CN118344369A - Method for preparing eptifibatide impurity I based on diphenylphosphonooxy label in auxiliary mode - Google Patents
Method for preparing eptifibatide impurity I based on diphenylphosphonooxy label in auxiliary mode Download PDFInfo
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- CN118344369A CN118344369A CN202410510404.9A CN202410510404A CN118344369A CN 118344369 A CN118344369 A CN 118344369A CN 202410510404 A CN202410510404 A CN 202410510404A CN 118344369 A CN118344369 A CN 118344369A
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- 108010056764 Eptifibatide Proteins 0.000 title claims abstract description 49
- GLGOPUHVAZCPRB-LROMGURASA-N eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 title claims abstract description 47
- 229960004468 eptifibatide Drugs 0.000 title claims abstract description 47
- 239000012535 impurity Substances 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 25
- -1 diphenylphosphonooxy Chemical group 0.000 title claims abstract description 22
- 238000005859 coupling reaction Methods 0.000 claims abstract description 36
- 108010016626 Dipeptides Proteins 0.000 claims abstract description 24
- 230000032050 esterification Effects 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 16
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 15
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 claims abstract description 10
- 125000006239 protecting group Chemical group 0.000 claims abstract description 10
- ADOHASQZJSJZBT-SANMLTNESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C12=CC=CC=C2N(C(=O)OC(C)(C)C)C=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ADOHASQZJSJZBT-SANMLTNESA-N 0.000 claims abstract description 9
- 230000009435 amidation Effects 0.000 claims abstract description 9
- 238000007112 amidation reaction Methods 0.000 claims abstract description 9
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 8
- 239000007791 liquid phase Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 81
- 238000006243 chemical reaction Methods 0.000 claims description 47
- 239000003153 chemical reaction reagent Substances 0.000 claims description 34
- 238000003756 stirring Methods 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 24
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 22
- 230000008878 coupling Effects 0.000 claims description 22
- 238000010168 coupling process Methods 0.000 claims description 22
- DYWUPCCKOVTCFZ-LBPRGKRZSA-N (2s)-2-amino-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=C(C[C@H](N)C(O)=O)C2=C1 DYWUPCCKOVTCFZ-LBPRGKRZSA-N 0.000 claims description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 15
- 230000009471 action Effects 0.000 claims description 14
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 11
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 230000002378 acidificating effect Effects 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 8
- 150000001408 amides Chemical class 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 229920001184 polypeptide Polymers 0.000 claims description 5
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 4
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 4
- RYFZBPVMVYTEKZ-KBPBESRZSA-N brevianamide F Chemical compound C1=CC=C2C(C[C@@H]3NC([C@@H]4CCCN4C3=O)=O)=CNC2=C1 RYFZBPVMVYTEKZ-KBPBESRZSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 3
- 239000007821 HATU Substances 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 19
- 238000009482 thermal adhesion granulation Methods 0.000 description 66
- 238000003786 synthesis reaction Methods 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 238000001556 precipitation Methods 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- 239000011734 sodium Substances 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 238000013146 percutaneous coronary intervention Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 208000004476 Acute Coronary Syndrome Diseases 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 208000000770 Non-ST Elevated Myocardial Infarction Diseases 0.000 description 1
- 102000015795 Platelet Membrane Glycoproteins Human genes 0.000 description 1
- 108010010336 Platelet Membrane Glycoproteins Proteins 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000006502 antiplatelets effects Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
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- 230000007017 scission Effects 0.000 description 1
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- 238000003860 storage Methods 0.000 description 1
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- 230000002194 synthesizing effect Effects 0.000 description 1
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- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Peptides Or Proteins (AREA)
Abstract
The invention relates to a method for preparing eptifibatide impurity I based on diphenylphosphonooxy label assistance, which comprises the steps of carrying out liquid-phase esterification coupling reaction on TAG label molecules and Boc-Pro-OH, carrying out Boc protection removal, carrying out Fmoc-Trp (Boc) -OH amidation coupling reaction to obtain linear dipeptide, removing Fmoc protecting group, carrying out self-cleavage-cyclization to remove TAG, and finally removing Boc protection to prepare eptifibatide impurity I. The preparation method is simple, the industrial preparation is easy, the total yield of the eptifibatide impurity I is 74%, and the purity of the product is more than 97%.
Description
Technical Field
The invention belongs to the technical fields of pharmaceutical technology and polypeptide chemical synthesis, and relates to a mild and efficient preparation method of eptifibatide impurity I.
Background
Eptifibatide (Eptifibatide) is a cyclic heptapeptide of natural origin, is used as a highly selective platelet glycoprotein IIb/IIIa receptor inhibitor, and has the characteristics of short plasma half-life, quick effect of antiplatelet effect, and quick and reversible platelet inhibition after treatment stopping. Clinically useful for the treatment of acute coronary syndromes (unstable angina/non-ST elevation myocardial infarction) including patients who will receive medical treatment or who are undergoing Percutaneous Coronary Intervention (PCI), the specific structure is as follows:
During the production and storage of eptifibatide, the following structure of eptifibatide impurity I appears, which may affect the efficacy and safety of eptifibatide drugs. The eptifibatide impurity I is prepared synthetically, which is helpful for knowing the property and content range of the impurity possibly existing in the research process of the eptifibatide preparation process, so that a corresponding quality control strategy can be formulated, and the quality of the medicine is ensured to accord with the standard.
CN 114685607a discloses a preparation method of eptifibatide impurity I, but the preparation can be completed only by a series of complex procedures including acid cleavage, group protection, deprotection, peptide cyclization and the like after dipeptide chain synthesis of impurities is performed by means of solid phase synthetic resin, the synthetic route is relatively complex, and the preparation efficiency of eptifibatide impurity I is greatly reduced.
In the field of organic synthesis, it has been an important and difficult challenge to find synthetic methods that are environmentally friendly, simple to operate, and economically viable. The preparation method of the eptifibatide impurity I disclosed in the above patent document is not easy to industrialize, and does not achieve good atomic utilization, so that development of a green, economical and efficient synthetic process route of the eptifibatide impurity I is urgently needed, raw material use is further reduced, and simple, convenient and efficient production and preparation of the eptifibatide impurity I are realized.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for preparing eptifibatide impurity I based on the assistance of a diphenylphosphonooxy label, so that the eptifibatide impurity I can be prepared simply and efficiently.
In order to achieve the above object, the method for preparing eptifibatide impurity I based on diphenylphosphonooxy TAG in the present invention specifically uses TAG (TAG) assisted polypeptide synthesis method to prepare linear dipeptide, and prepares eptifibatide impurity I by self-cleavage-cyclization under alkaline condition, and specifically includes:
S1: esterification coupling of Boc-Pro-OH with TAG
Under the action of an esterification coupling reagent, carrying out liquid-phase esterification coupling reaction on the TAG TAG molecules and the proline Boc-Pro-OH protected by Boc to generate an intermediate Boc-Pro-O-TAG loaded by the TAG TAG;
S2: removal of Boc protecting groups
Removing Boc protection from Boc-Pro-O-TAG under the action of an acidic deprotection reagent to obtain a Boc-removed intermediate H 2 N-Pro-O-TAG;
S3: fmoc-Trp (Boc) -OH amidated coupling with H 2 N-Pro-O-TAG
Under the action of an amide coupling reagent, carrying out amidation coupling reaction on H 2 N-Pro-O-TAG and Fmoc-protected tryptophan Fmoc-Trp (Boc) -OH to generate a linear dipeptide Fmoc-Trp (Boc) -Pro-O-TAG loaded with a TAG label;
s4: linear dipeptide self-cleavage-cyclization
Under the action of an alkaline reagent, fmoc protecting groups of Fmoc-Trp (Boc) -Pro-O-TAG are removed, and TAG is removed from the cleavage-cyclization to form a cyclic dipeptide derivative cyclo [ Trp (Boc) -Pro ] with Boc protection;
S5: removal of Boc protecting groups
Under the action of an acidic deprotection reagent, removing Boc protection from the cyclo [ Trp (Boc) -Pro ], and purifying to obtain the cyclo [ Trp-Pro ], namely the eptifibatide impurity I.
The TAG label molecule related in the preparation method disclosed by the invention is a benzophenone oxime compound TAG=N-OH based on diphenyl phosphonooxy groups, which is shown in the following structural general formula (I):
Or benzyl alcohol compound TAG-OH based on diphenyl phosphonooxy group shown in the following structural general formula (II):
Wherein the substituent R is selected from H, OPOPh 2, C1-C3 alkyl, C1-C3 alkoxy, halogen atom or NO 2.
Further, the substituent R is preferably selected from H, OPOPh 2、CH3、OCH3, cl, F or NO 2.
The specific synthetic route of the eptifibatide impurity I is as follows:
In the above-described method of the present invention, the esterification coupling reagent used in the esterification coupling reaction is various conventional coupling reagents for esterification, and the present invention is not particularly limited. Specifically, the esterification coupling reagent used in the invention can be one or more of conventional coupling combined reagents EDCl/DMAP, DIC/DMAP and DCC/DMAP. In some embodiments, the esterified coupling reagent is preferably EDCl/DMAP.
In the above-described method of the present invention, the amide coupling reagent used in the amidation coupling reaction is also various conventional coupling reagents for amidation, and the present invention is not particularly limited. Specifically, the amide coupling reagent used in the invention can be one or more of conventional coupling combined reagents EDCl/HOBt, EDCl/HOBt/DIPEA, DIC/HOBt, DCC/HOSU, HATU/HOAt/DIPEA and PyBOP/DIPEA for amidation. In some specific embodiments, the amide coupling reagent is preferably EDCl/HOBt.
More specifically, the esterification coupling reaction is preferably carried out for 0.5 to 10 hours under stirring at a temperature of between 0 and 40 ℃; the amidation coupling reaction is preferably carried out at 0-40 ℃ for 1-2h under stirring.
In the above method of the present invention, the acidic deprotection reagent for removing Boc protection may be any one of dioxane/dichloromethane, trifluoroacetic acid/dichloromethane, hydrochloric acid/methanol, etc. In some embodiments, the acidic deprotection reagent is preferably trifluoroacetic acid/dichloromethane.
Further, the specific reaction condition for removing Boc protection is stirring reaction for 3-6 h at 0-10 ℃.
In the above method of the present invention, the basic reagent for self-cleavage-cyclization of linear dipeptide may be any of diethylamine/acetonitrile mixture, piperidine/acetonitrile mixture, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) solution. In some embodiments, the basic reagent is preferably a diethylamine/acetonitrile mixture.
Further, the specific reaction condition of self-cracking-cyclization is that stirring reaction is carried out for 1-3 h at 30-50 ℃.
In the preparation process of the present invention, the reactions of the individual steps are carried out in a suitable solution system. The solvent system suitable for each reaction in the present invention is one or more of organic solvents capable of forming a good phase separation with water, such as chloroform, methylene chloride, etc.
Further, the eptifibatide impurity I is obtained after HPLC purification.
Specifically, the chromatographic conditions of the HPLC purification are reversed-phase C18 BP, 4.6X1250 mm, 5 μm chromatographic column, 0.1% trifluoroacetic acid/water as mobile phase A,0.1% trifluoroacetic acid/acetonitrile as mobile phase B, and gradient elution is carried out at 280nm detection wavelength.
In the preparation method, the TAG (TAG) plays the following three roles in the process of assisting in synthesizing the eptifibatide impurity I:
1) As a temporary protecting group of Carboxyl (COOH) at the carbon end of amino acid in a peptide chain, the peptide chain can be subjected to self-cleavage and cyclization in an alkaline environment to form a cyclic dipeptide derivative, and the removed tag molecule can be directly recovered and can be recycled after purification;
2) Compared with other carboxyl protecting groups, the intermediate has the function of improving the solubility of polypeptide chains in a medium, can assist in the precipitation and purification of the intermediate of the eptifibatide impurity I in a specific precipitation solvent, and avoids the purification of the intermediate by using a chromatographic method;
3) TAG-based multi-benzene ring system is easy to monitor by TLC for intermediate reaction process of homogeneous phase reaction.
According to the invention, the eptifibatide impurity I is prepared by using a tag-assisted polypeptide synthesis technology, the homogeneous reaction and the self-cleavage-cyclization reaction are realized by using the property of tag molecules, the tag molecules can be recycled, the atom utilization rate is improved, the raw material use is reduced, the synthesis steps are simplified, the preparation route is simple and convenient, the reaction condition is mild, the industrialized preparation is easy, the total yield of the eptifibatide impurity I is up to 74%, and the product purity is over 97%.
Drawings
Fig. 1 is a synthetic route for eptifibatide impurity I.
FIG. 2 is a mass spectrum of the linear dipeptide Fmoc-Trp (Boc) -Pro-O-TAG loaded with the preparation TAG TAG of example 1.
FIG. 3 is a mass spectrum of eptifibatide impurity I cyclo [ Trp-Pro ].
Fig. 4 is a mass spectrum of the intermediate Boc-Pro-O-n=tag loaded for the preparation of TAG TAGs of example 2.
FIG. 5 is a mass spectrum of the linear dipeptide Fmoc-Trp (Boc) -Pro-O-N=TAG loaded with the preparation TAG TAG of example 2.
FIG. 6 is a mass spectrum of the cyclic dipeptide derivative cyclo [ Trp (Boc) -Pro ].
Description of the embodiments
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are presented only to more clearly illustrate the technical aspects of the present invention so that those skilled in the art can better understand and utilize the present invention without limiting the scope of the present invention.
The production process, the experimental method or the detection method related to the embodiment of the invention are all conventional methods in the prior art unless otherwise specified, and the names and/or the abbreviations thereof are all conventional names in the field, so that the related application fields are very clear and definite, and a person skilled in the art can understand the conventional process steps according to the names and apply corresponding equipment to implement according to conventional conditions or conditions suggested by manufacturers.
The various instruments, equipment, materials or reagents used in the examples of the present invention are not particularly limited in source, and may be conventional products commercially available through regular commercial routes or may be prepared according to conventional methods well known to those skilled in the art.
The invention provides a method for preparing eptifibatide impurity I based on diphenylphosphonooxy label assistance, the synthetic route is shown in figure 1, wherein the related label molecule is diphenylphosphonooxy benzophenone oxime compound or diphenylphosphonooxy benzyl alcohol compound.
Firstly, taking Boc-Pro-OH as a raw material, carrying out liquid-phase esterification coupling reaction on the Boc-Pro-OH and TAG TAG molecules under the action of an esterification coupling reagent to generate a TAG TAG loaded intermediate Boc-Pro-O-TAG, and then removing Boc protection under the action of an acidic deprotection reagent to obtain a Boc-protected intermediate H 2 N-Pro-O-TAG.
Then, the amidation coupling reaction is continued by using the prepared H 2 N-Pro-O-TAG and Fmoc-protected tryptophan Fmoc-Trp (Boc) -OH as raw materials under the action of an amide coupling reagent to generate the linear dipeptide Fmoc-Trp (Boc) -Pro-O-TAG loaded by the TAG TAG.
The Fmoc protecting group is removed by acting on Fmoc-Trp (Boc) -Pro-O-TAG with an alkaline reagent, the self-cleavage-cyclization reaction is performed on the one hand, the TAG is removed to form a cyclic dipeptide derivative cyclo [ Trp (Boc) -Pro ] with Boc protection, and the TAG molecule is recovered for reuse.
Finally, removing Boc protection of the cyclo [ Trp (Boc) -Pro ] under the action of an acidic deprotection reagent, and eluting and purifying by HPLC to obtain the target product eptifibatide impurity I.
The meaning of the english abbreviations referred to in the present invention is as follows:
boc: boc-group
DBU:1, 8-diazabicyclo-bicyclo (5, 4, 0) -7-undecene
DCC: n, N-dicyclohexyl carbodiimine
DIC:1, 3-diisopropylcarbodiimide
DIPEA: n, N-diisopropylethylamine
DMAP: 4-dimethylaminopyridine
EDCl:1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
Fmoc: fluorene methoxycarbonyl group
HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate
HOAt: 1-hydroxy-7-azobenzotriazole
HOBt: 1-hydroxybenzotriazoles
HOSU: n-hydroxysuccinimide
Pro: proline (proline)
PyBOP: 1H-benzotriazol-1-yloxy tripyrrolidinylphosphonium hexafluorophosphate
Trp: tryptophan
Examples
Example 1
Step 1: synthesis of Boc-Pro-O-TAG
Boc-Pro-OH (2.37 g,11 mmol), EDCl (2.3 g,12 mmol) and DMAP (146 mg,1.2 mmol) were weighed in sequence, dissolved in 30mL of dichloromethane, placed under ice bath and stirred for reaction for 30min, 4-diphenylphosphonoxybenzyl alcohol tag molecule (3.24 g,10 mmol) was added, the reaction was continued at room temperature for 2h with stirring, and TLC was used to detect the end point of the reaction.
The reaction product was washed with saturated NH 4 Cl solution and 10% Na 2CO3 solution, respectively, dried over anhydrous sodium sulfate, concentrated to 3mL under reduced pressure, 30mL of petroleum ether was added dropwise to give a white precipitate and the solution was filtered off, and the above precipitation operation was repeated 3 times to give a purified Boc-Pro-O-TAG intermediate for use in 96% yield.
Step 2: synthesis of H 2 N-Pro-O-TAG
And (2) dissolving the Boc-Pro-O-TAG prepared in the step (1) in 6mL of dichloromethane solution, stirring at 0 ℃ for 10min, adding 6mL of trifluoroacetic acid, continuing stirring at 0 ℃ for 3h, ending the reaction, and detecting the reaction end point by TLC.
The reaction solution was concentrated under reduced pressure, redissolved with 30mL of dichloromethane, then washed once with 10% NaHCO 3 and 20% NaCl solution, and the obtained organic phase was concentrated under reduced pressure to obtain a purified H 2 N-Pro-O-TAG intermediate for use in 98% yield.
Step 3: synthesis of Fmoc-Trp (Boc) -Pro-O-TAG
Fmoc-Trp (Boc) -OH (5.53 g,10.5 mmol), EDCl (2.3 g,12 mmol) and HOBt (1.62 g,12 mmol) are sequentially weighed and dissolved in 30mL of dichloromethane, the mixture is placed in an ice bath for stirring reaction for 30min, H 2 N-Pro-O-TAG prepared in the step 2 is added, the mixture is transferred to room temperature for continuing stirring reaction for 1H, and TLC (thin layer chromatography) detects the end point of the reaction.
The reaction product was washed with 10% Na 2CO3 solution and 20% NaCl solution, respectively, dried over anhydrous sodium sulfate, concentrated to 3mL under reduced pressure, and 30mL of petroleum ether was added dropwise to give a white precipitate and the solution was filtered off, and the above precipitation operation was repeated 3 times to give purified linear dipeptide Fmoc-Trp (Boc) -Pro-O-TAG for use in 97% yield.
The structure of the product was confirmed by mass spectrum of FIG. 2 ,HRMS (ESI) m/z calcd for C55H53N3O9P+ (M+H)+ 930.35139,found 930.35156.
Step 4: synthesis of cyclo [ Trp (Boc) -Pro ]
Fmoc-Trp (Boc) -Pro-O-TAG prepared in the step 3 is dissolved in 6mL of acetonitrile, 6mL of diethylamine solution is added at 45 ℃, fmoc groups are removed by stirring for 1h, the solution is dissolved in 3mL of dichloromethane after reduced pressure concentration, 30mL of petroleum ether is added dropwise to generate white precipitate, the solution is filtered off, the above precipitation operation is repeated for 3 times, and the purified cyclic dipeptide derivative cyclo [ Trp (Boc) -Pro ] is prepared for standby, and the yield is 94%.
HRMS (ESI) m/z calcd for C21H26N3O4 + (M+H)+ 384.19178,found 384.19171.
Step 5: synthesis of eptifibatide impurity I
The cyclo [ Trp (Boc) -Pro ] prepared in the step 4 is dissolved in 6mL of dichloromethane solution, after stirring for 10min at 0 ℃, 6mL of trifluoroacetic acid is added, stirring is continued for 3h at 0 ℃ to finish the reaction, and TLC detects the end point of the reaction.
After concentrating the reaction solution under reduced pressure, redissolving the product with 30mL of dichloromethane, then washing once with 10% NaHCO 3 and 20% NaCl solution, concentrating the obtained organic phase under reduced pressure, and purifying by chromatography to obtain pure eptifibatide impurity I in 84% yield.
The mass spectrum of the product is shown in figure 3,HRMS (ESI) m/z calcd for C16H18N3O2 + (M+H)+ 284.13935,found 284.13950.
Example 2
Step 1: synthesis of Boc-Pro-O-n=tag
Boc-Pro-OH (2.37 g,11 mmol), EDCl (2.3 g,12 mmol) and DMAP (146 mg,1.2 mmol) were weighed in order, dissolved in 30mL of dichloromethane, placed under ice bath and stirred for reaction for 30min, 4' -diphenylphosphonooxy benzophenone oxime tag molecule (6.30 g,10 mmol) was added, and the reaction was continued at room temperature for 3h with stirring, and TLC was used to detect the end of the reaction.
The reaction product was washed with saturated NH 4 Cl solution and 10% Na 2CO3 solution, respectively, dried over anhydrous sodium sulfate, concentrated to 3mL under reduced pressure, 30mL of petroleum ether was added dropwise to give a white precipitate and the solution was filtered off, and the above precipitation operation was repeated 3 times to give a purified Boc-Pro-O-n=tag intermediate for use in 95% yield.
The mass spectrum of fig. 4 verifies the Boc-Pro-O-n=tag structure of the intermediate ,：HRMS (ESI) m/z calcd for C47H45N2O8P2 + (M+H)+ 827.26457,found 827.26489.
Step 2: synthesis of H 2 N-Pro-O-N=TAG
The Boc-Pro-O-N=TAG prepared in the step 1 is dissolved in 8mL of dichloromethane solution, 8mL of trifluoroacetic acid is added after stirring for 10min at 0 ℃, stirring is continued for 3.5h at 0 ℃, the reaction is ended, and TLC (thin layer chromatography) detects the end point of the reaction.
The reaction solution was concentrated under reduced pressure, redissolved with 30mL of dichloromethane, then washed once with 10% NaHCO 3 and 20% NaCl solution, respectively, and the obtained organic phase was concentrated under reduced pressure to give a purified H 2 N-Pro-O-n=tag intermediate for use in 96% yield.
Step 3: synthesis of Fmoc-Trp (Boc) -Pro-O-N=TAG
Fmoc-Trp (Boc) -OH (5.53 g,10.5 mmol), EDCl (2.3 g,12 mmol) and HOBt (1.62 g,12 mmol) were weighed sequentially and dissolved in 30mL of dichloromethane, stirred in an ice bath for reaction for 30min, H 2 N-Pro-O-N=TAG obtained in step 2 was added, and the reaction was continued at room temperature for 1H with stirring, and TLC was used to detect the end point of the reaction.
The reaction product was washed with 10% Na 2CO3 solution and 20% NaCl solution, respectively, dried over anhydrous sodium sulfate, concentrated to 3mL under reduced pressure, and 30mL of petroleum ether was added dropwise to give a white precipitate and the solution was filtered off, and the above precipitation operation was repeated 3 times to give the purified linear dipeptide Fmoc-Trp (Boc) -Pro-O-n=tag for use in 98% yield.
The structure of the linear dipeptide was confirmed by the mass spectrum of FIG. 5 ,HRMS (ESI) m/z calcd for C73H65N4O11P2 + (M+H)+ 1235.41196,found 1235.41296.
Step 4: synthesis of cyclo [ Trp (Boc) -Pro ]
Fmoc-Trp (Boc) -Pro-O-N=TAG prepared in the step 3 is dissolved in 6mL of acetonitrile, 6mL of diethylamine solution is added at 45 ℃, fmoc groups are removed by stirring for 1h, the mixture is concentrated under reduced pressure and then dissolved in 3mL of dichloromethane, 30mL of petroleum ether is added dropwise to generate white precipitate, the solution is filtered off, the above precipitation operation is repeated for 3 times, and the purified cyclodipeptide derivative cyclo [ Trp (Boc) -Pro ] is prepared for standby, and the yield is 96%.
HRMS (ESI) m/z calcd for C21H26N3O4 + (M+H)+ 384.19178,found 384.19128, The mass spectrum of fig. 6 verifies the structure of the cyclic dipeptide derivative.
Step 5: synthesis of eptifibatide impurity I
The cyclo [ Trp (Boc) -Pro ] prepared in the step 4 is dissolved in 6mL of dichloromethane solution, after stirring for 10min at 0 ℃, 6mL of trifluoroacetic acid is added, stirring is continued for 3h at 0 ℃ to finish the reaction, and TLC detects the end point of the reaction.
After concentrating the reaction solution under reduced pressure, redissolving the product with 30mL of dichloromethane, then washing once with 10% NaHCO 3 and 20% NaCl solution, concentrating the obtained organic phase under reduced pressure, and purifying by chromatography to obtain pure eptifibatide impurity I with a yield of 85%.
cyclo[Trp-Pro]：HRMS (ESI) m/z calcd for C16H17N3O2Na+ (M+Na)+ 306.12130,found 306.12103.
Example 3
Step 1: synthesis of Boc-Pro-O-TAG
Boc-Pro-OH (4.74 g,22 mmol), EDCl (4.6 g,24 mmol) and DMAP (292 mg,2.4 mmol) were weighed in turn, dissolved in 50mL of dichloromethane, placed under ice bath and stirred for reaction for 30min, 4-diphenylphosphonoxybenzyl alcohol tag molecule (6.5 g,20 mmol) was added, the reaction was continued at room temperature for 2h with stirring, and TLC was used to detect the end point of the reaction.
The reaction product was washed with saturated NH 4 Cl solution and 10% Na 2CO3 solution, respectively, dried over anhydrous sodium sulfate, concentrated to 5mL under reduced pressure, 50mL petroleum ether was added dropwise to give a white precipitate and the solution was filtered off, and the above precipitation operation was repeated 3 times to give a purified Boc-Pro-O-TAG intermediate for use in 97% yield.
Step 2: synthesis of H 2 N-Pro-O-TAG
And (2) dissolving the Boc-Pro-O-TAG prepared in the step (1) in 10mL of dichloromethane solution, stirring at 0 ℃ for 10min, adding 10mL of trifluoroacetic acid, continuing stirring at 0 ℃ for 3h, ending the reaction, and detecting the reaction end point by TLC.
The reaction solution was concentrated under reduced pressure, redissolved with 50mL of dichloromethane, then washed once with 10% NaHCO 3 and 20% NaCl solution, and the obtained organic phase was concentrated under reduced pressure to obtain a purified H 2 N-Pro-O-TAG intermediate for use in 98% yield.
Step 3: synthesis of Fmoc-Trp (Boc) -Pro-O-TAG
Fmoc-Trp (Boc) -OH (11.1 g,21 mmol), EDCl (4.6 g,24 mmol) and HOBt (3.24 g,24 mmol) are sequentially weighed and dissolved in 30mL of dichloromethane, the mixture is placed in an ice bath for stirring reaction for 30min, H 2 N-Pro-O-TAG prepared in the step 2 is added, the mixture is transferred to room temperature for continuing stirring reaction for 1H, and TLC (thin layer chromatography) detects the end point of the reaction.
The reaction product was washed with 10% Na 2CO3 solution and 20% NaCl solution, respectively, dried over anhydrous sodium sulfate, concentrated to 5mL under reduced pressure, 50mL of petroleum ether was added dropwise to give a white precipitate and the solution was filtered off, and the above precipitation operation was repeated 3 times to give the purified linear dipeptide Fmoc-Trp (Boc) -Pro-O-TAG for use in 98% yield.
Step 4: synthesis of cyclo [ Trp (Boc) -Pro ]
Fmoc-Trp (Boc) -Pro-O-TAG prepared in the step 3 is dissolved in 10mL of acetonitrile, 10mL of diethylamine solution is added at 45 ℃, fmoc groups are removed by stirring for 1h, the solution is dissolved in 5mL of dichloromethane after reduced pressure concentration, 50mL of petroleum ether is added dropwise to generate white precipitate, the solution is filtered off, the precipitation operation is repeated for 3 times, and the purified cyclic dipeptide derivative cyclo [ Trp (Boc) -Pro ] is prepared for standby, and the yield is 95%.
HRMS (ESI) m/z calcd for C21H26N3O4Na+ (M+Na)+ 407.18155,found 407.18234.
Step 5: synthesis of eptifibatide impurity I
The cyclo [ Trp (Boc) -Pro ] prepared in the step 4 is dissolved in 10mL of dichloromethane solution, 10mL of trifluoroacetic acid is added after stirring for 10min at 0 ℃, stirring is continued for 3h at 0 ℃, the reaction is ended, and TLC detects the end point of the reaction.
After concentrating the reaction solution under reduced pressure, redissolving the product with 50mL of dichloromethane, then washing once with 10% NaHCO 3 and 20% NaCl solution, concentrating the obtained organic phase under reduced pressure, and purifying by chromatography to obtain pure eptifibatide impurity I in 84% yield.
Among the above 3 examples, in example 2, the 4-diphenylphosphonooxybenzyl alcohol tag molecules in examples 1 and 3 were replaced with 4,4 '-diphenylphosphonooxybenzone oxime, and the total yield of the eptifibatide impurity I prepared by the three was equivalent, but the 4,4' -diphenylphosphonooxybenzone oxime tag molecule showed significantly more excellent precipitation effect during the precipitation and purification treatment of the product, and the synthesis efficiency of eptifibatide peptide chain could be greatly improved. However, the 4,4' -diphenylphosphonooxy benzophenone oxime tag molecule has a higher cost of synthesis than 4-diphenylphosphonooxy benzyl alcohol, and thus example 2 is less economical than examples 1 and 3.
In addition, oxime ester bonds formed by ketoxime tags and peptide chains are not as stable as those formed by benzyl alcohol, so that the self-cleavage-cyclization efficiency is higher when the ketoxime tags synthesize eptifibatide impurity I, but the requirements on environment such as air humidity are also higher when the eptifibatide peptide chains are prepared.
Example 3 expands the preparation batch of eptifibatide impurity I compared to examples 1 and 2, and the overall yield of eptifibatide impurity I after the expansion batch remains stable, demonstrating the great potential of the tag molecule in the large-scale preparation of eptifibatide impurity I.
The above embodiments of the invention are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Various changes, modifications, substitutions and alterations may be made by those skilled in the art without departing from the principles and spirit of the invention, and it is intended that the invention encompass all such changes, modifications and alterations as fall within the scope of the invention.
Claims (10)
1. A method for preparing eptifibatide impurity I based on diphenylphosphonooxy label in an assisted manner is to prepare linear dipeptide by using a label-assisted polypeptide synthesis method, and prepare the eptifibatide impurity I by self-cleavage-cyclization under alkaline conditions, and comprises the following steps:
S1: esterification coupling of Boc-Pro-OH with TAG
Under the action of an esterification coupling reagent, carrying out liquid-phase esterification coupling reaction on the TAG TAG molecules and the proline Boc-Pro-OH protected by Boc to generate an intermediate Boc-Pro-O-TAG loaded by the TAG TAG;
S2: removal of Boc protecting groups
Removing Boc protection from Boc-Pro-O-TAG under the action of an acidic deprotection reagent to obtain a Boc-removed intermediate H 2 N-Pro-O-TAG;
S3: fmoc-Trp (Boc) -OH amidated coupling with H 2 N-Pro-O-TAG
Under the action of an amide coupling reagent, carrying out amidation coupling reaction on H 2 N-Pro-O-TAG and Fmoc-protected tryptophan Fmoc-Trp (Boc) -OH to generate a linear dipeptide Fmoc-Trp (Boc) -Pro-O-TAG loaded with a TAG label;
s4: linear dipeptide self-cleavage-cyclization
Under the action of an alkaline reagent, fmoc protecting groups of Fmoc-Trp (Boc) -Pro-O-TAG are removed, and TAG is removed from the cleavage-cyclization to form a cyclic dipeptide derivative cyclo [ Trp (Boc) -Pro ] with Boc protection;
S5: removal of Boc protecting groups
Under the action of an acidic deprotection reagent, removing Boc protection from the cyclo [ Trp (Boc) -Pro ], and purifying to obtain the cyclo [ Trp-Pro ], namely eptifibatide impurity I;
wherein the TAG TAG molecule is a benzophenone oxime compound based on diphenyl phosphonooxy group shown in the following structural general formula (I):
，
Or a diphenyl phosphonooxy group-based benzyl alcohol compound represented by the following structural formula (II):
，
Wherein the substituent R is selected from H, OPOPh 2, C1-C3 alkyl, C1-C3 alkoxy, halogen atom or NO 2.
2. The method according to claim 1, characterized in that the substituent R is selected from H, OPOPh 2、CH3、OCH3, cl, F or NO 2.
3. The method according to claim 1, wherein the esterification coupling reagent is one or more of EDCl/DMAP, DIC/DMAP and DCC/DMAP.
4. The method according to claim 1, wherein the amide coupling reagent is one or more of EDCl/HOBt, EDCl/HOBt/DIPEA, DIC/HOBt, DCC/HOSU, HATU/HOAt/DIPEA, pyBOP/DIPEA.
5. The method according to claim 1, characterized in that the acidic deprotection reagent is any one of dioxane/dichloromethane, trifluoroacetic acid/dichloromethane, hydrochloric acid/methanol.
6. The method according to claim 1, wherein the basic reagent is any one of a diethylamine/acetonitrile mixture, a piperidine/acetonitrile mixture, and a1, 8-diazabicyclo [5.4.0] undec-7-ene solution.
7. The method according to claim 1, wherein the esterification coupling reaction is performed at 0 to 40 ℃ with stirring for 0.5 to 10 hours.
8. The method according to claim 1, wherein the amidation coupling reaction is performed by stirring at 0 to 40 ℃ for 1 to 2 hours.
9. The process according to claim 1, wherein the reaction is stirred at 0-10 ℃ for 3-6 h to remove Boc protection.
10. The method according to claim 1, wherein the self-cleavage-cyclization reaction is carried out by stirring at 30 to 50 ℃ for 1 to 3 hours.
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