CN107056927A - A kind of preparation method of Liraglutide - Google Patents
A kind of preparation method of Liraglutide Download PDFInfo
- Publication number
- CN107056927A CN107056927A CN201710030103.6A CN201710030103A CN107056927A CN 107056927 A CN107056927 A CN 107056927A CN 201710030103 A CN201710030103 A CN 201710030103A CN 107056927 A CN107056927 A CN 107056927A
- Authority
- CN
- China
- Prior art keywords
- liraglutide
- fmoc
- protected amino
- preparation
- coupled
- 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
- 108010019598 Liraglutide Proteins 0.000 title claims abstract description 58
- 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 claims abstract description 50
- 229960002701 liraglutide Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001413 amino acids Chemical class 0.000 claims abstract description 58
- 239000011347 resin Substances 0.000 claims abstract description 38
- 229920005989 resin Polymers 0.000 claims abstract description 38
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 31
- 238000005859 coupling reaction Methods 0.000 claims abstract description 29
- 230000004224 protection Effects 0.000 claims abstract description 27
- 239000012634 fragment Substances 0.000 claims abstract description 22
- 239000003875 Wang resin Substances 0.000 claims abstract description 16
- 238000010168 coupling process Methods 0.000 claims abstract description 16
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 16
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 15
- 230000008878 coupling Effects 0.000 claims abstract description 15
- 239000006166 lysate Substances 0.000 claims abstract description 8
- 239000012043 crude product Substances 0.000 claims abstract description 7
- OYXZPXVCRAAKCM-SANMLTNESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid Chemical group C1=NC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 OYXZPXVCRAAKCM-SANMLTNESA-N 0.000 claims abstract description 6
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims abstract description 4
- 230000000903 blocking effect Effects 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 17
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 150000003053 piperidines Chemical group 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 239000012190 activator Substances 0.000 claims description 5
- -1 alkyl phosphorus Chemical compound 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- FJVAQLJNTSUQPY-CIUDSAMLSA-N Ala-Ala-Lys Chemical group C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@H](C(O)=O)CCCCN FJVAQLJNTSUQPY-CIUDSAMLSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- PZTZYZUTCPZWJH-FXQIFTODSA-N Val-Ser-Ser Chemical group CC(C)[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)O)N PZTZYZUTCPZWJH-FXQIFTODSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 3
- 238000001152 differential interference contrast microscopy Methods 0.000 claims description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 3
- PNGLEYLFMHGIQO-UHFFFAOYSA-M sodium;3-(n-ethyl-3-methoxyanilino)-2-hydroxypropane-1-sulfonate;dihydrate Chemical compound O.O.[Na+].[O-]S(=O)(=O)CC(O)CN(CC)C1=CC=CC(OC)=C1 PNGLEYLFMHGIQO-UHFFFAOYSA-M 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical group CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims 1
- 230000002823 anti-activator Effects 0.000 claims 1
- 239000004327 boric acid Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- DBTMQODRSDEGRZ-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-(2-oxoethyl)carbamate Chemical compound C1=CC=C2C(COC(=O)NCC=O)C3=CC=CC=C3C2=C1 DBTMQODRSDEGRZ-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- AYMLQYFMYHISQO-QMMMGPOBSA-N (2s)-3-(1h-imidazol-3-ium-5-yl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CN=CN1 AYMLQYFMYHISQO-QMMMGPOBSA-N 0.000 description 2
- 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 2
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 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 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
- 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 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
- 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 1
- 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 1
- 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 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
- 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 1
- LZOLWEQBVPVDPR-VLIAUNLRSA-N (2s,3r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]butanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@H](OC(C)(C)C)C)C(O)=O)C3=CC=CC=C3C2=C1 LZOLWEQBVPVDPR-VLIAUNLRSA-N 0.000 description 1
- 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 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](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](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 101710176384 Peptide 1 Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000002780 morpholines Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Toxicology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Endocrinology (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses a kind of preparation method of Liraglutide, comprise the following steps：It is deprotected with deprotecting regent Fmoc Gly Wang resins, removes Fmoc blocking groups；12nd~the 14th three protected amino acids are to protect fragments of peptides X to be coupled；20th~the 22nd three protected amino acids are to protect fragments of peptides Y to be coupled；31st is coupled with Boc His (trt) OH forms of protection；Liraglutide main chain peptide resin is removed to the alloc protections of lysine side-chain, side chain is coupled one by one, Liraglutide peptide resin is obtained；Liraglutide peptide resin is cracked in lysate, Liraglutide crude product is obtained；By Liraglutide purifying crude, obtain Liraglutide fine work, by carrying out fragment coupling to most foldable amino sites in Liraglutide main chain building-up process, building-up process is avoided the problem of amino acid needs multiple coupling and low access rate caused by folding, the production cycle of Liraglutide is shortened, the synthesis yield of Liraglutide is improved.
Description
Technical field
The present invention relates to the synthesis of polypeptide, more particularly to a kind of preparation method of Liraglutide.
Background technology
At present, with the improvement of living standards, the number for suffering from diabetes gradually increases, and Liraglutide is that a kind of people's pancreas is high
Sugared (GLP-1) analog of element sample peptide -1, for treating diabetes.The structure of Liraglutide is：His-Ala-Glu-Gly-Thr-
Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys(Na-PAL-γ-Glu)-
Glu-Phe-Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH.So demand of the in the market for Liraglutide
Greatly.Existing synthetic method is more.The method difficulty of genetic engineering is big, and technical difficulty is big；During synthesizing, main chain synthesis
During most foldable amino sites (20-22 and 12-14) easily cause amino Fold, so as to produce by-product
Thing and other impurities, influence the yield and purity of product；And many synthetic method main chains thus can by synthesizing one by one
Cause that most foldable amino sites are easily folded or amino acid needs multiple coupling, further result in product production rate low or increase
Plus synthesis step.
The content of the invention
It is an object of the invention to：For it is above-mentioned due to building-up process caused by amino is folded amino acid need it is multiple even
Connection and the low further reduction yield and product purity problem of access rate, the invention provides it is a kind of in high yield, low cost, reaction
Mild condition, it is advantageously implemented industrialization Liraglutide preparation method.
The technical solution adopted by the present invention is as follows：
(1) Fmoc-Gly-Wang resins are deprotected with deprotecting regent, remove Fmoc blocking groups；The deprotection examination
Agent is piperidines/DMF solution, and the percent by volume that piperidines accounts for the deprotecting regent is 30~50%；The reaction of the deprotection
Temperature is 10~25 DEG C；
(2) the de-protected Fmoc-Gly-Wang resins and protected amino acid are coupled acquisition Liraglutide master one by one
Chain resin；Wherein
12nd~the 14th three protected amino acids are to protect fragments of peptides X to be coupled；
20th~the 22nd three protected amino acids are to protect fragments of peptides Y to be coupled；
31st is coupled with Boc-His (trt)-OH forms of protection；
Its coupling amino acid fragment is：
Boc-His(trt)-Ala-Glu(otbu)-Gly-Thr(tbu)-Phe-Thr(tbu)-Ser(tbu)-Asp
(otbu)-Y(tbu)-Tyr(tbu)-Leu-Glu(otbu)-Gly-Gln(trt)-X(alloc)-Glu(otbu)-Phe-Ile-
Ala-Trp (boc)-Leu-Val-Arg (pbf)-Gly-Arg (pbf)-Gly-Wang resins,
Wherein X is Ala-Ala-Lys；Y is Val-Ser-Ser；
(3) alloc that Liraglutide main chain peptide resin is removed into lysine side-chain is protected, and side chain is coupled one by one, profit is obtained
Draw Shandong peptide peptide resin；
(4) Liraglutide peptide resin is cracked in lysate, obtains Liraglutide crude product；
(5) by Liraglutide purifying crude, Liraglutide fine work is obtained.
It is preferred that, substitution value≤0.35mmol/g of Fmoc-Gly-Wang resins.
Most preferably, the substitution value of Fmoc-Gly-Wang resins is 0.25mmol/g.
It is, using Gly amino acid in Fmoc-Gly-Wang resins as the 1st amino acids, calculating position to be retrodicted successively in the present invention
Number sequence number, and using His amino acid as the 31st amino acids.
It is preferred that, activator is added in the coupling reaction of step (2), the activator is I-hydroxybenzotriazole or N- hydroxyls
Base -7- azepine BTAs.
It is preferred that, the condensing agent selected in step (2) is N, N- DICs, hexafluorophosphoric acid BTA-
1- bases-epoxide tripyrrole alkyl phosphorus, 2- (7- azepine -1H- BTA -1- bases) -1,1,3,3- tetramethylurea hexafluorophosphoric acids
Ester, BTA-N, N, N', N'- tetramethylurea hexafluorophosphate or O- BTAs-N, N, N', N'- tetramethylurea four
One kind in fluoboric acid ester；The mole dosage of condensing agent is 1.2 times~6 times of Fmoc-Gly-Wang resin total mole numbers, preferably
For 2.5~4.5 times.
It is preferred that, that is selected in step (2) goes Fmoc to protect reagent to be piperidines/DMF mixed solution,
It is 10%~50% (v/v) to contain piperidines in mixed solution.The consumption of activating reagent is Fmoc-Gly-Wang resin total mole numbers
1.2 times~6 times, preferably 2.5~4.5 times.
It is preferred that, in step (2), the corresponding protection fragments of peptides of access X is Fmoc-Ala-Ala-Lys (alloc)-OH；Connect
It is Fmoc-Val-Ser (tbu)-Ser (tbu)-OH to enter the corresponding protection fragments of peptides of Y；Accessing the corresponding forms of protection of histidine is
Boc-His(trt)-OH；It is preferred that, the consumption of protected amino acid or protection fragments of peptides is 2 times~6 times of resin integral molar quantity；
More preferably 2~4 times.It is preferred that, the coupling reaction time is 2-6 hours.
It is preferred that, it is first anti-when Fmoc-Gly-Wang resins are with protected amino acid and protection fragments of peptides coupling in step (2)
The protected amino acid resin that should be obtained slough after Fmoc protection groups again with next protected amino acid coupling reaction；Coupled reaction knot
Beam and slough Fmoc protection after by Kaiser Test detect.
It is preferred that, in step (3), the alloc protection reagents of Liraglutide main chain peptide resin removing lysine side-chain are four
Triphen first phosphorus palladium and morpholine/THF mixed solutions；The consumption of four triphen first phosphorus palladiums is 0.3~0.5 times of peptide resin molal quantity；
Quinoline consumption is 5~10 times of peptide resin molal quantity；Deprotection is carried out under a nitrogen atmosphere；The deprotection time is 5~10 hours.
It is preferred that, in step (3), the Liraglutide main chain of removing alloc protections couples side chain, obtains Li Lalu one by one
Peptide peptide resin, side chain is respectively with Fmoc-Glu (OH)-otbu and palmitic acid form application；It is preferred that, side chain coupled reaction, Li La
Shandong peptide backbone resin：Side chain：The mol ratio of coupling reagent is 1:4:6；It is described to couple conditional synchronization suddenly (2)；The coupled reaction
Time is 6-8 hours.The coupled reaction one by one is detected after terminating and sloughing Fmoc protections by Kaiser Test.
It is preferred that, in step (4), lysate contain trifluoracetic acid 80%~95% (v/v), 1,2- dithioglycols 1%~
10% (v/v), tri isopropyl silane 1%~5% (v/v), solvent is water；The volume proportion of preferred mixed solvent is：TFA
It is that 4%, TIS is 2% for 90%, EDT, surplus is water.
It is preferred that, in step (5), the octadecyl bonding that the chromatographic column of purifying is diameter 10cm, filler is particle diameter 10um
Silica gel, aperture areC18 posts, mobile phase is respectively dilute ammonia solution and acetonitrile, and flow velocity is 120ml/min, loading
Measure as 5~10g, chromatographic Detection wavelength is 230nm.After purified, products obtained therefrom purity is more than 99.0%.
In summary, by adopting the above-described technical solution, the beneficial effects of the invention are as follows：
1. the application by Liraglutide main chain building-up process using most foldable amino sites (12-14 with
20-22) fragment coupling is carried out, easy folding point is just coupled by main chain building-up process, thus is avoided that building-up process because of folding
The problem of caused amino acid needs repeatedly to be coupled and access rate is low, the present processes shorten the production week of Liraglutide
Phase, reduction purifying difficulty improves the synthesis yield of Liraglutide.Protected amino acid fragment two short and small easily prepares synthesis,
And purity is high, preparation cost is low, and then reduces the production cost of Liraglutide；
2. using suitable deprotection condition so that deprotection reaction is more thorough；
Substitution value≤0.35mmol/g of 3.Fmoc-Gly-Wang resins, because the substitution value of Fmoc-Gly-Wang resins
It is too high, cause the space structure of late-stage products uncontrollable, easily cause product impure.
4. adding activator in coupling reaction, increase the speed of coupling reaction, the yield of protected amino acid is higher；
5. rationally control the consumption of reactant, it is to avoid because impurity is excessive；
6. rational reaction sequence, it is to avoid unnecessary accessory substance occurs；
7. trifluoracetic acid is used, the lysate of 1,2- ethylene dithiol alcohol and water composition so that cracking is more thorough.
The implication of abbreviation used in the present invention is listed in the following table：
The corresponding protected amino acid table of comparisons of amino acid that the present invention is used：
| Abbreviation | Protected amino acid form |
| Gly | Fmoc-Gly-OH |
| Arg | Fmoc-Arg(pbf)-OH |
| Val | Fmoc-Val-OH |
| Leu | Fmoc-Leu-OH |
| Trp | Fmoc-Trp(boc)-OH |
| Ala | Fmoc-Ala-OH |
| Ile | Fmoc-Ile-OH |
| Phe | Fmoc-Phe-OH |
| Glu | Fmoc-Glu(OtBu)-OH |
| Ala-Ala-Lys | Fmoc-Ala-Ala-Lys(alloc)-OH |
| Gln | Fmoc-Gln(Trt)-OH |
| Tyr | Fmoc-Tyr(tBu)-OH |
| Val-Ser-Ser | Fmoc-Val-Ser(tbu)-Ser(tbu)-OH |
| Asp | Fmoc-Asp(otBu)-OH |
| Ser | Fmoc-Ser(tBu)-OH |
| Thr | Fmoc-Thr(tBu)-OH |
| His | Boc-His(Trt)-OH |
| Side chain Glu | Fmoc-Glu(OH)-OtBu |
All features disclosed in this specification, can be with any in addition to mutually exclusive feature and/or step
Mode is combined.
Embodiment
Embodiment 1
Prepare Liraglutide peptide backbone resin：
Using Fmoc-Gly-Wang resins as carrier is started, by going Fmoc to protect and coupling reaction, ammonia is protected in coupling successively
Base acid, is made Liraglutide peptide backbone resin, using Gly as the 1st coupling amino acid, His is used as the 31st coupling amino acid
Sort, coupling amino acid fragment is：
Boc-His(trt)-Ala-Glu(otbu)-Gly-Thr(tbu)-Phe-Thr(tbu)-Ser(tbu)-Asp
(otbu)-Y(tbu)-Tyr(tbu)-Leu-Glu(otbu)-Gly-Gln(trt)-X(alloc)-Glu(otbu)-Phe-Ile-
Ala-Trp (boc)-Leu-Val-Arg (pbf)-Gly-Arg (pbf)-Gly-Wang resins,
Wherein X is Ala-Ala-Lys, and Y is Val-Ser-Ser；
When accessing X, corresponding protected amino acid is Fmoc-Ala-Ala-Lys (alloc)-OH；
When accessing Y, corresponding protected amino acid is Fmoc-Val-Ser (tbu)-Ser (tbu)-OH；
When accessing His, corresponding protected amino acid is Boc-His (trt)-OH.
Comprise the following steps that：
(1), it is coupled Arg on Fmoc-Gly-Wang resins
0.15mol the 2nd protected amino acid Fmoc-Arg (pbf)-OH and 0.15mol HOBt are taken, is dissolved with appropriate DMF；
Another take is slowly added into the DMF solution containing protected amino acid under 0.15mol DIC, stirring, the stirring reaction in room temperature environment
30 minutes, the protected amino acid solution after being activated was standby.
Fmoc-Gly-Wang resin 200g are taken, substitution value is 0.25mmol/g, gone with 2000mL 30%PIP/DMF solution
Protection 30 minutes, washing suction filtration obtains Fmoc resin.
The 2nd protected amino acid solution after activation is added to and gone in Fmoc resin, coupling reaction 4 hours is taken out
Filter washing, obtains the resin containing 2 protected amino acids.
(2) the 3rd~11 protected amino acid, is accessed
Using the method in step (1), by the 3rd~11 amino acid couplings on resin.
(3) the 12nd~14 protected amino acid fragment, is accessed
0.2mol protected amino acids fragment i.e. Fmoc-Ala-Ala-Lys (alloc)-OH and 0.2mol HOBt are taken, with suitable
Measure DMF dissolvings；Another take is slowly added into protected amino acid DMF solution under 0.2mol DIC, stirring, is stirred in room temperature environment
Reaction 30 minutes, Fmoc-Ala-Ala-Lys (alloc)-OH fragment solution after being activated.
Fmoc-Ala-Ala-Lys (the alloc)-OH fragment solution added after activation is added to 11 peptides for removing Fmoc
Resin, coupling reaction 3~5 hours, filtration washing obtains the resin containing the 14th protected amino acid.
(4) the 15th~19 protected amino acid, is accessed
Using the 2nd protected amino acid same procedure of access, above-mentioned corresponding 15th~19 protection amino is sequentially ingressed into
Acid.
(5) the 20th~22 protected amino acid fragment, is accessed
0.2mol protected amino acids fragment i.e. Fmoc-Val-Ser (tbu)-Ser (tbu)-OH and 0.2mol HOAt is taken, is used
Appropriate DMF dissolvings；Another take is slowly added into protected amino acid DMF solution under 0.2mol DIC, stirring, is stirred in room temperature environment
Mix reaction 30 minutes, Fmoc-Val-Ser (tbu)-Ser (tbu)-OH fragment solution after being activated.
Fmoc-Val-Ser (tbu)-Ser (the tbu)-OH fragment solution added after activation is added to and goes the 19 of Fmoc
Peptide resin, coupling reaction 3~5 hours, filtration washing obtains the resin containing the 22nd protected amino acid.
HOAT/DIC can activate protected amino acid as activator in the present invention, it is carried out with resin even
During connection
It is easier to make for, reaction rate is fast, and yield is also higher.By contrast test it is known that adding step (5)
It is living
After agent, the yield of protected amino acid is higher.
(6) the 23rd~29 protected amino acid, is accessed
Using the 2nd protected amino acid same procedure of access, above-mentioned corresponding 23rd~29 protection amino is sequentially ingressed into
Acid.
(7) the 30th~31 protected amino acid, is accessed
Using the same procedure of access protected amino acid fragment, above-mentioned corresponding 30th~31 protection amino is sequentially ingressed into
Acid.Obtain Liraglutide main chain peptide resin.
(8) the de- alloc protections of Liraglutide main chain peptide resin
Take the triphenyl phosphorus palladiums of 0.02mol tetra- and 0.3mol morpholines to be dissolved in 3000ml THF solutions, deprotection examination is made
Agent is standby.Liraglutide main chain peptide resin, is washed 3 times with 15% appropriate triethylamine/DCM respectively, and THF/DCM is washed 3 times and taken out
It is dry standby；Deprotecting regent is added in Liraglutide main chain peptide resin, nitrogen is passed through, removing alloc protection reactions are carried out.
The deprotection time is 5-10 hours, entered Kaiser Test and detects whether removing alloc protections.
(9) access side chain Glu and Pal
Using the same procedure of access protected amino acid fragment, above-mentioned corresponding side chain Glu and Pal is sequentially ingressed into.Obtain
Liraglutide peptide resin.
Embodiment 2
On the basis of embodiment 1, Liraglutide crude product is prepared：
Liraglutide peptide resin is taken, addition volume ratio is TFA ︰ EDT：The ︰ 2 of TIS ︰ water=90 ︰ 4：4 lysate, lysate
Consumption is 5mL/g resins, is stirred.Reaction 3 hours is stirred at room temperature, reactant mixture is filtered using sand core funnel, collects filter
Liquid, resin is washed 3 times with a small amount of TFA again, is concentrated under reduced pressure after merging filtrate, adds absolute ether precipitation, then washed with absolute ether
Precipitation 3 times, drain off-white powder is Liraglutide crude product.
Embodiment 3
On the basis of embodiment 2, the purifying process of Liraglutide crude product：
Liraglutide crude product ammoniacal liquor adjusts pH value to be dissolved for 10 20% acetonitrile solution, with 0.45 μm of mixing miillpore filter
Filtering, is purified standby；
Purified using high performance liquid chromatography, the chromatographic column of purifying is diameter 10cm, ten that filler is particle diameter 10um
Eight alkyl linked silica gel, apertureC18 posts, mobile phase is respectively dilute ammonia solution and acetonitrile solution, and flow velocity is
120ml/min, applied sample amount is 5~10g, and chromatographic Detection wavelength is 230nm.
Entered multiple purifying, and collected qualified main peak, analysis liquid phase detects its purity, is concentrated under reduced pressure, obtains Liraglutide
Dilute ammonia solution, freeze-drying, obtain Liraglutide 18.8g, total recovery is 10.1%.
Single isotopic number molecular weight：3750.98 (100%M+H)；Purity：99.01%.
When stating embodiment on the implementation, condensing agent is N, N- DICs, hexafluorophosphoric acid BTA -1-
Base-epoxide tripyrrole alkyl phosphorus, 2- (7- azepine -1H- BTA -1- bases) -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester,
BTA-N, N, N', N'- tetramethylurea hexafluorophosphate or O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro
One kind in borate；That selects goes Fmoc to protect reagent for piperidines/DMF mixed solution, in mixed solution
It is 10%~50% (v/v) containing piperidines.With extensive practical value and application prospect.
The application can preferably be implemented using above-described embodiment, but the application does not limit to and above-described embodiment.
Claims (9)
1. a kind of preparation method of Liraglutide, it is characterised in that comprise the following steps：
(1) it is deprotected with deprotecting regent Fmoc-Gly-Wang resins, removes Fmoc blocking groups；
(2) the de-protected Fmoc-Gly-Wang resins and protected amino acid are coupled acquisition Liraglutide main chain tree one by one
Fat；Wherein
12nd~the 14th three protected amino acids are to protect fragments of peptides X to be coupled；
20th~the 22nd three protected amino acids are to protect fragments of peptides Y to be coupled；
31st is coupled with Boc-His (trt)-OH forms of protection；
The X is Ala-Ala-Lys；The Y is Val-Ser-Ser；
(3) alloc that Liraglutide main chain peptide resin is removed into lysine side-chain is protected, and side chain is coupled one by one, Li Lalu is obtained
Peptide peptide resin；
(4) Liraglutide peptide resin is cracked in lysate, obtains Liraglutide crude product；
(5) by Liraglutide purifying crude, Liraglutide fine work is obtained.
2. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that the deprotection of the step (1)
Reagent is piperidines/DMF solution, and the percent by volume that piperidines accounts for the deprotecting regent is 30~50%；The deprotection it is anti-
It is 10~25 DEG C to answer temperature.
3. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that：The Fmoc-Gly-Wang trees
Substitution value≤0.35mmol/g of fat.
4. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that the coupling of the step (2) is anti-
Activator middle should be added, the activator is I-hydroxybenzotriazole or N- hydroxyl -7- azepine BTAs.
5. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that selected in the step (2)
Coupling reagent is N, N- DICs, hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl phosphorus, 2- (7- nitrogen
Miscellaneous -1H- BTAs -1- bases) -1,1,3,3- tetramethylurea hexafluorophosphoric acids ester, BTA-N, N, N', N'- tetramethyl
One kind in urea hexafluorophosphate, O- BTAs-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester.
6. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that protect ammonia in the coupling process
The consumption of base acid or protection fragments of peptides is 2 times~6 times of resin integral molar quantity.
7. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that in the step (2), accesses X
Corresponding protection fragments of peptides is Fmoc-Ala-Ala-Lys (alloc)-OH；It is Fmoc-Val- to access the corresponding protection fragments of peptides of Y
Ser(tbu)-Ser(tbu)-OH；When Fmoc-Gly-Wang resins are with protected amino acid and protection fragments of peptides coupling, first react
To protected amino acid resin slough after Fmoc protection groups again with next protected amino acid coupling reaction.
8. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that：In the step (3), removing relies
The reagent of the alloc protection groups of propylhomoserin side chain is four triphen first phosphorus palladiums and morpholine/THF mixed solutions.
9. a kind of preparation method of Liraglutide as claimed in claim 1, it is characterised in that in the step (4), lysate
It is that 80%~95%, 1,2- dithioglycol volume accountings are 1%~10%, tri isopropyl silane containing trifluoracetic acid volume accounting
Volume accounting is 1%~5%, and solvent is water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710030103.6A CN107056927B (en) | 2017-01-16 | 2017-01-16 | Preparation method of liraglutide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710030103.6A CN107056927B (en) | 2017-01-16 | 2017-01-16 | Preparation method of liraglutide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107056927A true CN107056927A (en) | 2017-08-18 |
| CN107056927B CN107056927B (en) | 2021-03-02 |
Family
ID=59598399
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710030103.6A Active CN107056927B (en) | 2017-01-16 | 2017-01-16 | Preparation method of liraglutide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107056927B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880111A (en) * | 2017-11-14 | 2018-04-06 | 杭州湃肽生化科技有限公司 | A kind of method for preparing Liraglutide |
| CN109575117A (en) * | 2018-12-14 | 2019-04-05 | 昆明积大制药股份有限公司 | The preparation method of [Pyr1]-apelin-13 |
| CN110183531A (en) * | 2019-05-17 | 2019-08-30 | 河北常山生化药业股份有限公司 | A kind of preparation method of Ai Benna peptide precursor |
| WO2020127476A1 (en) | 2018-12-19 | 2020-06-25 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising glp-1 analogue |
| CN111349153A (en) * | 2020-04-10 | 2020-06-30 | 四川吉晟生物医药有限公司 | Preparation method of atrial natriuretic peptide |
| WO2021123228A1 (en) | 2019-12-18 | 2021-06-24 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising glp-1 analogue |
| CN113135989A (en) * | 2020-01-20 | 2021-07-20 | 深圳市健元医药科技有限公司 | Method for preparing liraglutide |
| WO2021143159A1 (en) * | 2020-01-19 | 2021-07-22 | 深圳市健元医药科技有限公司 | Method for preparing liraglutide |
| CN118834262A (en) * | 2024-09-20 | 2024-10-25 | 杭州信海医药科技有限公司 | Synthesis of key intermediate of semaglutin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286092A (en) * | 2011-09-14 | 2011-12-21 | 深圳翰宇药业股份有限公司 | Solid-phase synthesis method of liraglutide |
| WO2016005960A1 (en) * | 2014-07-11 | 2016-01-14 | Dr. Reddy's Laboratories Limited | Process for preparation of liraglutide |
-
2017
- 2017-01-16 CN CN201710030103.6A patent/CN107056927B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102286092A (en) * | 2011-09-14 | 2011-12-21 | 深圳翰宇药业股份有限公司 | Solid-phase synthesis method of liraglutide |
| WO2016005960A1 (en) * | 2014-07-11 | 2016-01-14 | Dr. Reddy's Laboratories Limited | Process for preparation of liraglutide |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880111A (en) * | 2017-11-14 | 2018-04-06 | 杭州湃肽生化科技有限公司 | A kind of method for preparing Liraglutide |
| CN107880111B (en) * | 2017-11-14 | 2021-02-05 | 浙江湃肽生物有限公司 | Method for preparing liraglutide |
| CN109575117A (en) * | 2018-12-14 | 2019-04-05 | 昆明积大制药股份有限公司 | The preparation method of [Pyr1]-apelin-13 |
| CN109575117B (en) * | 2018-12-14 | 2021-09-21 | 昆明积大制药股份有限公司 | Preparation method of [ Pyr1] -apelin-13 |
| WO2020127476A1 (en) | 2018-12-19 | 2020-06-25 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising glp-1 analogue |
| CN110183531A (en) * | 2019-05-17 | 2019-08-30 | 河北常山生化药业股份有限公司 | A kind of preparation method of Ai Benna peptide precursor |
| WO2021123228A1 (en) | 2019-12-18 | 2021-06-24 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising glp-1 analogue |
| WO2021143159A1 (en) * | 2020-01-19 | 2021-07-22 | 深圳市健元医药科技有限公司 | Method for preparing liraglutide |
| CN113135989A (en) * | 2020-01-20 | 2021-07-20 | 深圳市健元医药科技有限公司 | Method for preparing liraglutide |
| CN113135989B (en) * | 2020-01-20 | 2023-10-03 | 深圳市健元医药科技有限公司 | Method for preparing liraglutide |
| CN111349153A (en) * | 2020-04-10 | 2020-06-30 | 四川吉晟生物医药有限公司 | Preparation method of atrial natriuretic peptide |
| CN118834262A (en) * | 2024-09-20 | 2024-10-25 | 杭州信海医药科技有限公司 | Synthesis of key intermediate of semaglutin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107056927B (en) | 2021-03-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107056927A (en) | A kind of preparation method of Liraglutide | |
| CN102875655B (en) | Linaclotide synthesis method | |
| CN102199205B (en) | Synthetic method of polypeptide thymosin alpha1 | |
| CN101357936B (en) | Method for synthesizing triptorelin from solid phase polypeptide | |
| US20080287650A1 (en) | High purity peptides | |
| CN104844693B (en) | A method of synthesis Linaclotide | |
| CN105111303B (en) | A kind of method that solid-liquid combination prepares Liraglutide | |
| CN106167514A (en) | The synthesis of a kind of Linaclotide and purification process | |
| CN107573408B (en) | Synthetic method of high-purity leuprorelin | |
| CN103304660A (en) | Synthetic method of liraglutide | |
| CN103992392B (en) | A kind of solid phase synthesis process of Ac-D-2Nal-D-4Cpa-D-3Pal-Ser-4Aph(Hor)-D-4Aph(Cbm)-Leu-Lys(iPr)-Pro-D-Ala-NH2 | |
| CN103012564B (en) | High-purity triptorelin and purification method thereof | |
| CN103333237A (en) | Synthesis of exenatide through solid phase fragment method | |
| CN102702327A (en) | Solid-liquid phase synthesis method for alarelin acetate | |
| CN112111001B (en) | Method for synthesizing thymosin T alpha-1 | |
| CN110922470A (en) | Preparation method of somaglutide | |
| CN102174082B (en) | Method for preparing exenatide | |
| CN101357938A (en) | Method for synthesizing Exenatide from solid phase polypeptide | |
| CN110818790A (en) | Preparation method of temeprelin | |
| CN112321699B (en) | Synthesis method of semaglutide | |
| CN106478805A (en) | A kind of preparation method of GLP-1 derivant | |
| CN104844706B (en) | A method of synthesis lixisenatide | |
| CN107778351B (en) | Method for synthesizing octreotide by all-solid-phase method | |
| CN106632655B (en) | Preparation method of exenatide and product thereof | |
| CN105111301B (en) | A kind of preparation method of salmon calcitonin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of liraglutide Effective date of registration: 20231204 Granted publication date: 20210302 Pledgee: China Construction Bank Corporation Leshan branch Pledgor: SICHUAN JISHENG BIOPHARMACEUTICAL Co.,Ltd. Registration number: Y2023980068875 |