CN103145828A - 一种利拉鲁肽的全固相合成方法 - Google Patents
一种利拉鲁肽的全固相合成方法 Download PDFInfo
- Publication number
- CN103145828A CN103145828A CN2012105337597A CN201210533759A CN103145828A CN 103145828 A CN103145828 A CN 103145828A CN 2012105337597 A CN2012105337597 A CN 2012105337597A CN 201210533759 A CN201210533759 A CN 201210533759A CN 103145828 A CN103145828 A CN 103145828A
- Authority
- CN
- China
- Prior art keywords
- resin
- solution
- reactor
- fmoc
- draining
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000010532 solid phase synthesis reaction Methods 0.000 title claims abstract description 18
- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 title abstract description 8
- 108010019598 Liraglutide Proteins 0.000 title abstract description 8
- 229960002701 liraglutide Drugs 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 86
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 41
- 238000009833 condensation Methods 0.000 claims abstract description 39
- 230000005494 condensation Effects 0.000 claims abstract description 39
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 22
- 238000004108 freeze drying Methods 0.000 claims abstract description 18
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 11
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 7
- 239000007790 solid phase Substances 0.000 claims abstract description 5
- 239000011347 resin Substances 0.000 claims description 205
- 229920005989 resin Polymers 0.000 claims description 205
- 238000005406 washing Methods 0.000 claims description 72
- 238000010511 deprotection reaction Methods 0.000 claims description 37
- 229940024606 amino acid Drugs 0.000 claims description 18
- 150000001413 amino acids Chemical class 0.000 claims description 18
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 238000006482 condensation reaction Methods 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 5
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- GOPWHXPXSPIIQZ-FQEVSTJZSA-N (4s)-4-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(O)=O)C(=O)OC(C)(C)C)C3=CC=CC=C3C2=C1 GOPWHXPXSPIIQZ-FQEVSTJZSA-N 0.000 claims description 3
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 238000003760 magnetic stirring Methods 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 2
- 238000010168 coupling process Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 238000005336 cracking Methods 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 abstract description 32
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 abstract description 16
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 11
- 229920001184 polypeptide Polymers 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000005516 engineering process Methods 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 6
- 238000001035 drying Methods 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- -1 ion salt Chemical class 0.000 abstract description 3
- 238000012545 processing Methods 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 abstract 2
- 238000012986 modification Methods 0.000 abstract 2
- 230000004048 modification Effects 0.000 abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 abstract 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract 1
- 239000004472 Lysine Substances 0.000 abstract 1
- 238000006011 modification reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 252
- 238000004042 decolorization Methods 0.000 description 84
- 239000003153 chemical reaction reagent Substances 0.000 description 73
- 238000001514 detection method Methods 0.000 description 69
- 150000003053 piperidines Chemical class 0.000 description 67
- 238000012360 testing method Methods 0.000 description 63
- 238000010438 heat treatment Methods 0.000 description 62
- 230000003252 repetitive effect Effects 0.000 description 42
- 238000002360 preparation method Methods 0.000 description 39
- 239000000203 mixture Substances 0.000 description 33
- 239000011259 mixed solution Substances 0.000 description 32
- 230000004913 activation Effects 0.000 description 31
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 239000012071 phase Substances 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 8
- 238000005520 cutting process Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 239000000523 sample Substances 0.000 description 6
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 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 description 3
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 3
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 2
- FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 2
- OJBNDXHENJDCBA-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-(prop-2-enoxycarbonylamino)hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OCC=C)C(=O)O)C3=CC=CC=C3C2=C1 OJBNDXHENJDCBA-QFIPXVFZSA-N 0.000 description 2
- DVBUCBXGDWWXNY-SFHVURJKSA-N (2s)-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C3=CC=CC=C3C2=C1 DVBUCBXGDWWXNY-SFHVURJKSA-N 0.000 description 2
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 230000003014 reinforcing effect Effects 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- XXMYDXUIZKNHDT-QNGWXLTQSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(1-tritylimidazol-4-yl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(N=C1)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 XXMYDXUIZKNHDT-QNGWXLTQSA-N 0.000 description 1
- MGHMWKZOLAAOTD-DEOSSOPVSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(1h-indol-3-yl)propanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(=O)O)CC1=CNC2=CC=CC=C12 MGHMWKZOLAAOTD-DEOSSOPVSA-N 0.000 description 1
- 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 description 1
- UGNIYGNGCNXHTR-SFHVURJKSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UGNIYGNGCNXHTR-SFHVURJKSA-N 0.000 description 1
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 description 1
- WDGICUODAOGOMO-DHUJRADRSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDGICUODAOGOMO-DHUJRADRSA-N 0.000 description 1
- KSDTXRUIZMTBNV-INIZCTEOSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)butanedioic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)O)C(O)=O)C3=CC=CC=C3C2=C1 KSDTXRUIZMTBNV-INIZCTEOSA-N 0.000 description 1
- HNICLNKVURBTKV-NDEPHWFRSA-N (2s)-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C HNICLNKVURBTKV-NDEPHWFRSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000009514 concussion Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water 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
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
Description
NO. | Mresin(mg) | Abs301nm | SD(mmol/g) |
1 | 5.1 | 0.210 | 0.291 |
2 | 5.1 | 0.207 | 0.287 |
3 | 5.0 | 0.205 | 0.285 |
4 | 5.0 | 0.210 | 0.291 |
Time/min | B.cone% |
0.01 | 30 |
25.00 | 95 |
28.00 | 100 |
35.00 | 100 |
40.00 | 30 |
50.00 | Stop |
Time/min | B.cone% |
0.00 | 30 |
5.00 | 30 |
15.00 | 50 |
25.00 | 54 |
125.00 | 65 |
135.00 | 70 |
Time/min | B.cone% |
0.01 | 30 |
25.00 | 95 |
28.00 | 100 |
35.00 | 100 |
40.00 | 30 |
50.00 | Stop |
Claims (4)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210533759.7A CN103145828B (zh) | 2012-12-12 | 2012-12-12 | 一种利拉鲁肽的全固相合成方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210533759.7A CN103145828B (zh) | 2012-12-12 | 2012-12-12 | 一种利拉鲁肽的全固相合成方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103145828A true CN103145828A (zh) | 2013-06-12 |
CN103145828B CN103145828B (zh) | 2014-08-13 |
Family
ID=48544192
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210533759.7A Expired - Fee Related CN103145828B (zh) | 2012-12-12 | 2012-12-12 | 一种利拉鲁肽的全固相合成方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103145828B (zh) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103288951A (zh) * | 2013-06-19 | 2013-09-11 | 深圳翰宇药业股份有限公司 | 一种利拉鲁肽的制备方法 |
CN103304660A (zh) * | 2013-07-12 | 2013-09-18 | 上海昂博生物技术有限公司 | 一种利拉鲁肽的合成方法 |
CN103421088A (zh) * | 2013-08-15 | 2013-12-04 | 广东八加一医药有限公司 | 单核细胞移动抑制因子的固相合成方法 |
WO2016046753A1 (en) | 2014-09-23 | 2016-03-31 | Novetide, Ltd. | Synthesis of glp-1 peptides |
WO2016067271A1 (en) | 2014-10-31 | 2016-05-06 | Auro Peptides Ltd | A process for the preparation of liraglutide |
CN106397573A (zh) * | 2016-10-24 | 2017-02-15 | 合肥国肽生物科技有限公司 | 一种利拉鲁肽的固相合成方法 |
CN106478806A (zh) * | 2016-10-24 | 2017-03-08 | 合肥国肽生物科技有限公司 | 一种索玛鲁肽的固相合成方法 |
CN106633084A (zh) * | 2016-10-14 | 2017-05-10 | 中国药科大学 | 一种用于构建囊泡的具有肿瘤部位酶敏感特性的高分子材料的全固相合成方法 |
WO2017162650A1 (en) | 2016-03-23 | 2017-09-28 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
CN108976296A (zh) * | 2018-07-23 | 2018-12-11 | 安徽省国平药业有限公司 | 一种利拉鲁肽的合成方法 |
WO2019069274A1 (en) | 2017-10-04 | 2019-04-11 | Chemical & Biopharmaceutical Laboratories Of Patras S.A. | PROCESS FOR THE PREPARATION OF A GLUCAGON-LIKE PEPTIDE |
WO2021007701A1 (en) * | 2019-07-12 | 2021-01-21 | Shanghai Space Peptides Pharmaceutical Co., Ltd. | A method for preparing liraglutide via a solid phase peptide synthesis |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102286092A (zh) * | 2011-09-14 | 2011-12-21 | 深圳翰宇药业股份有限公司 | 利拉鲁肽的固相合成方法 |
CN102584982A (zh) * | 2012-02-10 | 2012-07-18 | 深圳翰宇药业股份有限公司 | 一种纯化固相合成利拉鲁肽粗肽的方法 |
-
2012
- 2012-12-12 CN CN201210533759.7A patent/CN103145828B/zh not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102286092A (zh) * | 2011-09-14 | 2011-12-21 | 深圳翰宇药业股份有限公司 | 利拉鲁肽的固相合成方法 |
CN102584982A (zh) * | 2012-02-10 | 2012-07-18 | 深圳翰宇药业股份有限公司 | 一种纯化固相合成利拉鲁肽粗肽的方法 |
Non-Patent Citations (3)
Title |
---|
姜和等: "Fmoc法肽合成中正交保护赖氨酸的研究进展", 《重庆理工大学学报(自然科学)》, vol. 25, no. 4, 15 April 2011 (2011-04-15) * |
李文曲等: "末端N-Ivdde保护的氨基酸的合成", 《合成化学》, vol. 17, no. 2, 20 April 2009 (2009-04-20) * |
李鹏等: "2氯三苯甲基树脂的制备机器在多肽固相合成中的应用", 《过程工程学报》, vol. 9, no. 3, 15 June 2009 (2009-06-15) * |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103288951A (zh) * | 2013-06-19 | 2013-09-11 | 深圳翰宇药业股份有限公司 | 一种利拉鲁肽的制备方法 |
CN103304660A (zh) * | 2013-07-12 | 2013-09-18 | 上海昂博生物技术有限公司 | 一种利拉鲁肽的合成方法 |
CN103304660B (zh) * | 2013-07-12 | 2016-08-10 | 上海昂博生物技术有限公司 | 一种利拉鲁肽的合成方法 |
CN103421088A (zh) * | 2013-08-15 | 2013-12-04 | 广东八加一医药有限公司 | 单核细胞移动抑制因子的固相合成方法 |
WO2016046753A1 (en) | 2014-09-23 | 2016-03-31 | Novetide, Ltd. | Synthesis of glp-1 peptides |
WO2016067271A1 (en) | 2014-10-31 | 2016-05-06 | Auro Peptides Ltd | A process for the preparation of liraglutide |
WO2017162650A1 (en) | 2016-03-23 | 2017-09-28 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
US11117946B2 (en) | 2016-03-23 | 2021-09-14 | Bachem Holding Ag | Method for preparing glucagon-like peptides |
CN106633084A (zh) * | 2016-10-14 | 2017-05-10 | 中国药科大学 | 一种用于构建囊泡的具有肿瘤部位酶敏感特性的高分子材料的全固相合成方法 |
CN106478806A (zh) * | 2016-10-24 | 2017-03-08 | 合肥国肽生物科技有限公司 | 一种索玛鲁肽的固相合成方法 |
CN106397573A (zh) * | 2016-10-24 | 2017-02-15 | 合肥国肽生物科技有限公司 | 一种利拉鲁肽的固相合成方法 |
CN106478806B (zh) * | 2016-10-24 | 2019-08-30 | 合肥国肽生物科技有限公司 | 一种索玛鲁肽的固相合成方法 |
WO2019069274A1 (en) | 2017-10-04 | 2019-04-11 | Chemical & Biopharmaceutical Laboratories Of Patras S.A. | PROCESS FOR THE PREPARATION OF A GLUCAGON-LIKE PEPTIDE |
CN108976296A (zh) * | 2018-07-23 | 2018-12-11 | 安徽省国平药业有限公司 | 一种利拉鲁肽的合成方法 |
WO2021007701A1 (en) * | 2019-07-12 | 2021-01-21 | Shanghai Space Peptides Pharmaceutical Co., Ltd. | A method for preparing liraglutide via a solid phase peptide synthesis |
Also Published As
Publication number | Publication date |
---|---|
CN103145828B (zh) | 2014-08-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103145828B (zh) | 一种利拉鲁肽的全固相合成方法 | |
CN102286092B (zh) | 利拉鲁肽的固相合成方法 | |
CN102875655B (zh) | 一种合成利那洛肽的方法 | |
CN104017064B (zh) | 一种制备特立帕肽的方法 | |
CN108359006A (zh) | 一种索玛鲁肽的制备方法 | |
CN108676087B (zh) | 一种索玛鲁肽的合成方法 | |
CN109627317A (zh) | 片段缩合制备索马鲁肽的方法 | |
CN109456402A (zh) | 一种索玛鲁肽的合成方法 | |
CN113880936B (zh) | 一种阿巴帕肽的固相合成方法 | |
CN104530218A (zh) | 一种特立帕肽的固相合成方法 | |
CN101357938B (zh) | 固相多肽合成Exenatide的制备方法 | |
CN103880945B (zh) | 制备高纯度胸腺法新的方法 | |
CN106478805A (zh) | 一种glp-1衍生物的制备方法 | |
CN103992389B (zh) | 一种固环合成去氨加压素的方法 | |
CN104211777A (zh) | 一种皮卡那肽的制备方法 | |
CN105418736A (zh) | 一种固液结合制备特利加压素的方法 | |
CN104177491B (zh) | 一种替莫瑞林的制备方法 | |
CN103214550A (zh) | 多对二硫键定点环化固相合成多肽新工艺 | |
CN105037496A (zh) | 一种依替巴肽的制备方法 | |
CN106008674A (zh) | 一种制备利那洛肽的方法 | |
CN112175066B (zh) | 一种制备舍莫瑞林的方法 | |
CN101538317B (zh) | 凝血酶直接抑制剂多肽水合盐及合成方法 | |
CN108976296A (zh) | 一种利拉鲁肽的合成方法 | |
CN102241746B (zh) | 恩夫韦肽的制备方法 | |
CN104558149B (zh) | 胸腺素α1的固相片段合成方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
ASS | Succession or assignment of patent right |
Owner name: NINGBO REAL DATA MEDICAL RESARCH INC. Free format text: FORMER OWNER: NINGBO SHENGTAI BIOMEDICAL TECHNOLOGY CO., LTD. Effective date: 20150202 |
|
C41 | Transfer of patent application or patent right or utility model | ||
COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 315201 NINGBO, ZHEJIANG PROVINCE TO: 315000 NINGBO, ZHEJIANG PROVINCE |
|
TR01 | Transfer of patent right |
Effective date of registration: 20150202 Address after: Beilun District of Zhejiang city in Ningbo Province, 315000 West Road No. 483 building block A2-1 Tylin Patentee after: Ningbo Ruida pharmaceutical science and Technology Co Ltd Address before: West Street in the official Zhejiang city of Ningbo province Zhenhai District 315201 Village No. 777 Patentee before: Ningbo Shengtai Biomedical Technology Co., Ltd. |
|
C41 | Transfer of patent application or patent right or utility model | ||
TR01 | Transfer of patent right |
Effective date of registration: 20160504 Address after: 212000 Jiangsu city of Zhenjiang province Dantu high tech Industrial Zone No. 168 Leng Yu Lu Gaochuang building room 423 Patentee after: Zhenjiang Shengtai Biological Medical Technology Co., Ltd. Address before: Beilun District of Zhejiang city in Ningbo Province, 315000 West Road No. 483 building block A2-1 Tylin Patentee before: Ningbo Ruida pharmaceutical science and Technology Co Ltd |
|
TR01 | Transfer of patent right | ||
TR01 | Transfer of patent right |
Effective date of registration: 20181105 Address after: 315000 Tianlin block 483, minzhou West Road, Beilun District, Ningbo, Zhejiang, A2-1 Patentee after: Ningbo Ruida pharmaceutical science and Technology Co Ltd Address before: 212000 room 423, Gao Chuang building, 168 cold road, Dantu hi tech park, Zhenjiang, Jiangsu. Patentee before: Zhenjiang Shengtai Biological Medical Technology Co., Ltd. |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140813 Termination date: 20201212 |