CN101538316B - Method for preparing Eptifibatide with solid phase method - Google Patents
Method for preparing Eptifibatide with solid phase method Download PDFInfo
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- CN101538316B CN101538316B CN 200910104994 CN200910104994A CN101538316B CN 101538316 B CN101538316 B CN 101538316B CN 200910104994 CN200910104994 CN 200910104994 CN 200910104994 A CN200910104994 A CN 200910104994A CN 101538316 B CN101538316 B CN 101538316B
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Abstract
The invention discloses a method for preparing Eptifibatide with a solid phase method, which comprises the following steps of: 1) selecting Sieber resin to remove Fmoc, and obtaining H2N-Sieber resin; 2) adopting Fmoc/tBu solid phase method to couple and synthesize linear peptide Eptifibatide-Sieber resin with full protective lateral chains in sequence; 3) conducting solid phase oxidation to the resin, and obtaining oxidant peptide Eptifibatide-Sieber resin with full protective lateral chains; 4) cutting the resin and removing the lateral chain protection, and obtaining crude product of Eptifibatide; and 5) conducting separation and purification, and breeze drying by a freeze dryer, and obtaining refined Eptifibatide peptide. The technology is characterized by simple operation, easy post treatment, less investment of raw material, low cost, high yield and the like, and has considerable economical and practical value and wide application prospect in the field of polypeptide drug design and synthesis simultaneously.
Description
Technical field
The present invention the invention belongs to the pharmaceutical technology field, especially relates to the novel method of the synthetic Eptifibatide (Eptifibatide) of a kind of solid phase method.
Background technology
Eptifibatide has another name called Integrilin, Eptifibatide, English name: Eptifibatide, molecular formula: C
35H
49N
11O
9S
2, CAS accession number 148031-34-9, its structure does
Eptifibatide is an anti-platelet aggregation agent, is developed jointly by U.S. COR Therapeutics company and U.S. Schering-Plough company.In July, 1998 by Schering-Plough company with trade(brand)name Intrifiban in U.S.'s Initial Public Offering, went on the market in Europe with trade(brand)name Intrifiban in 1999.Different name IntrifibanTM, Sch-60936, C68-22, SB-1.
Eptifibatide is a cyclic peptide; It is platelet glycoprotein GP IIb/IIIa receptor antagonist; The platelet aggregation reaction that is caused by various activator capable of blocking is a strongest known specificity platelet aggregation inhibitor, is mainly used in and prevents the myocardial oxygen delivery arterial occlusion; Heart attack, the sudden death that unstable angina pectoris, non-q wave myocardial infarction, coronary artery PCI cause.The clinical study result shows; Patient injects Eptifibatide and treats; 48 hours after surgery, the associating terminal point incidence of death or serious problems (main terminal point index comprises: heart attack, case fatality rate and needs are emergency treatment intervention or thromboembolism treatment rate once more) Eptifibatide reduced 37% than other agent groups.Death or incidence rate of myocardial infarction, the Eptifibatide group is than other agent groups low 40%.
Eptifibatide is dose-dependently ground and suppresses external hematoblastic gathering in the acute coronary syndrome patient, can suppress in healthy volunteer and the patient who does the PCI art that fiber is former to be combined with ADP activatory thrombocyte.To the acute coronary syndrome patient, ADP inductive platelet aggregation promptly was suppressed as far back as the injection of these article in back 5 minutes, and it recovered normal in lasting 4～8 hours of administration phase.This article 180 quiet notes of μ g/kg dosage and all can reach with PM 2 μ g/kg speed venoclysises and to suppress thrombocyte and focus on more than 80%.
Utilize the evaluation of citrate antithrombotics, these article suppress the thrombocyte focussing force than the strong 2-4 of other non-chelating type antithrombotics doubly.The bleeding time that these article can make the acute coronary syndrome patient and carry out PCI art patient prolongs 2-4 doubly (comparing with its baseline value), stop infusion originally article recover normal in back 1 hour.These article are not seen the sign of toxic reaction through the safety evaluation test of rat, rabbit and monkey, give the continuous venoclysis of monkey 28 days, and every day, dosage was not seen the toxicity performance up to 7.2mg/kg yet.
Platelet glycoprotein GP IIb/IIIa receptor antagonist has been represented one of maximum progress of present intervention property Cardiology.On a large scale, at random, contrast clinical trial has been confirmed its status in the heart trouble PCI undisputedly; It can approximately reduce patients'perioperative ischemic complication 50%～60%; And, can not obvious increase bleeding episode incidence when the heparin using dosage is suitable.
Eptifibatide is applicable to the treatment acute coronary syndrome, comprises unstable angina pectoris or non-q wave myocardial infarction (both pectoralgia continued outbreak, ECG change and/or the rising of cardiovascular systems enzyme in 24 hours); Also can be used for comprising angioplasty or atherosclerotic plaque surgical blanking through skin coronary artery interventional therapy.Generally be not used in the angioplasty of no acute coronary syndrome.Supervise down the special messenger, these article can be assisted with Frosst) or heparin and used.The advantage of Eptifibatide: 1. the retardance to platelet glycoprotein IIb/IIIa acceptor is a reversible, in case untoward reaction drug withdrawal immediately occurs, untoward reaction is light.2. selectivity is high, and effect is strong.3. no antigen almost itself can not cause allergic reaction.
The preparation of Eptifibatide is similar with the peptide class that other little disulphide is connected, can be by the solid phase method of peptide synthesis of routine or the preparation of the fragment that in solution, carries out synthesis method.There have been some research institutions and individual to deliver some synthetic patent CN1500805, EP1735345, US482263, US542488, US5968902 and US20060036071 etc. now.The Eptifibatide preparation technology who has announced at present has certain defective, can not reach a kind of at aspects such as Operating Complexity, danger, production cycle, total yield of products, product cost and contaminate environment and combine preferably; Using value is not high.
Summary of the invention
The Eptifibatide solid phase method synthesis technique that the purpose of this invention is to provide a kind of high yield, low cost, reaction conditions is gentle, environmental pollution is little, helps realizing industrialization solves the defective that prior art exists.
For realizing above-mentioned purpose, the present invention takes following technical scheme:
A kind of method of preparing Eptifibatide with solid phase method may further comprise the steps:
1) selecting substitution degree is that the Sieber resin of 0.2mmol/g～1.0mmol/g goes the Fmoc reaction, obtains H
2The N-Sieber resin;
2) with H
2The N-Sieber resin is a starting raw material, and employing Fmoc/tBu solid phase method coupling one by one connects the amino acid with blocking group successively, the synthetic side chain full guard linear peptides Eptifibatide-Sieber resin that obtains;
3) side chain full guard linear peptides Eptifibatide-Sieber resin is carried out phase oxidative, obtain side chain full guard oxidation peptide Eptifibatide-Sieber resin;
4) side chain full guard oxidation peptide Eptifibatide-Sieber resin is carried out the cutting of resin and removing of side chain protected, obtain the Eptifibatide bullion;
5) the Eptifibatide bullion obtains the smart peptide of Eptifibatide through high-pressure liquid phase column separating purification, Freeze Drying Equipment freeze-drying.
Preferred scheme is: said Sieber resin substitution degree is 0.4mmol/g～0.6mmol/g.
More preferred scheme is: said amino amino with blocking group all adopts the Fmoc radical protection; And side chain adopts specific protection, and each seed amino acid is used with the form of Fmoc-Cys (Acm)-OH, Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp (OtBu)-OH, Fmoc-Gly-OH, Fmoc-HomoArg (pbf)-OH and Acm-Mpr-OH respectively.
More preferred scheme is: coupling agent system DIC+A or B+A that described coupling is one by one adopted, and wherein A is HOBt or HOAt; B is HBTU or HATU or TBTU or PyBOP.
More preferred scheme is: the coupling agent system that described coupling is one by one adopted is DIC/HOAt.
More preferred scheme is: the oxygenant that said side chain full guard linear peptides Eptifibatide-Sieber resin carries out the phase oxidative employing is an iodine, and the consumption of this oxygenant iodine is 5-20 times with respect to synthetic scale mole number; Reaction solvent is N, one or several mixtures in dinethylformamide (DMF), methylene dichloride (DCM), N-Methyl pyrrolidone (NMP) and the DMSO 99.8MIN. (DMSO); Reaction times adopted 4 hours; 20～30 degrees centigrade of temperature of reaction.
More preferred scheme is: the consumption of said oxygenant iodine is with respect to 10 times that synthesize the scale mole number, and reaction solvent adopts N, dinethylformamide (DMF).
More preferred scheme is: said linear peptides Eptifibatide-Sieber resin is carried out oxidation; Obtain oxidation peptide Eptifibatide-Sieber resin; Reaction finishes the removing of reactant iodine and adopts N; Dinethylformamide (DMF) and methylene dichloride (DCM) clean by turns, use hexahydropyridine/DMF solution to clean then.
More preferred scheme is: the reaction of said side chain full guard Eptifibatide-Sieber through taking off the side chain protected group; Obtain in the process of Eptifibatide bullion; The lysate system of using is a trifluoroacetic acid: water=95: 5 (v/v); Or trifluoroacetic acid: water: triethyl silicane=90: 5: 5 (v/v), or trifluoroacetic acid: thioanisole: water: phenol: 1=82.5: 5: 5: 5: 2.5 (v/v); Or trifluoroacetic acid: thioanisole: water: phenol: 1; 2-dithioglycol: tri isopropyl silane=82.5: 5: 5: 5: 2.5: 1 (v/v), or trifluoroacetic acid: thioanisole: methyl-phenoxide: 1=90: 5: 3: 2 (v/v).
More preferred scheme is: said lysate system is a trifluoroacetic acid: thioanisole: methyl-phenoxide: 1=90: 5: 3: 2 (v/v).
Compared with present technology, the present invention has following advantage and beneficial effect:
The invention provides that a kind of reaction conditions is gentle, environmental pollution is little, help realizing the process for solid phase synthesis of the Eptifibatide of industrialization.Technology of the present invention has that operation is simple, aftertreatment easily, characteristics such as low, the yield height of raw material less investment, cost, have considerable economical and practical value, be with a wide range of applications in the synthetic field of polypeptide drugs design simultaneously.
Description of drawings
Fig. 1 is the total process flow sheet of the present invention.
Embodiment
Below in conjunction with accompanying drawing and specific embodiment the present invention is explained further details:
The implication of employed abbreviation row are as shown in table 1 in specification sheets and claims:
Table 1 breviary vocabulary
| Fmoc | 9-fluorenylmethyloxycarbonyl |
| HBTU | O-benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate |
| HATU | O-(7-azo benzotriazole-1-oxygen)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate |
| TBTU | O-(benzotriazole-1-oxygen)-N, N, N ', N '-tetramethyl-urea hexafluoro borate |
| PyBOP | (benzotriazole-1-oxygen) tripyrrole alkane subbase phosphorus hexafluorophosphate |
| DIC | DIC |
| HOBt | I-hydroxybenzotriazole |
| HOAt | 1-hydroxyl-7-azo benzotriazole |
| DIPEA | Diisopropylethylamine |
| TMP | 2 |
| |
2,2,4,6,7-pentamethyl-Dihydrobenzofuranes-5-alkylsulfonyl |
| Trt | Trityl |
| tBu | The tertiary butyl |
| DMF | N, dinethylformamide |
| DCM | Methylene |
| 20％ |
20% hexahydropyridine/DMF solution |
| Acm | Acetamidomethyl |
| Mpr | The 3-thiohydracrylic acid |
| Sieber?Resin | 9-amino-xanthene-3-oxygen-Merrifield resin |
The preparation of embodiment 1 linear side chain full guard Eptifibatide peptide resin
With Sieber resin 100.0g, substitution degree is 0.6mmol/g, joins in the solid state reaction post, with DMF swelling resin 30 minutes.After swelling is complete, remove Fmoc protection 10min+20min with 20% DBLK, the back is with DMF washing six times.Fmoc-Cys (Acm)-OH 49.74g, HBTU 38.52g, HOBt16.2g and DIPEA 41.8ml are joined in the reaction column, react end in two hours.Repeat the operation of front, respectively Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp (OtBu)-OH, Fmoc-Gly-OH, Fmoc-Homoarg (pbf)-OH and Acm-Mpr-OH are carried out coupling.Coupling finishes, and resin is with DMF washing three times, and DCM washs three times, and methyl alcohol shrinks three times, weighs after the vacuum-drying to obtain the linear side chain full guard of 172.1g Eptifibatide peptide resin.Another preferred version of present embodiment is: with Sieber resin 1200.0g, substitution degree is 0.59mmol/g, joins in the solid state reaction post, with DMF swelling resin 30 minutes.After swelling is complete, remove Fmoc protection 10min+20min with 20% DBLK, the back is with DMF washing six times.Fmoc-Cys (Acm)-OH 597g, HBTU 462g, HOBt 194g and DIPEA502ml are joined in the reaction column, react end in three hours.Repeat the operation of front, respectively Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp (OtBu)-OH, Fmoc-Gly-OH, Fmoc-Homoarg (pbf)-OH and Acm-Mpr-OH are carried out coupling.Coupling finishes, and resin is with DMF washing three times, and DCM washs three times, and methyl alcohol shrinks three times, weighs after the vacuum-drying to obtain the linear side chain full guard of 2031g Eptifibatide peptide resin.
The preparation of embodiment 2 oxidized form side chain full guard Eptifibatide peptide resins
With the linear side chain full guard of 172.1g Eptifibatide peptide resin with DMF swelling 30 minutes.After swelling is complete, will join in the reaction column that resin is housed oxidizing reaction 2 hours with an amount of DMF dissolved 304.8g iodine.Reaction finishes, with DMF washing ten times, and DCM washing three times, methyl alcohol shrinks three times, and weighing after the vacuum-drying obtains 164.1g oxidized form side chain full guard Eptifibatide peptide resin.
The preparation of embodiment 3 oxidized form side chain full guard Eptifibatide peptide resins
With the linear side chain full guard of 1893g Eptifibatide peptide resin with DMF swelling 30 minutes.After swelling is complete, will join in the reaction column that resin is housed oxidizing reaction 3 hours with an amount of DMF dissolved 3350g iodine.Reaction finishes, with DMF washing ten times, and DCM washing three times, methyl alcohol shrinks three times, and weighing after the vacuum-drying obtains 1740g oxidized form side chain full guard Eptifibatide peptide resin.
The preparation of the thick peptide of embodiment 4 Eptifibatide
164.1g oxidized form side chain full guard Eptifibatide peptide resin is added in the round-bottomed flask of 3L, and the back adds 1641ml lysate (proportioning trifluoroacetic acid: water: tri isopropyl silane=95: 2.5: 2.5), reacted two hours.Scission reaction finishes, and filters, and filtrating is iced ether sedimentation, centrifugal, washing, centrifugal, washing, centrifugal more again, last vacuum-drying with 16.4L.Weigh and obtain the thick peptide 46.9g of Eptifibatide.
The preparation of the thick peptide of embodiment 5 Eptifibatide
1477g oxidized form side chain full guard Eptifibatide peptide resin is added in the reaction flask of 30L, and the back adds 14.8L lysate (proportioning trifluoroacetic acid: water: tri isopropyl silane=95: 2.5: 2.5), reacted two hours.Scission reaction finishes, and filters, and filtrating is iced ether sedimentation, centrifugal, washing, centrifugal, washing, centrifugal more again, last vacuum-drying with 140L.Weigh and obtain the thick peptide 420g of Eptifibatide.
The preparation of the smart peptide of embodiment 6 Eptifibatide
After the preparation of the thick peptide 46.9g employing of Eptifibatide high-pressure liquid phase, through commentaries on classics salt, freeze-drying, weighing at last obtains the smart peptide 30.9g of Eptifibatide.Total recovery can reach 61.2%.
The preparation of the smart peptide of embodiment 7 Eptifibatide
After the preparation of the thick peptide 375g employing of Eptifibatide high-pressure liquid phase, through commentaries on classics salt, freeze-drying, weighing at last obtains the smart peptide 251g of Eptifibatide.Total recovery can reach 62.3%.
Above content is to combine concrete preferred implementation to the further explain that the present invention did, and can not assert that practical implementation of the present invention is confined to these explanations.For the those of ordinary skill of technical field under the present invention, under the prerequisite that does not break away from the present invention's design, can also make some simple deduction or replace, all should be regarded as belonging to protection scope of the present invention.
Claims (1)
1. the method for a preparing Eptifibatide with solid phase method may further comprise the steps:
1) with Sieber resin 100.0g, substitution degree is 0.6mmol/g, joins in the solid state reaction post, with DMF swelling resin 30 minutes; After swelling is complete, remove Fmoc protection 10min+20min with 20% DBLK, the back is with DMF washing six times; Fmoc-Cys (Acm)-OH 49.74g, HBTU 38.52g, HOBt 16.2g and DIPEA 41.8ml are joined in the reaction column, react end in two hours; Repeat the operation of front, respectively Fmoc-Pro-OH, Fmoc-Trp-OH, Fmoc-Asp (OtBu)-OH, Fmoc-Gly-OH, Fmoc-Homoarg (pbf)-OH and Acm-Mpr-OH are carried out coupling; Coupling finishes, and resin is with DMF washing three times, DCM washing three times, methyl alcohol shrinks three times, weigh after the vacuum-drying linear side chain full guard Eptifibatide peptide resin;
2) with the linear side chain full guard of 1893g Eptifibatide peptide resin with DMF swelling 30 minutes; After swelling is complete, will join in the reaction column that resin is housed oxidizing reaction 3 hours with an amount of DMF dissolved 3350g iodine; Reaction finishes, with DMF washing ten times, DCM washing three times, methyl alcohol shrinks three times, weigh after the vacuum-drying oxidized form side chain full guard Eptifibatide peptide resin;
3) 1477g oxidized form side chain full guard Eptifibatide peptide resin is added in the reaction flask of 30L, the back adds the 14.8L lysate, and the lysate proportioning is: trifluoroacetic acid: water: tri isopropyl silane=95:2.5:2.5, reacted two hours; Scission reaction finishes, and filters, and filtrating is iced ether sedimentation, centrifugal, washing, centrifugal, washing, centrifugal more again, last vacuum-drying with 140L;
4) with after the preparation of the thick peptide 375g employing of Eptifibatide high-pressure liquid phase, through commentaries on classics salt, freeze-drying, weighing at last obtains the smart peptide of Eptifibatide.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9475837B2 (en) | 2011-12-23 | 2016-10-25 | Ipsen Manufacturing Ireland Limited | Process for the synthesis of therapeutic peptides |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747412A (en) * | 2009-12-30 | 2010-06-23 | 江苏诺泰制药技术有限公司 | Synthesis and preparation process of eptifibatide |
| CN102174081B (en) * | 2011-03-09 | 2013-05-29 | 杭州华津允上医药有限公司 | Method for preparing eptifibatide and precursor thereof |
| CN102702320B (en) * | 2012-06-01 | 2013-08-21 | 深圳翰宇药业股份有限公司 | Method for preparing eptifibatide |
| CN103408637B (en) | 2013-06-27 | 2015-12-02 | 深圳翰宇药业股份有限公司 | A kind of preparation method of Eptifibatide |
| CN104710509B (en) * | 2013-12-11 | 2018-01-02 | 深圳翰宇药业股份有限公司 | A kind of preparation method of Eptifibatide |
| CN106554389A (en) * | 2015-09-29 | 2017-04-05 | 深圳翰宇药业股份有限公司 | A kind of synthetic method of Eptifibatide |
| CN105218641A (en) * | 2015-11-09 | 2016-01-06 | 叶仲林 | A kind of preparation method of Integrilin |
| CN110317188B (en) * | 2018-03-29 | 2023-01-17 | 深圳翰宇药业股份有限公司 | Compound and preparation method and application thereof |
| CN110498834A (en) * | 2018-05-16 | 2019-11-26 | 深圳翰宇药业股份有限公司 | A kind of method of eptifibatide solid phase preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9475837B2 (en) | 2011-12-23 | 2016-10-25 | Ipsen Manufacturing Ireland Limited | Process for the synthesis of therapeutic peptides |
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