CN115109118A - Method for solid-phase synthesis of DS-8201 intermediate and preparation method of DS-8201 - Google Patents
Method for solid-phase synthesis of DS-8201 intermediate and preparation method of DS-8201 Download PDFInfo
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- CN115109118A CN115109118A CN202110295018.9A CN202110295018A CN115109118A CN 115109118 A CN115109118 A CN 115109118A CN 202110295018 A CN202110295018 A CN 202110295018A CN 115109118 A CN115109118 A CN 115109118A
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- 238000000034 method Methods 0.000 title claims abstract description 25
- 238000010532 solid phase synthesis reaction Methods 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000008878 coupling Effects 0.000 claims abstract description 20
- 238000010168 coupling process Methods 0.000 claims abstract description 20
- 238000005859 coupling reaction Methods 0.000 claims abstract description 20
- 229920005989 resin Polymers 0.000 claims abstract description 20
- 239000011347 resin Substances 0.000 claims abstract description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 17
- 239000007790 solid phase Substances 0.000 claims abstract description 15
- -1 succinimido ester Chemical class 0.000 claims abstract description 9
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 claims abstract description 7
- 229940125898 compound 5 Drugs 0.000 claims abstract description 7
- WOJKKJKETHYEAC-UHFFFAOYSA-N 6-Maleimidocaproic acid Chemical compound OC(=O)CCCCCN1C(=O)C=CC1=O WOJKKJKETHYEAC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 13
- 238000005336 cracking Methods 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical group C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 6
- 239000012317 TBTU Substances 0.000 claims description 6
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 6
- 150000002332 glycine derivatives Chemical class 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- OOWSDKUFKGVADH-UHFFFAOYSA-N 1-diphenylphosphoryloxy-2,3,4,5,6-pentafluorobenzene Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1OP(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 OOWSDKUFKGVADH-UHFFFAOYSA-N 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 4
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 claims description 4
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical compound C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- FPQVGDGSRVMNMR-JCTPKUEWSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.CCOC(=O)C(\C#N)=N/OC(N(C)C)=[N+](C)C FPQVGDGSRVMNMR-JCTPKUEWSA-N 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- AJDPNPAGZMZOMN-UHFFFAOYSA-N diethyl (4-oxo-1,2,3-benzotriazin-3-yl) phosphate Chemical compound C1=CC=C2C(=O)N(OP(=O)(OCC)OCC)N=NC2=C1 AJDPNPAGZMZOMN-UHFFFAOYSA-N 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 claims description 3
- FBKUOPULLUJMOC-UHFFFAOYSA-N 2-[[2-(9h-fluoren-9-ylmethoxycarbonylamino)acetyl]amino]acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 FBKUOPULLUJMOC-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
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- 238000002156 mixing Methods 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000010647 peptide synthesis reaction Methods 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- HBAHZZVIEFRTEY-UHFFFAOYSA-N 2-heptylcyclohex-2-en-1-one Chemical compound CCCCCCCC1=CCCCC1=O HBAHZZVIEFRTEY-UHFFFAOYSA-N 0.000 claims description 2
- 229920001367 Merrifield resin Polymers 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 150000001718 carbodiimides Chemical class 0.000 claims description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims 5
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- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 3
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- 238000009833 condensation Methods 0.000 abstract 1
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- 125000003630 glycyl group Chemical class [H]N([H])C([H])([H])C(*)=O 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
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- 238000006243 chemical reaction Methods 0.000 description 13
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229960002317 succinimide Drugs 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
- PTUJJIPXBJJLLV-UHFFFAOYSA-N 2-[[2-[[2-[[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]acetic acid Chemical group CC(C)(C)OC(=O)NCC(=O)NCC(=O)NC(C(=O)NCC(O)=O)CC1=CC=CC=C1 PTUJJIPXBJJLLV-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a method for solid-phase synthesis of a DS-8201 intermediate and a preparation method of DS-8201. The method for solid-phase synthesis of the DS-8201 intermediate comprises the steps of coupling the hydroxyl end of a compound 5 to solid-phase resin, sequentially splicing Fmoc-Phe-OH, glycine analogue, 6-maleimidocaproic acid or succinimido ester thereof, quickly and efficiently synthesizing a linker fragment by using a solid-phase synthesis method, wherein solid-phase synthesis does not need purification in each step, only the residual reagents/raw materials need to be washed after condensation in each step, and finally the linker is cut off from branches to obtain the linker with higher purity.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for solid-phase synthesis of a DS-8201 intermediate and a preparation method of DS-8201.
Background
DS-8201 is an antibody conjugate drug (ADC) targeting Her2, which is prepared by coupling humanized anti-Her 2 antibody trastuzumab (herceptin) with a topoisomerase-I inhibitor camptothecin derivative (DX-8951 derivative DXd) and conjugating the antibody with a tetrapeptide (GGFG) linker. The linker-payload structure of DS-8201 is shown as follows:
the first three commonly owned patent WO2014057687A1 discloses three synthetic routes for DS-8201, as follows:
the synthesis methods all use a liquid phase synthesis method, and the route 1 introduces the Yicetikang too early, the Yicetikang participates in 5-step reaction, repeated deprotection is needed, and the yield is low; the route 2 is optimized, but the Yixingtang still participates in multi-step reaction, so that the cost is still high; the route 3 is improved, the linker is synthesized and then condensed with the ixitancan, although the steps of the reaction of the ixitancan are reduced, and the cost of the ixitancan is reduced, the synthesis of the linker fragment is still complicated, the deprotection is carried out in a repeated liquid phase, each step needs to be purified, the yield is low, the cost is high, the efficiency is low, and the method is not suitable for industrial production.
Therefore, the development of a synthesis method of the linker and DS-8201, which is simple, convenient, low in cost and suitable for industrial production, has a very good application prospect.
Disclosure of Invention
The first purpose of the invention is to provide a method for solid-phase synthesis of a DS-8201 intermediate, which has simple steps and is suitable for industrial production.
The second purpose of the invention is to provide a preparation method of DS-8201.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for solid phase synthesis of a DS-8201 intermediate, comprising the following solid phase peptide synthesis route:
wherein the glycine analogue is Fmoc-Gly-OH or Fmoc-Gly-Gly-OH, and the Fmoc is fluorenylmethyloxycarbonyl.
When the glycine analogue is Fmoc-Gly-OH, Fmoc-Gly-OH and Fmoc-Gly-OH are required to be coupled to the solid-phase resin in sequence.
The preparation method of the DS-8201 intermediate by solid phase synthesis adopts an Fmoc solid phase synthesis method, sequentially couples the compound 5, Fmoc-Phe-OH, glycine analogue, 6-maleimide caproic acid or succinimide ester thereof to solid phase resin, then washes and dries, and adds a cracking reagent for cracking reaction to obtain the compound 6.
The solid phase Resin is 2-CTC Resin or Merrifield Resin; the degree of substitution of the solid phase resin is 0.2 to 2.0 mmol/g.
The coupling reagent adopted by the coupling is a carbodiimide type condensing agent, a phosphorus positive ion type condensing agent or a urea positive ion type condensing agent.
The cracking reagent is 0.5-5% TFA/DCM, 30% AcOH/DCM or AcOH/TFE/DCM, and the cracking time is 1-5 h. The percentage is volume percentage.
Specifically, the coupling reagent used for the above coupling is any one or more of HOBt, HOAt, HOOBt, HOPyU, TBTU, HBPyU, HBPipU, HBMDU, HATU, HAPyU, HAMDU, TAPipU, HDTU, HPyOPfp, HPySPfp, HAPyTU, TOTU, HAPipU, BOP-Cl, FDP, FDPP, DEPBT, EEDQ, EDC.HCl, DCC, DIC, DIEA, and TEA.
Preferably, the coupling reagent is used by mixing HOBt, HOAt or HOOBt with any one of EDC.HCl, DCC and DIC.
Preferably, when the above coupling reagent is used, DIEA or TEA is used in combination with any one of HBMDU, HATU, HAPyU, HAMDU, TAPipU, HDTU, HPyOPfp, HPySPfp, HAPyTU, TOTU, HAPipU, BOP-Cl, FDP, FDPP, DEPBT and EEDQ.
In the cracking reagent AcOH/TFE/DCM, the volume ratio of AcOH to TFE to DCM is 0.5-2: 1-4: 4 to 8.5.
Preferably, the volume ratio of the AcOH, the TFE and the DCM is 1: 2: 7.
After the cracking reaction, concentrating, adding MTBE for precipitation, washing, purifying and concentrating to obtain a compound 6.
When the cracking agent is 0.5-5% TFA/DCM, an organic base is added to neutralize the acid after the cracking reaction, preferably, the organic base is pyridine, triethylamine or DIEA.
The washing agent adopted by the washing is any one or more of DMF, DCM, methanol, ethyl acetate, methyl tert-butyl ether and acetone.
Preferably, in the above method, the molar ratio of the solid phase resin to the amino acid used may be 1.0: 1.0 to 5.0. It is understood that the molar ratio is not limited to this range, and it is theoretically possible to use the amino acid in an amount not exceeding the maximum loading of the solid phase resin.
Preferably, in the above process, the molar ratio of amino acid used to coupling reagent may be 1.0: 1.0 to 5.5. It is understood that the molar ratio is not limited to this range, and the amount of the coupling agent capable of supporting the amino acid on the resin is theoretically possible.
A preparation method of DS-8201 comprises the following steps:
1) compound 6 was prepared using the above method;
2) and mixing the compound 6, the compound 7 and an organic solvent, cooling to below 10 ℃, adding TBTU and DIEA, heating to room temperature, and reacting for 0.5-3 hours to obtain a DS-8201 crude product, namely a compound 8.
The organic solvent in the step 2) is DMF.
The invention relates to a method for solid-phase synthesis of a DS-8201 intermediate, which comprises the steps of coupling a hydroxyl end of a compound 5 to solid-phase resin, sequentially splicing Fmoc-Phe-OH, a glycine analogue and 6-maleimide caproic acid or succinimide ester thereof, and quickly and efficiently synthesizing a linker fragment by using a solid-phase synthesis method.
According to the preparation method of the DS-8201, the linker is prepared by adopting solid-phase peptide synthesis, then the linker and the Icetic are condensed and spliced by adopting a TBTU and DIEA condensing agent, and the DS-8201 can be obtained by reacting at room temperature for 1-3 h, so that the production cost is reduced, and the production efficiency is improved.
Drawings
FIG. 1 is a LC-MS spectrum of Compound 6;
FIG. 2 is a nuclear magnetic spectrum of Compound 6;
FIG. 3 is an LC-MS spectrum of Compound 8;
FIG. 4 is a nuclear magnetic spectrum of Compound 8;
figure 5 is an HPLC purity profile of compound 8.
Detailed Description
Example 1
Synthesis of Compound 5:
synthesis of Compound 2
10.00g of Compound 1(1.0eq), 300mL of tetrahydrofuran, 100mL of toluene, 2.68g of pyridine (1.2eq) and 15.01g of lead tetraacetate (1.2eq) were charged into a 500mL three-necked flask, and heated under reflux, and after the TLC monitoring reaction was completed, the temperature was lowered to room temperature, and insoluble matter was removed by filtration, and after concentration, ethyl acetate was added, and after washing with dilute hydrochloric acid and washing with sodium bicarbonate, the mixture was concentrated, and after column chromatography, an off-white solid compound was obtained in an amount of 27.30 g with a yield of 70.2%.
LC/MS(m/z):calcd for C 20 H 20 N 2 O 5 368.14;found 369[M+H] + ,367[M-H] - .
Synthesis of Compound 4
7.00g of Compound 2(1.0eq), 9.47g of Compound 3(3.0eq), 100mL of tetrahydrofuran, and 4.26g of Potassium tert-butoxide (2.0eq) were charged into a 250mL three-necked flask, and after stirring at room temperature for 0.5 hour, water and dichloromethane were added to the reaction mixture to extract and fractionate the mixture, and the organic phase was collected, after concentration, 100mL of water and 3.19g of sodium bicarbonate (2.0eq) were added, and after concentration, 7.05g of Fmoc-OSU (fluorenylmethoxycarbonylsuccinimid, 1.1eq) in 100mL of ethyleneglycol dimethyl ether was added, and then 50mL of tetrahydrofuran was added, and after stirring at room temperature, after TLC monitoring reaction, ethyl acetate was added after concentration to extract, diluted hydrochloric acid was washed, sodium bicarbonate was washed and then concentrated to obtain a white-like solid compound 45.12 g, with a yield of 56.8%.
LC/MS(m/z):calcd for C 27 H 26 N 2 O 6 474.18;found 475[M+H] + .
Synthesis of Compound 5
4.00g of Compound 4(1.0eq), 50mL of methanol and 0.4g of palladium on carbon were added to a 250mL hydrogenation vessel, and after displacement with nitrogen, hydrogen was introduced while maintaining 4 atmospheres, and the reaction was carried out at room temperature for 2 hours, and after completion of the TLC monitoring reaction, the mixture was filtered and concentrated to obtain 53.01 g of off-white solid compound with a yield of 92.8%.
LC/MS(m/z):calcd for C 20 H 20 N 2 O 6 384.13;found 385[M+H] + ,383[M-H] - .
Example 2
Synthesis of Compound 6
Weighing 16.25 g (6.5mmol) of 2-CTC Resin with a degree of substitution of 0.40mmol/g into a 500ml solid phase reaction column, adding 200ml DCM (dichloromethane), 2.50g (6.5mmol) of compound 5, 2.52g (19.5mmol) of DIEA (N, N-diisopropylethylamine), and carrying out nitrogen bubbling reaction for 2 h; then 16ml methanol was added, 2.52g DIEA was reacted for 1h, the resin was washed three times with DMF, the Fmoc protecting group was removed with 20% piperidine/DMF for 20min and washed 6 times with DMF, after which 5.04g (13.0mmol) Fmoc-Phe-OH, 1.93g (14.3mmol) HOBt, 1.80g (14.3mmol) DIC (N, N-diisopropylcarbodiimide) were weighed, dissolved with DMF, added to the reaction column, reacted for 2h, the resin was washed three times with DMF, the Fmoc protecting group was removed with 20% piperidine/DMF for 20min, washed 6 times with DMF and washed 3 times with DCM. The coupling operation is repeated, and Fmoc-Gly-OH, Fmoc-Gly-OH and 6-maleimide caproic acid are sequentially coupled according to peptide sequences. After the reaction is finished, the resin is shrunk by methanol, and 20.25g of peptide resin is obtained after vacuum drying;
the resulting 20.25g peptide resin was added to a 500ml single neck flask, 250ml DCM solution prepared with 1% TFA was added to the flask, reacted at room temperature for 2.0 hours, the resin was filtered off, pyridine was added to neutralize TFA, the solvent was removed by concentration, 200ml methyl t-butyl ether was added to precipitate, slurried, filtered, and the filter cake was collected to give compound 6 as white in 2.56g yield 64%.
LC/MS(m/z):calcd for C 28 H 36 N 6 O 10 616.25;found 615.25[M-H] - The LC-MS diagram of compound 6 is shown in figure 1 and the nmr diagram of compound 6 is shown in figure 2.
In other embodiments, the coupling reagent may be HOAt or HOOBt used in combination with any one of EDC.HCl, DCC, and DIC.
In other embodiments, the coupling reagent may also be DIEA or TEA used in combination with any one of HBMDU, HATU, HAPyU, HAMDU, TAPipU, HDTU, HPyOPfp, HPySPfp, HAPyTU, TOTU, HAPipU, BOP-Cl, FDP, FDPP, DEPBT, EEDQ.
In other embodiments, the cracking reagent may also be 30% AcOH/DCM or AcOH/TFE/DCM, wherein the volume ratio of AcOH, TFE, DCM is 1: 2: 7.
example 3
Synthesis of Compound 6
This example differs from example 2 only in that 6-maleimidocaproic acid in example 2 was replaced with 6- (maleimido) caproic acid succinimidyl ester.
Example 4
Synthesis of Compound 6
This example differs from example 2 only in that "Fmoc-Gly-OH, 6-maleimidocaproic acid coupled in sequence according to the peptide sequence" in example 2 was replaced by "Fmoc-Gly-Gly-OH, 6-maleimidocaproic acid coupled in sequence according to the peptide sequence".
Example 5
Synthesis of Compound 8
Adding 1.22g of compound 6(1.05eq) and 1.00g of compound 7(1.00eq) into a 25mL three-necked flask and 10mL of DMF, cooling to below 10 ℃, adding 0.63g of TBTU (1.05eq) and 0.73g of DIEA (3.0eq), heating to room temperature for reacting for 1h, after TLC monitoring reaction is finished, pouring the reaction liquid into water, extracting for 2 times by ethyl acetate, combining organic phases, washing by dilute hydrochloric acid and sodium bicarbonate solution, washing by saturated saline, drying by anhydrous sodium sulfate, concentrating to obtain a crude product, and performing column chromatography on the crude product (DCM: MeOH: 200: 1-10: 1) to obtain 81.59 g of a light yellow solid compound with the yield of 81.5%. The LC-MS pattern of compound 8 is shown in FIG. 3, the nuclear magnetic pattern is shown in FIG. 4, and the HPLC purity pattern is shown in FIG. 5.
LC/MS(m/z):calcd for C 52 H 56 FN 9 O 13 1033.40;found 1032.25[M-H] - .
Various other modifications and changes may be made by those skilled in the art based on the above-described technical solutions and concepts, and all such modifications and changes should fall within the scope of the claims of the present invention.
Claims (10)
2. The method of claim 1, wherein the compound 5, Fmoc-Phe-OH, glycine analog, 6-maleimidocaproic acid or succinimidyl ester thereof are sequentially coupled to a solid resin by Fmoc solid phase synthesis, and then washed and dried, and a cleavage reagent is added for cleavage reaction to obtain the compound 6.
3. The method of claim 2, wherein the solid phase Resin is 2-CTC Resin or Merrifield Resin; the degree of substitution of the solid phase resin is 0.2 to 2.0 mmol/g.
4. The method according to claim 2, wherein the coupling reagent used for the coupling is a carbodiimide type condensing agent, a phosphorus cationic type condensing agent or a urea cationic type condensing agent.
5. The method of claim 2, wherein the cleavage reagent is 0.5-5% TFA/DCM, 30% AcOH/DCM or AcOH/TFE/DCM, and the cleavage time is 1-5 h.
6. The method according to claim 2, wherein the coupling reagent used for the coupling is any one or more of HOBt, HOAt, HOOBt, HOPyU, TBTU, HBPyU, HBPipU, HBMDU, HATU, HAPyU, HAMDU, TAPipU, HDTU, HPyOPfp, HPySPfp, HAPyTU, TOTU, HAPipU, BOP-Cl, FDP, FDPP, DEPBT, EEDQ, EDC.HCl, DCC, DIC, DIEA, TEA.
7. The method of claim 5, wherein in the cracking reagent AcOH/TFE/DCM, the volume ratio of AcOH, TFE and DCM is 0.5-2: 1-4: 4 to 8.5.
8. The method of claim 2, wherein the Fmoc-protecting group is removed with piperidine/DMF after coupling compound 5 to the solid phase resin, followed by coupling Fmoc-Phe-OH.
9. The process of claim 2, wherein the cleavage reaction is followed by concentration, precipitation with MTBE, washing, purification and concentration to obtain compound 6.
10. A preparation method of DS-8201 is characterized by comprising the following steps:
1) preparing compound 6 using the method of any one of claims 1-9;
2) and mixing the compound 6, the compound 7 and an organic solvent, cooling to below 10 ℃, adding TBTU and DIEA, heating to room temperature, and reacting for 0.5-3 h to obtain a DS-8201 crude product, namely a compound 8.
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