CN1500805A - Preparing process for Eptifibatide - Google Patents
Preparing process for Eptifibatide Download PDFInfo
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- CN1500805A CN1500805A CNA02145292XA CN02145292A CN1500805A CN 1500805 A CN1500805 A CN 1500805A CN A02145292X A CNA02145292X A CN A02145292XA CN 02145292 A CN02145292 A CN 02145292A CN 1500805 A CN1500805 A CN 1500805A
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Abstract
The present invention relates to the preparation of cyclic peptide, and is especially new Fmoc-solid phase process of preparing Eptifibatide. The new process is superior to liquid phase process, which has long synthesis period, and BOC solid phase process, which uses virulent and corrosive material. The technological scheme is that the Eptifibatide preparing process includes the following steps: eliminating Fmoc protection of Fmoc-Rink Amide AM resin to obtain H2N-Rink Amide AM resin; connecting various protective amino acids successively to obtain corresponding resin; eliminating Fmoc-protection radical and Kaiser test to detect reaction procedure; preparing S-triphenyl mercapto propionyl-N, N-ditert butyl oxycarbonyl-homoarginine with lysine; grafting S-triphenyl mercapto propionyl-N, N-ditert butyl oxycarbonyl-homoarginine; eliminating side chain protecting radical and resin to reduce into coarse product; and cyclization, oxidation, HPLC tracking purification to obtain pure product.
Description
One, technical field
The present invention relates to a kind of preparation technology of cyclic peptide, the particularly a kind of Fmoc-of utilization strategy solid phase method prepares the novel process of Integrilin.
Two, background technology
Eptifibatide (Integrilin) is a kind of cyclic peptide that contains sulfydryl propionyl and six amino-acid residues, and it is the main active ingredient of cardiovascular medicine Intergrelin.Molecular formula: C
35H
49N
11O
9S
2At present, the manufacturer of this product is the Bachem company of Switzerland in the world, and two circuits that they adopt are respectively: liquid phase method and Boc-strategy solid phase method.Liquid phase method is preparation technology comprise: 1, Gly-OMe and Boc-Lys (Tfa)-OH condensation products therefrom Boc-Lys (Tfa)-Gly-OMe and Mpa (Trt)-ONSu reaction, get product Mpa (Trt)-Lys (Tfa)-Gly-OMe, guanidine radicalsization, saponification gets Mpa (Trt)-Har-Gly-OH (fragment one); 2, Z-Asp (OtBu)-OH and Trp-Pro-OMe condensation reaction get product A sp (OtBu)-Trp-Pro-OMe (fragment two); 3, Mpa (Trt)-Har-Gly-OH (fragment one) and Asp (OtBu)-Trp-Pro-OH (fragment two) condensation, saponification get product Mpa (Trt)-Har-Gly-Asp (OtBu)-Trp-Pro-OH; 4, product and Cys (Trt)-NH
2Condensation gets also ortho states crude product of product; 5, crude product oxidation, cyclisation, be purified to final product; The solid-phase synthesis ultimate principle: solid-phase synthesis is to have the group of reactive behavior and reactant has this reactant structure in conjunction with formation carrier by in solid phase carrier (solid resin particle) structure some, then under solid-liquid heterogeneous reaction condition, be connected to other reactant on the carrier one by one, adopt certain method that target product is disintegrated down from solid phase carrier at last, through isolation identification, obtain product.The characteristics of solid-phase synthesis are that reaction finishes back product and reagent separate easily, and product purity is higher, is specially adapted to the multistep building-up reactions.Boc-strategy solid-phase process preparation comprises: 1, connect peptide according to the Boc-solid phase method, meet Boc-Cys (OMeBzl)-OH successively, Boc-Pro-OH, Boc-Trp-OH,, Boc-Lys (Fmoc)-OH obtains Boc-Cys (OMeBzl)- and connects the amino acid whose resin of follow-up protection, slough Boc-group 2, Piperdine therebetween successively and take off Fmoc-protection, washing; With 3,5-dimethyl Pyrazole carboxamidine reacts
3, trifluoroacetic acid (TFA) removes the Boc-protection, and product and S-Bzl (OMe)-Mpr condensation is reacted to such an extent that go back the ortho states crude product; 4, crude product oxidation, cyclisation, purifying get the finished product.The advantage of liquid phase method is to have avoided using expensive resin, but shortcoming is that a whenever synthetic step all need be expended a large amount of time purifying, so synthesis cycle is long, roughly needs the wheat harvesting period time.And solid phase method has overcome long shortcoming in man-hour, and the whole cycle only needs 1-2 days time.Also there are two shortcomings in BOC strategy solid phase method: 1, carry out under heterogeneous conditions in that arginine is converted in the homoarginine process, reaction is difficult for fully.And whether this transforming degree can't detect tracking fully on resin, therefore influences the purity of crude product, causes the purifying difficulty to strengthen, and productive rate reduces.2, polypeptide has been used the hydrogen fluoride of severe corrosive, severe toxicity when resin is washed, and easily causes environmental pollution, produces a series of environment social concerns.
Three, summary of the invention
The technical issues that need to address of the present invention: shorten synthesis cycle, make that separation and purification is carried out easily, building-up process is not used hydrogen fluoride; A kind of novel process for preparing Integrilin is provided.
For solving above-mentioned technical problem; provide a kind of Fmoc-solid phase method of peptide synthesis ultimate principle: at first an amino acid of alpha-amino group being protected with the Fmoc group is attached on the insoluble carrier by a support arm; subsequently with the alpha-amino group deprotection; with solution washing amino acid-support arm-resin. the amino acid of second activatory alpha-amino group protection is in advance connected up by coupled reaction. in addition; also can replace one amino acid to carry out coupled reaction with the peptide segment of α-N end and side chain protected; after condensation reaction is finished; use solution washing; repeat deprotection; the coupling connection; up to obtaining the purpose peptide. at last with peptide-support arm-resin cracking. the solid-phase synthesis of this prolongation peptide chain both can adopt the method for interruption, also can use the method for continuous flow. and its processing step is:
(1) C-terminal amino acid and resin-bonded
(2) N
aThe removing of-Fmoc, wash and obtain
(3) add Fmoc-amino acid-carry out the coupling connection, washing obtains
(4) repeating (2)～(3) step obtains
(5) the deprotection base obtains
(6) carry out obtaining polypeptide after the cracking
Utilize the technical solution of the synthetic Eptifibatide of ultimate principle of Fmoc-solid-phase synthesis to be: a kind of novel process for preparing Integrilin may further comprise the steps:
A) Fmoc-Rink Amide AM resin obtains H after taking off the Fmoc-protection
2N-Rink Amide AM resin;
B) method according to solid phase synthesis connects following protection amino acid: Fmoc-Cys (Trt)-OH successively; Fmoc-Pro-OH; Fmoc-Trp (Boc)-OH; Fmoc-Asp (tBu)-OH; Fmoc-G1y-OH; Obtain Fmoc-Cys (Trt)-NH-Rinkd Amide AM resin and connect the amino acid whose resin of follow-up protection;
C) slough the Fmoc-blocking group therebetween, with Kaiser test detection reaction process;
D) utilize Methionin (H-Lys-OH) to be its beginning raw material, preparation S-triphenyl sulfydryl propionyl-N, N-two tertbutyloxycarbonyls-homoarginine (Mpr (Trt)-Har (Boc)
2-OH): employing H-Lys-OH is a starting raw material, successively experience: Z radical protection side chain amino; Esterification; Connect Mpr (trt); Hydrogenation; Amino side-chain is converted to the croak base; Methyl ester removal; Obtain Mpr (Trt)-Har (Boc)
2-OH;
E) adjunction S-triphenyl sulfydryl propionyl-N, N-two tertbutyloxycarbonyls-homoarginine: with Mpr (Trt)-Har (Boc)
2-OH is connected to NH
2Obtain Mpr (Trt)-Har (Boc) 2-Gly-Asp (otBu)-Trp-Pro-Cys (Trt)-NH Rink Amide AM resin on-Gly-Asp (OtBu)-Trp-Pro-Cys (Trt)-NH-Rink AM resin;
F) take off and cut the side chain protected group and resin must be gone back the ortho states crude product;
G) crude product carries out cyclization, and follows the tracks of cyclization to fully with HPLC, promptly gets pure product ring seven peptide Eptifibatide through the HPLC preparation then.
The invention has the beneficial effects as follows:
1, with after triphenyl thiohydracrylic acid [Mpr (Trt)] the protection lysine amino part; under homogeneous phase condition, change the amino on the lysine side-chain into the croak base; be about to Methionin and be converted into homoarginine; owing to be homogeneous phase condition; conversion process is followed the tracks of easily, and plays the thiohydracrylic acid part of Eptifibatide just in the triphenyl thioserine of protection homoarginine amino.
2, the present invention adopts the Fmoc-strategy, has avoided hydrogen fluoride hypertoxic, severe corrosive in building-up process, makes production process safer, has alleviated environmental protection pressure, and has made the entire synthesis process condition gentle more.The original shortcoming of Fmoc-strategy is, Fmoc-protection amino acid price is higher than corresponding Boc-protection amino acid, but scale operation Fmoc-protection amino acid can make production cost descend greatly.
Four, description of drawings
Accompanying drawing is a process flow diagram of the present invention
Five, embodiment
With reference to accompanying drawing, a kind of novel process for preparing Integrilin, its step of preparation process is:
A.Fmoc-Rink Amide AM resin is at 20% piperidines, and DMF under the room temperature 20 minutes, obtains H after taking off the Fmoc-protection
2N-Rink Amide AM resin;
B. according to the method for solid phase synthesis at H
2Carry out condensation reaction successively on the N-Rink Amide AM resin and connect following protection amino acid: Fmoc-Cys (Trt)-OH; Fmoc-Pro-OH; Fmoc-Trp (Boc)-OH; Fmoc-Asp (tBu)-OH; Fmoc-Gly-OH; (not shown) obtains Fmoc-Cys (Trt)-NH-Rink Amide AM resin and connects the amino acid whose resin of follow-up protection, and the selection condensing agent is HBTU, HOBt, and DMF, the reaction times is following 2 hours of room temperature.
C. utilize piperidines to slough the Fmoc-blocking group therebetween, obtain NH
2-Gly-Asp (OtBu)-Trp-Pro-Cys (Trt)-NH-Rink AM resin is with Kaiser test detection reaction process;
D. prepare S-triphenyl sulfydryl propionyl-N, N-two tertbutyloxycarbonyls-homoarginine, its step preface is:
1. H-Lys-OH side amino adds Z group (benzene methoxycarbonyl) protection: Methionin is dissolved in the aqueous solution of ventilation breather, refluxes to add Z-Cl after 30 minutes, and transfers pH value with 2 equivalent NaOH; React and get product H-Lys (Z)-OH after 1 hour
2. H-Lys (Z)-OH esterification: H-Lys (Z)-OH is added CH
3OH drips SOCl
2, and refluxed 4 hours, obtain H-Lys (Z)-OMe after the separation and purification
3. connect S-triphenyl sulfydryl propionyl: H-Lys (Z)-OMe and adding Mpr (Trt) are dissolved among the DMF, behind adding DCC and the HOBt, stirring at room 4 hours, separation and purification gets Mpr (Trt)-Lys (Z)-OMe.With palladium carbon is that catalyzer hydrogenation at room temperature got Mpr (Trt)-Lys-OMe in 12 hours
4. change amino on the lysine side-chain into the croak base, be about to Methionin and change homoarginine into:
Add in the DMF solution of Mpr (Trt)-Lys-OMe
DCC, stirring at room 12 hours, separation and purification gets Mpr (Trt)-Har (Boc)
2-OMe
5. methyl ester removal: add 2 equivalent NaOH/CH
3OH through room temperature, 2 hours, obtains Mpr (Trt)-Har (Boc)
2-OH
E. with Mpr (Trt)-Har (Boc)
2-OH is at HBTU, HOBt, and DMF, room temperature is connected to NH under 2 hours conditions
2Obtain Mpr (Trt)-Har (Boc) on-Gly-Asp (OtBu)-Trp-Pro-Cys (Trt)-NH-Rink AM resin
2-Gly-Asp (otBu)-Trp-Pro-Cys (Trt)-NH Rink Amide AM resin.
F. slough resin among the e with Reagent K, must go back ortho states crude product Mpr-Har-Gly-Asp-Trp-Pro-Cys-NH
2
G. crude product adding iodine carries out oxidation, cyclization, obtains
And it is extremely complete to follow the tracks of cyclization with high pressure liquid chromatographic analysis (HPLC), promptly gets pure product ring seven peptide Eptifibatide through the HPLC preparation then.
Among the step f: Reagent K proportioning (volume ratio) TFA: phenol: H
2O: thioanisole: 1,2-ethanethiol=82.5: 5: 5: 5: 2.5.
Claims (8)
1, a kind of novel process for preparing Integrilin may further comprise the steps:
A.Fmoc-Rink Amide AM resin obtains H after taking off the Fmoc-protection
2N-Rink Amide AM resin;
B. according to the method for solid phase synthesis at H
2Carry out condensation reaction successively on the N-Rink Amide AM resin and connect following protection amino acid: Fmoc-Cys (Trt)-OH; Fmoc-Pro-OH; Fmoc-Trp (Boc)-OH; Fmoc-Asp (tBu)-OH; Fmoc-Gly-OH; Obtain Fmoc-Cys (Trt)-NH-Rink Amide AM resin and connect the amino acid whose resin of follow-up protection;
C. prepare S-triphenyl sulfydryl propionyl-N, N-two tertbutyloxycarbonyls-homoarginine;
D. with Mpr (Trt)-Har (Boc)
2-OH (S-triphenyl sulfydryl propionyl-N, N-two tertbutyloxycarbonyls-homoarginine) is connected to NH
2Obtain Mpr (Trt)-Har (Boc) on-Gly-Asp (OtBu)-Trp-Pro-Cys (Trt)-NH-Rink AM resin
2-Gly-Asp (otBu)-Trp-Pro-Cys (Trt)-NH Rink Amide AM resin;
E. slough the Fmoc-blocking group therebetween successively, with Kaiser test detection reaction process;
F. take off and cut the side chain protected group and resin must be gone back the ortho states crude product;
G. crude product carries out cyclization, and follows the tracks of cyclization to fully with HPLC, promptly gets pure product ring seven peptide Eptifibatide through the HPLC preparation then; It is characterized in that: homoarginine is prepared by Methionin.
2, a kind of novel process for preparing Integrilin according to claim 1 is characterized in that: Methionin is converted into S-triphenyl sulfydryl propionyl-N, and the technology step preface of N-two tert.-butoxies-homoarginine is:
H-Lys-OH→H-Lys(Z)-OH→H-Lys(Z)-OMe→Mpr(Trt)-Lys(Z)-OMe→Mpr(Trt)-Lys-OMe→Mpr(Trt)-Har(Boc)
2-OMe→Mpr(Trt)-Har(Boc)
2-OH。
3, a kind of novel process for preparing Integrilin according to claim 2, it is characterized in that: prepare high S-S-triphenyl sulfydryl propionyl-N, N-two tertbutyloxycarbonyls-homoarginine specifically goes on foot the preface condition: 1. H-Lys-OH side amino adds Z group (benzene methoxycarbonyl) protection: Methionin is dissolved in the aqueous solution of ventilation breather, refluxing added Z-C1 after 30 minutes, and transferred pH value with 2 equivalent NaOH; React and get product H-Lys (Z)-OH after 1 hour; 2. H-Lys (Z)-OH esterification: H-Lys (Z)-OH is added CH
3OH drips SOCl
2, and refluxed 4 hours, obtain H-Lys (Z)-OMe after the separation and purification; 3. connect S-triphenyl sulfydryl propionyl: H-Lys (Z)-OMe and adding Mpr (Trt) are dissolved among the DMF, after adding DCC and HOBt, stirring at room 4 hours, separation and purification get Mpr (Trt)-Lys (Z)-OMe, are that catalyzer hydrogenation at room temperature got Mpr (Trt)-Lys-OMe in 12 hours with palladium carbon; 4. change amino on the lysine side-chain into the croak base, be about to Methionin and change homoarginine into: in the DMF solution of Mpr (Trt)-Lys-OMe, add
DCC, stirring at room 12 hours, separation and purification gets Mpr (Trt)-Har (Boc)
2-OMe; 5. methyl ester removal: add 2 equivalent NaOH/CH
3OH through room temperature, 2 hours, obtains Mpr (Trt)-Har (Boc)
2-OH.
4, a kind of novel process for preparing Integrilin according to claim 1 is characterized in that: reaction conditions is among the step preface a: 20% piperidines, DMF, room temperature 20 minutes.
5, a kind of novel process for preparing Integrilin according to claim 1 is characterized in that: condensing agent adopts HBTU, HOBt, DMF among the step preface c, and the reaction times is following 2 hours of room temperature.
6, a kind of novel process for preparing Integrilin according to claim 1 is characterized in that: condensing agent adopts HBTU, HOBt, DMF among the step preface d, and the reaction times is following 2 hours of room temperature.
7, a kind of novel process for preparing Integrilin according to claim 1 is characterized in that: reaction conditions is among the step preface e: Reagent K, room temperature, 2hour and air, H
2O, room temperature, 48hour.
8, a kind of novel process for preparing Integrilin according to claim 7 is characterized in that: Reagent K proportioning (volume ratio) TFA: phenol: H
2O: thioanisole: 1,2-ethanethiol=82.5: 5: 5: 5: 2.5.
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| CN 02145292 CN1222537C (en) | 2002-11-14 | 2002-11-14 | Preparing process for Eptifibatide |
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|---|---|---|---|
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| WO2006045483A2 (en) * | 2004-10-19 | 2006-05-04 | Lonza Ag | On-resin peptide cyclization |
| WO2009150657A1 (en) * | 2008-06-09 | 2009-12-17 | Natco Pharma Limited | Improved process for preparation of eptifibatide by fmoc solid phase synthesis |
| CN101289498B (en) * | 2008-05-01 | 2010-09-08 | 杭州中肽生化有限公司 | Cyclic peptide with -val-sta-leu- residue segment and used as immunity inhibitor and synthetic process thereof |
| CN101289499B (en) * | 2008-05-01 | 2010-09-08 | 杭州中肽生化有限公司 | Cyclic peptide with -Ile-Sta-Sta-Pro- residue segment and used as immunity inhibitor and synthetic process thereof |
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| CN1858060B (en) * | 2005-05-08 | 2010-09-29 | 周达明 | Process for preparing solid phase polypeptide synthetic eptifibatide |
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| CN102174081A (en) * | 2011-03-09 | 2011-09-07 | 杭州华津允上医药有限公司 | Method for preparing eptifibatide and precursor thereof |
| CN1865280B (en) * | 2005-05-20 | 2012-03-21 | 上海苏豪逸明制药有限公司 | Solid phase polypeptide synthesis preparation method for leuprorelin |
| CN101372506B (en) * | 2007-08-23 | 2012-04-25 | 深圳翰宇药业股份有限公司 | Novel process for purifying and preparing eptifibatide |
| CN101838308B (en) * | 2009-03-17 | 2012-06-27 | 无锡市凯利药业有限公司 | Solid-phase synthesis method for eptifibatide |
| CN101538314B (en) * | 2009-01-13 | 2012-10-03 | 深圳翰宇药业股份有限公司 | Method for purifying Eptifibatide |
| WO2013117083A1 (en) * | 2012-02-06 | 2013-08-15 | 成都圣诺科技发展有限公司 | Eptifibatide preparation method |
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2002
- 2002-11-14 CN CN 02145292 patent/CN1222537C/en not_active Expired - Lifetime
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| US7994280B2 (en) | 2004-10-19 | 2011-08-09 | Lonza Ag | On-resin peptide cyclization |
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| CN1858060B (en) * | 2005-05-08 | 2010-09-29 | 周达明 | Process for preparing solid phase polypeptide synthetic eptifibatide |
| CN1865282B (en) * | 2005-05-18 | 2010-09-29 | 周达明 | Solid phase polypeptide synthesis preparation method for terlipressin |
| CN1865280B (en) * | 2005-05-20 | 2012-03-21 | 上海苏豪逸明制药有限公司 | Solid phase polypeptide synthesis preparation method for leuprorelin |
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| WO2009150657A1 (en) * | 2008-06-09 | 2009-12-17 | Natco Pharma Limited | Improved process for preparation of eptifibatide by fmoc solid phase synthesis |
| CN101538314B (en) * | 2009-01-13 | 2012-10-03 | 深圳翰宇药业股份有限公司 | Method for purifying Eptifibatide |
| CN101838308B (en) * | 2009-03-17 | 2012-06-27 | 无锡市凯利药业有限公司 | Solid-phase synthesis method for eptifibatide |
| WO2011079621A1 (en) * | 2009-12-30 | 2011-07-07 | 江苏诺泰制药技术有限公司 | Method for synthesizing and preparing eptifibatide |
| CN102174081A (en) * | 2011-03-09 | 2011-09-07 | 杭州华津允上医药有限公司 | Method for preparing eptifibatide and precursor thereof |
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| US20160017002A1 (en) * | 2011-07-27 | 2016-01-21 | Laurus Labs Private Limited | Process for Preparing Eptifibatide |
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| WO2013117083A1 (en) * | 2012-02-06 | 2013-08-15 | 成都圣诺科技发展有限公司 | Eptifibatide preparation method |
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| CN104861045A (en) * | 2014-02-20 | 2015-08-26 | 复旦大学 | Cyclopeptide compound GG6F and preparation method thereof |
| CN105037496A (en) * | 2015-09-17 | 2015-11-11 | 四川吉晟生物医药有限公司 | Preparation method for eptifibatide |
| CN105218641A (en) * | 2015-11-09 | 2016-01-06 | 叶仲林 | A kind of preparation method of Integrilin |
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