12 hours, add sodium carbonate (Na 2 CO 3 ) Maintain the pH of the reaction solution at 7-9. After the reaction is complete, add 6N aqueous hydrochloric acid to adjust the pH to...

Embodiment 3

[0058] Example 3: Peptide resin 1: Synthesis of Cys(Mmt)-Resin

[0059] Weigh 184.7g of Fmoc-Cys(Mmt)-OH and 48.6g of HOBt, add 1600mL of DMF and stir to dissolve, add 48.8ml of DIC under stirring with ice-water cooling, and react for 0.5 hours to obtain an activated ester solution of protected amino acids for use. Weigh 158.7g (100mmol) of RinkAMResin with a substitution value of 0.63mmol / g, add it to the solid phase reactor, add 1600ml DMF and stir the swelling resin for 30 minutes, drain it, add 20% PIP / DMF solution (volume ratio) 1600mL, stir to react 0.5 After hours, drain it, wash it with DMF 6 times, and drain it to get RinkAMResin with Fmoc group removed. Add the activated ester solution of the protected amino acid to the Fmoc group-removed RinkAMResin, stir the reaction at room temperature, check the reaction with ninhydrin, and monitor every 1 hour until it is complete (the ninhydrin detection resin is colorless), and the reaction After completion, it was washed 6 time...

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Abstract

The invention belongs to the field of polypeptide drug synthesis, and particularly relates to an eptifibatide preparing method. The method comprises the steps of 1, conducting coupling sequentially by means of the polypeptide solid-phase synthesis method with protected amino acid, fragments and amino resin as raw materials to obtain eptifibatide peptide resin X-Gly-Asp(OtBu)-Trp(Boc)-pro-Cys(R1)-amino resin, wherein R1 is Trt, Mtt, Mmt or Dmt, X is Mpr(R2)-Harg, and R2 is Mtt, Mmt or Dmt; 2, adding an acidolysis reagent to the eptifibatide peptide resin for acidolysis to obtain a reduced eptifibatide crude product; 3, oxidizing the reduced eptifibatide crude product to obtain an eptifibatide crude product; 4, conducting separation and purification on the eptifibatide crude product through a C18 column to obtain eptifibatide. The method has the advantages that due to the adoption of Fmoc-Cys(R1) and the fragment Mpr(R2)-Harg, usage of the expensive raw material Fmoc-Harg(Pbf)-OH is avoided, peptide resin acidolysis condition is made milder, generation of impurities can be effectively avoided, product purity can be over 99.5%, and industrial prospects are broad.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a new preparation method of efibati. Background technique [0002] Eptifibatide is a synthetic cyclic heptapeptide which is an antagonist of glycoprotein (GP)Ⅱb / Ⅲa receptor (platelet coagulation factor Ⅰ receptor), which can block platelet aggregation and has a very powerful anti-platelet aggregation effect. The peptide sequence structure is as follows: [0003] [0004] The structure of Efebat is: [0005] [0006] CAS#: 148031-34-9; Molecular formula: C 35 H 49 N 11 O 9 S 2 ; Molecular weight: 831.96. [0007] Efebat is a glycoprotein (GP) IIb / IIIa receptor (platelet coagulation factor I receptor) antagonist. The final common pathway that can selectively and reversibly inhibit platelet aggregation (the combination of plasma coagulation factor Ⅰ and GPⅡb / Ⅲa) can reverse the ischemic state caused by thrombosis. This species was developed by the American company CORTherapeutics a...

Claims

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Application Information

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IPC IPC(8): C07K7/06C07K1/36C07K1/30C07K1/16C07K1/06C07K1/04
Inventor 叶仲林
Owner 叶仲林
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