CN109251234A - A kind of preparation method of medicament for resisting platelet aggregation Eptifibatide - Google Patents
A kind of preparation method of medicament for resisting platelet aggregation Eptifibatide Download PDFInfo
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- CN109251234A CN109251234A CN201811169739.XA CN201811169739A CN109251234A CN 109251234 A CN109251234 A CN 109251234A CN 201811169739 A CN201811169739 A CN 201811169739A CN 109251234 A CN109251234 A CN 109251234A
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- trt
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Abstract
The invention discloses a kind of preparation methods of medicament for resisting platelet aggregation Eptifibatide, belong to the synthesis technical field of pharmaceutical intermediate.Technical solution of the present invention main points are as follows: utilize peptide condensing agent A, step 1 first synthesizes tripeptide fragment, step 2 synthesizes four peptide fragments again, step 3, which is taken, is initially formed the linear peptide of disulfide bond, last condensation forms ring peptide, that is, target product Eptifibatide for the tripeptide fragment that step 1 obtains and four peptide fragments that step 2 obtains.Present invention process high income, processing is easy, and the Eptifibatide bulk pharmaceutical chemicals purity is high of preparation, is a kind of synthetic method with industrial production value.
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of preparation side of medicament for resisting platelet aggregation Eptifibatide
Method.
Background technique
Eptifibatide (shown in structural formula as I) also known as eptifibatide (Eptifibatide) angstrom replace non-Bart, by seven ammonia
Base acid or amino acid derivativges residue composition, by disulfide bond cyclization, structure can be split as seven components: L-cysteine
(Cys), L-PROLINE (Pro), L-Trp (Trp), L-Aspartic acid (Asp), glycine (Gly), L- homoarginine (Har)
It is a kind of anti-platelet aggregation agent with β-mercaptopropionic acid (Mpr).The affinity of eptifibatide and GPIIb/IIIa receptor compares blood coagulation
Factor I is strong, the KGD sequence modified in eptifibatide molecule can in conjunction with IIb/IIIa receptor-specific on platelet glycoprotein,
" closing " IIb/IIIa receptor, prevents the factor I from combining with IIb/IIIa receptor on platelet glycoprotein.Due to 1
A factor I can be combined with 2 GPIIb/IIIa receptors, the result that factor I is combined with GPIIb/IIIa receptor
It is to cause blood platelet " bridging ", causes platelet aggregation.And 1 eptifibatide molecule can only be with 1 IIb/IIIa receptor phase
In conjunction with, according to for bar skin combine with GPIIb/IIIa receptor the result is that " closing " GPIIb/IIIa receptor performance antiplatelet
Aggtegation.Eptifibatide was listed in 1998 in the U.S., as anti-platelet aggregation medicinal for acute coronary syndrome
Treatment, and its clinical application is more and more extensive.
The synthetic method for the eptifibatide being currently known very much (CN 106554389 A, CN 105218641 A, CN
103408637 A of 105001304 A, CN 104710509 A, IN 2013DE00020 A, IN 2010MU03591 A, CN,
WO 2013057736 A2, CN 102924569 A, WO 2013014527 A1, CN 102827249 A, CN 102702320
2005100381 A2 of A, CN 102174081 A, WO).It is divided into solid-phase synthesis (applied chemistry in these synthetic methods
(2012), 29 (3), 275-279.CN 101759776 A, WO 2009150657 A1, IN 2008CH01402A, CN
1858060 A of 101538316 A, US 20070249806 A1, CN) and liquid phase synthesizing method (CN 101993475 A, CN
101747412 A) or two methods simultaneously use (102040652 A of CN).Synthesis in solid state is one as laboratory research
A preferable method, the method is efficient, rapid, but synthesis in solid state raw material availability is low, the expensive reagents used, and uses
It is more toxic and reluctant solvent, is not suitable for large-scale application.Eptifibatide liquid phase synthesis is a kind of reasonable method,
It studies at present more.In these synthetic methods, peptide condensing agent is mostly DCC/HOBt, DCC/HOAt, DIC/HOBt, DIC/
HOAt、HBTU/DIPEA、HBTU/NMM、HBTU/DIPEA、TBTU/NMM、TBTU/TEA、HATU/DIPEA、HATU/NMM、
HATU/TEA etc..But these condensing agents at present in the synthesis of Eptifibatide performance can not achieve the effect that it is satisfied.In addition,
Sulfydryl is aoxidized in disulfide bond annulation process, dimer impurity (two lines peptide is connected with disulfide bond) easy to form finds temperature
It is most important to bulk pharmaceutical chemicals quality is improved with highly selective oxidising agent.Therefore existing method is generally existing at present: synthesis
Step is more, complex process, it is difficult to which industrialized disadvantage, especially product purity are difficult to reach desirable, and single miscellaneous height is easy to draw
Play adverse drug reaction.Therefore the preparation method for developing the Eptifibatide of new high yield, high-quality is significant.
Summary of the invention
The technical problem to be solved by the present invention is to provide a kind of reaction conditions mildly, yield is higher and product purity is high resists
The preparation method of platelet aggregation drugs Eptifibatide, this method utilize polypeptide condensing agent A, first synthesize tripeptide fragment and tetrapeptide piece
Section, then technique, which is taken, is initially formed the linear peptide of disulfide bond, last condensation forms ring peptide, has process recovery ratio height, processing easy
And prepare the advantages that Eptifibatide bulk pharmaceutical chemicals are with high purity.
The present invention adopts the following technical scheme that solve above-mentioned technical problem, a kind of medicament for resisting platelet aggregation Eptifibatide
Preparation method, it is characterised in that specific steps are as follows:
Step S1: compound PNZ-Harg-OH is condensed under peptide condensing agent A effect with compound H-Gly-OBu-t
It is removed to compound PNZ-Harg-Gly-OBu-t, compound PNZ-Harg-Gly-OBu-t through palladium carbon/hydrogen or platinum carbon/hydrogen
Obtain compound H-Harg-Gly-OBu-t after PNZ protection, compound H-Harg-Gly-OBu-t under peptide condensing agent A effect with
Compound Mpa (Trt)-OH is condensed to yield compound Mpa (Trt)-Harg-Gly-OBu-t, compound Mpa (Trt)-Harg-
Sulfhydryl protected tripeptide fragment Mpa (Trt)-Harg-Gly-OH is obtained after Gly-OBu-t hydrolysis；
Step S2: by compound PNZ-Pro-OH peptide condensing agent A effect under with compound H-Cys (Trt)-NH2Condensation
Obtain compound PNZ-Pro-Cys (Trt)-NH2, compound PNZ-Pro-Cys (Trt)-NH2Through palladium carbon/hydrogen or platinum carbon/hydrogen
Qi exhaustion obtains compound H-Pro-Cys (Trt)-NH after protecting except PNZ2, then peptide condensing agent A effect under with compound PNZ-
Trp-OH carries out tripeptide fragment PNZ-Trp-Pro-Cys (the Trt)-NH for being condensed to yield PNZ protection2, then through palladium carbon/hydrogen or platinum
Compound H-Trp-Pro-Cys (Trt)-NH is obtained after carbon/hydrogen removing PNZ protection2, then peptide condensing agent A effect under with
Compound PNZ-Asp (OTBS)-OH is condensed to yield four peptide fragment PNZ-Asp (OTBS)-Trp-Pro-Cys of PNZ protection
(Trt)-NH2, then removed after PNZ is protected through palladium carbon/hydrogen or platinum carbon/hydrogen and obtain four sulfhydryl protected peptide fragment H-Asp
(OTBS)-Trp-Pro-Cys(Trt)-NH2；
Step S3: sulfhydryl protected tripeptide fragment Mpa (the Trt)-Harg-Gly-OH and step S2 that step S1 is obtained is obtained
Four sulfhydryl protected peptide fragment H-Asp (OTBS)-Trp-Pro-Cys (the Trt)-NH arrived2It is generated under the action of oxidising agent
Heptapeptide NH of the linear protection containing disulfide bond2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS), wherein oxidising agent
For trichlorine isocyanic acid, I2Or NCS, heptapeptide of the linear protection containing disulfide bond form the ring of TBS protection under the action of peptide condensing agent A
HeptapeptideThe ring seven peptide of TBS protection is protected through tetrabutyl ammonium fluoride removing TBS
Target product Eptifibatide is obtained after shield
The structural formula of the peptide condensing agent A are as follows:
Preferably, the alkali of the collocation of peptide condensing agent A described in step S1 is diisopropylethylamine or triethylamine.
Preferably, hydroxide is selected in-Harg-Gly-OBu-t the hydrolytic process of compound Mpa (Trt) described in step S1
Lithium, sodium hydroxide or potassium hydroxide select methanol or ethyl alcohol as solvent as alkali.
Preferably, the alkali of the collocation of peptide condensing agent A described in step S2 is diisopropylethylamine or triethylamine.
Preferably, the alkali of the collocation of peptide condensing agent A described in step S3 is diisopropylethylamine or triethylamine.
The meaning of abbreviation used in the present invention is listed in the following table.
Compared with the prior art, the present invention has the following advantages: use new type of peptides condensing agent, reaction condition is mild, high income
And product purity is high, using PNZ protecting group, removing is easy, using trichlorine isocyanic acid as the novel deprotection agent of Trt, high selection
Property form asymmetric disulfide bond, it is at low cost and be suitable for industrial application.
Specific embodiment
Above content of the invention is described in further details by the following examples, but this should not be interpreted as to this
The range for inventing above-mentioned theme is only limitted to embodiment below, and all technologies realized based on above content of the present invention belong to this hair
Bright range.
Embodiment 1
PNZ-Harg-OH preparation
H-Harg-OH (188g, 1mol) is added in reaction flask, adds water and tetrahydro dissolved with 60g sodium hydroxide
Furans (volume ratio 1:1) solution 600mL, be cooled to -30 DEG C (temperature is more than -30 DEG C, and PNZ has other amino impurity to occur) with
Under, the tetrahydrofuran solution 100mL for being dissolved with PNZ-Cl (1.1mol) is slowly added dropwise, is added dropwise, it is small that low temperature is kept stirring 1
When, it is then slowly ramped to stir at room temperature, TLC is monitored to fully reacting.Most of tetrahydrofuran is steamed, residual reaction liquid is used
Methylene chloride extraction, water layer are adjusted to 3-4 with hydrochloric acid, a large amount of white precipitates are precipitated, and filter, and distill water washing, and it is solid to obtain white
Body PNZ-Harg-OH, yield 97.5%, purity 98.5%, MS [M+1]+368。
Embodiment 2
PNZ-Harg-Gly-OBu-t preparation
H-Gly-OBu-t (131g, 1mol) is added in reaction flask, is dissolved in methylene chloride 500mL, under ice bath is cooling, slowly
It is slow that DIEA (1.2mol) 220mL is added；Peptide condensing agent A (470g, 1.0mol) and PNZ-Harg-OH (367g, 1mol) is dissolved
In 1000mL methylene chloride, activated 10 minutes at 0 DEG C, the methylene chloride for being then slowly added drop-wise to above-mentioned H-Gly-OBu-t is molten
It in liquid, is stirred 30 minutes at 0 DEG C, TLC monitors fully reacting.After reaction solution filtering, with sodium bicarbonate aqueous solution, aqueous hydrochloric acid solution
With distillation water washing, after methylene chloride organic phase anhydrous sodium sulfate is dry, obtained after ethyl acetate and chloroform purification after reduced pressure
White solid PNZ-Harg-Gly-OBu-t, yield 94.8%, purity 98.6%, MS [M+1]+481。
Embodiment 3
H-Harg-Gly-OBu-t preparation
PNZ-Harg-Gly-OBu-t (480g, 1mol) is dissolved in 1000mL methanol, add palladium carbon (5wt% palladium,
24g)/hydrogen, room temperature reaction, is filtered after reaction, and being concentrated into system is 200mL, and 0 DEG C of cooled and filtered obtains solid H-
Harg-Gly-OBu-t, yield 94.8%, MS [M+1]+302。
Embodiment 4
H-Harg-Gly-OBu-t preparation
PNZ-Harg-Gly-OBu-t (480g, 1mol) is dissolved in 1000mL methanol, add platinum carbon (5wt% palladium,
24g)/hydrogen, room temperature reaction, is filtered after reaction, and being concentrated into system is 200mL, and 0 DEG C of cooled and filtered obtains solid H-
Harg-Gly-OBu-t, yield 92.8%, MS [M+1]+302。
Embodiment 5
Mpa (Trt)-Harg-Gly-OBu-t preparation
In there-necked flask, H-Harg-Gly-OBu-t (301g, 1mol) is dissolved in 1000mL methylene chloride, ice bath is cold
But under, it is added with stirring DIEA (1.2mol) 220mL；By condensing agent A (470g, 1.0mol) and Mpa (Trt)-OH (348g,
Methylene chloride 500mL 1mol) is added, the cooling lower activation of ice bath after ten minutes, is dripped this mixed solution by constant pressure funnel
It is added in the dichloromethane solution of H-Harg-Gly-OBu-t, is stirred 30 minutes under ice bath, TLC detects fully reacting.Reaction solution
After filtering, with sodium bicarbonate aqueous solution, aqueous hydrochloric acid solution and saturated salt solution distill water washing, and methylene chloride organic phase is anhydrous
After sodium sulphate is dry, it is concentrated to dryness, solid Mpa (Trt)-Harg-Gly- is obtained by ethyl acetate and Gossypol recrystallized from chloroform
OBu-t, yield 97.8%, purity 98.8%, MS [M+1]+633。
Embodiment 6
Mpa (Trt)-Harg-Gly-OH preparation
In there-necked flask, Mpa (Trt)-Harg-Gly-OBu-t (632g, 1mol) is dissolved in 1500mL methanol, is stirred
Mix lower addition 10wt% lithium hydroxide aqueous solution 400mL, TLC tracking reaction, fully reacting in 1 hour.System is concentrated into 800mL use
The pH that dilute hydrochloric acid adjusts mixed system is 3-4, white solid Mpa (Trt)-Harg-Gly-OH is precipitated, yield 93.9% is pure
Degree is 98.0%, MS [M+1]+576。
Embodiment 7
PNZ-Pro-Cys(Trt)-NH2Preparation
By H-Cys (Trt)-NH2(362g, 1mol) is dissolved in 1000mL methylene chloride, under ice bath is cooling, is added with stirring
DIEA (220mL, 6mol)；Methylene chloride is added in peptide condensing agent A (470g, 1.0mol) and PNZ-Pro-OH (294g, 1mol)
This mixed solution after ten minutes, is added drop-wise to H-Cys (Trt)-NH by constant pressure funnel by 600mL, the cooling lower activation of ice bath2
Dichloromethane solution in, the cooling lower stirring of ice bath 30 minutes, TLC detects fully reacting.After reaction solution filtering, sodium bicarbonate is used
Aqueous solution, aqueous hydrochloric acid solution and saturated salt solution distill water washing, after methylene chloride organic phase anhydrous sodium sulfate is dry, decompression
It is concentrated to get grease, precipitates to obtain solid PNZ-Pro-Cys (Trt)-NH by petroleum ether and ether2, yield 94.1%,
Purity is 98.0%, MS [M+1]+639。
Embodiment 8
H-Pro-Cys(Trt)-NH2
Take PNZ-Pro-Cys (Trt)-NH2(638g, 1mol) is dissolved in 1000mL methanol, adds palladium carbon (5wt%
Palladium, 24g)/hydrogen, it reacts at room temperature, filters after reaction, being concentrated into system is 200mL, and zero degree cooled and filtered obtains solid
H-Pro-Cys(Trt)-NH2, yield 94.5%, purity 98.9%, MS [M+1]+460。
Embodiment 9
PNZ-Trp-Pro-Cys(Trt)-NH2Preparation
Take H-Pro-Cys (Trt)-NH2(459g, 1mol) is dissolved in 1500mL methylene chloride, under ice bath is cooling, stirring
Lower addition DIEA (220mL, 1.2mol)；Peptide condensing agent A (470g, 1mol) and PNZ-Trp-OH (383g, 1mol) is added two
This mixed solution after ten minutes, is added drop-wise to H-Pro- by constant pressure funnel by chloromethanes 600mL, the cooling lower activation of ice bath
Cys(Trt)-NH2Dichloromethane solution in, the cooling lower stirring of ice bath 30 minutes, TLC detects fully reacting.Reaction solution filtering
Afterwards, with sodium bicarbonate aqueous solution, aqueous hydrochloric acid solution and saturated salt solution, water washing, methylene chloride organic phase anhydrous slufuric acid are distilled
After sodium is dry, it is concentrated under reduced pressure to give grease, precipitates to obtain solid PNZ-Trp-Pro-Cys (Trt)-by petroleum ether and ether
NH2, yield 95.1%, purity 98.5%, MS [M+1]+826。
Embodiment 10
H-Trp-Pro-Cys(Trt)-NH2Preparation
By PNZ-Trp-Pro-Cys (Trt)-NH2(413g, 0.5mol) is dissolved in 1000mL methanol, adds palladium carbon
(5wt% palladium, 24g)/hydrogen, room temperature reaction, is filtered after reaction, and being concentrated into system is 200mL, and 0 DEG C of cooled and filtered obtains
Solid H-Trp-Pro-Cys (Trt)-NH2, yield 97.8%, MS [M+1]+646。
Embodiment 11
PNZ-Asp(OTBS)-Trp-Pro-Cys(Trt)-NH2Preparation
Take H-Trp-Pro-Cys (Trt)-NH2(645g, 1mol) is dissolved in 1500mL methylene chloride, under ice bath is cooling,
It is added with stirring DIEA (220mL, 1.2mol)；By peptide condensing agent A (470g, 1.0mol) and PNZ-Asp (OTBS)-OH (426g,
Methylene chloride 600mL 1mol) is added, the cooling lower activation of ice bath after ten minutes, is dripped this mixed solution by constant pressure funnel
It is added to H-Trp-Pro-Cys (Trt)-NH2Dichloromethane solution in, the cooling lower stirring of ice bath 30 minutes, TLC detection has been reacted
Entirely.After reaction solution filtering, with sodium bicarbonate aqueous solution, aqueous hydrochloric acid solution and saturated salt solution distill water washing, and methylene chloride has
After machine phase anhydrous sodium sulfate is dry, it is concentrated under reduced pressure to give grease, precipitates to obtain solid PNZ-Asp by petroleum ether and ether
(OTBS)-Trp-Pro-Cys(Trt)-NH2, yield 95.7%, purity 98.1%, MS [M+1]+1054。
Embodiment 12
H-Asp(OTBS)-Trp-Pro-Cys(Trt)-NH2Preparation
By PNZ-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2(526.5g, 0.5mol) is dissolved in 1000mL methanol
In, add palladium carbon (5wt% palladium, 24g)/hydrogen, react at room temperature, filter after reaction, be concentrated into system be 200mL, 0 DEG C
Cooled and filtered obtains solid H-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2, yield 98.8%, MS [M+1]+875。
Embodiment 13
NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS) preparation
By H-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2(438g, 0.5mol) and Mpa (Trt)-Harg-Gly-OH
(288g, 0.5mol) is dissolved in 2000mL methylene chloride, and the dichloromethane solution of trichlorine isocyanic acid (2.5mol) is slowly added dropwise,
Reaction temperature is controlled at -10 DEG C hereinafter, oxygen flow slow transits through solution in the form of being bubbled simultaneously.After reaction, carbonic acid is used
Hydrogen sodium water solution, aqueous hydrochloric acid solution and saturated salt solution distill water washing, after methylene chloride organic phase anhydrous sodium sulfate is dry,
It is concentrated under reduced pressure to give solid NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS), yield 95.2%, purity
For 97.5%, MS [M+1]+964。
Embodiment 14
NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS) preparation
By H-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2(438g, 0.5mol) and Mpa (Trt)-Harg-Gly-OH
(288g, 0.5mol) is dissolved in 2000mL methylene chloride, and I is slowly added dropwise2The dichloromethane solution of (2.5mol), control reaction
Temperature is at -10 DEG C hereinafter, oxygen flow slow transits through solution in the form of being bubbled simultaneously.After reaction, water-soluble with sodium bicarbonate
Liquid, aqueous hydrochloric acid solution and saturated salt solution distill water washing, after methylene chloride organic phase anhydrous sodium sulfate is dry, are concentrated under reduced pressure
Obtain solid.Solid contains asymmetric disulfide NH2The pole-Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS)
It is few, contain Asp (OTBS)-Gly-Harg-Mpa-S-S-Mpa-Harg-Gly-Asp (OTBS), NH2-Cys-Pro-Trp-S-S-
Trp-Pro-Cys-NH2Based on.
Embodiment 15
NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS) preparation
By H-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2(438g, 0.5mol) and Mpa (Trt)-Harg-Gly-OH
(288g, 0.5mol) is dissolved in 2000 methylene chloride, and the dichloromethane solution of NCS (2.5mol), control reaction is slowly added dropwise
Temperature is at -10 DEG C hereinafter, oxygen flow slow transits through solution in the form of being bubbled simultaneously.After reaction, water-soluble with sodium bicarbonate
Liquid, aqueous hydrochloric acid solution and saturated salt solution distill water washing, after methylene chloride organic phase anhydrous sodium sulfate is dry, are concentrated under reduced pressure
Solid is obtained, solid contains asymmetric disulfide NH2The pole-Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS)
It is few, contain Asp (OTBS)-Gly-Harg-Mpa-S-S-Mpa-Harg-Gly-Asp (OTBS), NH2-Cys-Pro-Trp-S-S-
Trp-Pro-Cys-NH2Based on.
Embodiment 16
Preparation
By NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS) (482g, 0.5mol) is dissolved in 1500mL
It in methylene chloride, under ice bath is cooling, is added peptide condensing agent A (235g, 0.5mol), under ice bath is cooling, stirs 10 minutes, then stir
It mixes down and is slowly added dropwise to DIEA (110mL, 0.6mol), TLC detects fully reacting.It is water-soluble with sodium bicarbonate after reaction solution filtering
Liquid, aqueous hydrochloric acid solution and saturated salt solution distill water washing, after methylene chloride organic phase anhydrous sodium sulfate is dry, are concentrated under reduced pressure
Grease is obtained, precipitates to obtain solid by petroleum ether and etherYield is 90.7%, purity 98.5%, MS [M+1]+947。
Embodiment 17
Preparation
By NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS) (482g, 0.5mol) is dissolved in 1500mL
It in methylene chloride, under ice bath is cooling, is added peptide condensing agent HOCt (0.5mol), under ice bath is cooling, stirs 30 minutes, then stir
Under be slowly added dropwise to DIEA (110mL, 0.6mol), TLC detect fully reacting.After reaction solution filtering, with sodium bicarbonate aqueous solution,
Aqueous hydrochloric acid solution and saturated salt solution distill water washing and are concentrated under reduced pressure to give after methylene chloride organic phase anhydrous sodium sulfate is dry
Grease precipitates to obtain solid by petroleum ether and etherYield
It is 62.7%, purity 97.8%, MS [M+1]+947。
Embodiment 18
Preparation
By NH2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS) (482g, 0.5mol) is dissolved in 1500mL
It in methylene chloride, under ice bath is cooling, is added peptide condensing agent A (235g, 0.5mol), under ice bath is cooling, stirs 10 minutes, then stir
It mixes down and is slowly added dropwise to Et3N (0.6mol), TLC detect fully reacting.After reaction solution filtering, with sodium bicarbonate aqueous solution, hydrochloric acid
Aqueous solution and saturated salt solution distill water washing and are concentrated under reduced pressure to give oily after methylene chloride organic phase anhydrous sodium sulfate is dry
Object precipitates to obtain solid by petroleum ether and etherYield is
90%, purity 98.0%, MS [M+1]+947。
Embodiment 19
Eptifibatide preparation
It will(474g, 0.5mol) is dissolved in 1000mL THF
In, tetrabutyl ammonium fluoride (TBAF) (157g, 0.6mol) is added, is stirred at room temperature, after reaction, is spin-dried for solvent, solid is used
Methanol and chloroform purification obtain target product Eptifibatide, yield 89.5%, purity 99.85%, linear dithia matter twice
Detect nothing, MS [M+1]+832。
Embodiment above describes basic principles and main features of the invention and advantage, the technical staff of the industry should
Understand, the present invention is not limited to the above embodiments, and the above embodiments and description only describe originals of the invention
Reason and best embodiment, under the range for not departing from the principle of the invention, various changes and improvements may be made to the invention, these changes
In change and improvement are all fallen within the protection scope of the present invention.
Claims (5)
1. a kind of preparation method of medicament for resisting platelet aggregation Eptifibatide, it is characterised in that specific steps are as follows:
Step S1: by compound PNZ-Harg-OH peptide condensing agent A effect under with compound being condensed to yield of H-Gly-OBu-t
Object PNZ-Harg-Gly-OBu-t is closed, compound PNZ-Harg-Gly-OBu-t removes PNZ through palladium carbon/hydrogen or platinum carbon/hydrogen
Obtain compound H-Harg-Gly-OBu-t after protection, compound H-Harg-Gly-OBu-t under peptide condensing agent A effect with change
It closes object Mpa (Trt)-OH and is condensed to yield compound Mpa (Trt)-Harg-Gly-OBu-t, compound Mpa (Trt)-Harg-Gly-
Sulfhydryl protected tripeptide fragment Mpa (Trt)-Harg-Gly-OH is obtained after OBu-t hydrolysis；
Step S2: by compound PNZ-Pro-OH peptide condensing agent A effect under with compound H-Cys (Trt)-NH2Being condensed to yield
Close object PNZ-Pro-Cys (Trt)-NH2, compound PNZ-Pro-Cys (Trt)-NH2Through palladium carbon/hydrogen or platinum carbon/hydrogen removing
Compound H-Pro-Cys (Trt)-NH is obtained after PNZ protection2, then peptide condensing agent A effect under with compound PNZ-Trp-OH into
Row is condensed to yield tripeptide fragment PNZ-Trp-Pro-Cys (Trt)-NH of PNZ protection2, then through palladium carbon/hydrogen or platinum carbon/hydrogen
Compound H-Trp-Pro-Cys (Trt)-NH is obtained after removing PNZ protection2, then peptide condensing agent A effect under with compound
PNZ-Asp (OTBS)-OH is condensed to yield four peptide fragment PNZ-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH of PNZ protection2,
Four sulfhydryl protected peptide fragment H-Asp (OTBS)-Trp- are obtained after palladium carbon/hydrogen or platinum carbon/hydrogen removing PNZ protection again
Pro-Cys(Trt)-NH2；
Step S3: what sulfhydryl protected tripeptide fragment Mpa (the Trt)-Harg-Gly-OH and step S2 that step S1 is obtained was obtained
Four sulfhydryl protected peptide fragment H-Asp (OTBS)-Trp-Pro-Cys (Trt)-NH2It is generated under the action of oxidising agent linear
Protect the heptapeptide NH containing disulfide bond2- Cys-Pro-Trp-S-S-Mpa-Harg-Gly-Asp (OTBS), wherein oxidising agent is three
Chlorine isocyanic acid, I2Or NCS, heptapeptide of the linear protection containing disulfide bond form the ring seven peptide of TBS protection under the action of peptide condensing agent AThe ring seven peptide of TBS protection is after tetrabutyl ammonium fluoride removing TBS protection
Obtain target product Eptifibatide
The structural formula of the peptide condensing agent A are as follows:
2. the preparation method of medicament for resisting platelet aggregation Eptifibatide according to claim 1, it is characterised in that: in step S1
The alkali of the peptide condensing agent A collocation is diisopropylethylamine or triethylamine.
3. the preparation method of medicament for resisting platelet aggregation Eptifibatide according to claim 1, it is characterised in that: in step S1
Lithium hydroxide, sodium hydroxide or potassium hydroxide is selected to make in compound Mpa (the Trt)-Harg-Gly-OBu-t hydrolytic process
For alkali, select methanol or ethyl alcohol as solvent.
4. the preparation method of medicament for resisting platelet aggregation Eptifibatide according to claim 1, it is characterised in that: in step S2
The alkali of the peptide condensing agent A collocation is diisopropylethylamine or triethylamine.
5. the preparation method of medicament for resisting platelet aggregation Eptifibatide according to claim 1, it is characterised in that: in step S3
The alkali of the peptide condensing agent A collocation is diisopropylethylamine or triethylamine.
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| WO2022016343A1 (en) * | 2020-07-20 | 2022-01-27 | 深圳迈瑞生物医疗电子股份有限公司 | Use of composition for platelet disaggregation, disaggregation reagent, and disaggregation method |
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| WO2022016343A1 (en) * | 2020-07-20 | 2022-01-27 | 深圳迈瑞生物医疗电子股份有限公司 | Use of composition for platelet disaggregation, disaggregation reagent, and disaggregation method |
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