CN103980358B - 一种制备利拉鲁肽的方法 - Google Patents
一种制备利拉鲁肽的方法 Download PDFInfo
- Publication number
- CN103980358B CN103980358B CN201410001671.XA CN201410001671A CN103980358B CN 103980358 B CN103980358 B CN 103980358B CN 201410001671 A CN201410001671 A CN 201410001671A CN 103980358 B CN103980358 B CN 103980358B
- Authority
- CN
- China
- Prior art keywords
- fmoc
- palmitoyl
- resin
- otbu
- glu
- 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.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
- 239000011347 resin Substances 0.000 claims abstract description 82
- 229920005989 resin Polymers 0.000 claims abstract description 82
- 230000008878 coupling Effects 0.000 claims abstract description 48
- 238000010168 coupling process Methods 0.000 claims abstract description 48
- 238000005859 coupling reaction Methods 0.000 claims abstract description 48
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 24
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 24
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 22
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 21
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 19
- 235000001014 amino acid Nutrition 0.000 claims abstract description 17
- 150000001413 amino acids Chemical class 0.000 claims abstract description 17
- 239000012634 fragment Substances 0.000 claims abstract description 17
- 238000010532 solid phase synthesis reaction Methods 0.000 claims abstract description 17
- 239000004472 Lysine Substances 0.000 claims abstract description 14
- 238000000746 purification Methods 0.000 claims abstract description 11
- 239000012190 activator Substances 0.000 claims abstract description 8
- 239000007791 liquid phase Substances 0.000 claims abstract description 8
- 238000005336 cracking Methods 0.000 claims abstract description 6
- 239000007790 solid phase Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 31
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 22
- 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 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 239000007821 HATU Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 7
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 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 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 3
- 235000021314 Palmitic acid Nutrition 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 3
- 229940098695 palmitic acid Drugs 0.000 claims description 3
- 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 claims description 2
- 108010016626 Dipeptides Proteins 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 239000012530 fluid Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 37
- 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 19
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 18
- 238000002474 experimental method Methods 0.000 description 16
- 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 15
- 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 14
- 229940024606 amino acid Drugs 0.000 description 14
- 239000011259 mixed solution Substances 0.000 description 14
- 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 12
- 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 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- 238000003746 solid phase reaction Methods 0.000 description 11
- 238000010671 solid-state reaction Methods 0.000 description 11
- 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 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 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 9
- 239000005457 ice water Substances 0.000 description 9
- 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 8
- OYXZPXVCRAAKCM-SANMLTNESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(1-tritylimidazol-4-yl)propanoic acid Chemical compound 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 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000004913 activation Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 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 7
- 239000012071 phase Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 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 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 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 4
- 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 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical class COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound 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 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 239000002269 analeptic agent Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000004665 fatty acids Chemical group 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 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 1
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 102000007446 Glucagon-Like Peptide-1 Receptor Human genes 0.000 description 1
- 108010086246 Glucagon-Like Peptide-1 Receptor Proteins 0.000 description 1
- 101800004266 Glucagon-like peptide 1(7-37) Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 108010019598 Liraglutide Proteins 0.000 description 1
- 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 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- -1 alkyl phosphorus Chemical compound 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000030136 gastric emptying Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 229960002701 liraglutide Drugs 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000026792 palmitoylation Effects 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound 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(=O)NCC(O)=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 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 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 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/04—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length on carriers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
-
- 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
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410001671.XA CN103980358B (zh) | 2014-01-03 | 2014-01-03 | 一种制备利拉鲁肽的方法 |
| PCT/CN2014/075113 WO2015100876A1 (fr) | 2014-01-03 | 2014-04-10 | Procédé de préparation de liraglutide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410001671.XA CN103980358B (zh) | 2014-01-03 | 2014-01-03 | 一种制备利拉鲁肽的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103980358A CN103980358A (zh) | 2014-08-13 |
| CN103980358B true CN103980358B (zh) | 2016-08-31 |
Family
ID=51272546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410001671.XA Active CN103980358B (zh) | 2014-01-03 | 2014-01-03 | 一种制备利拉鲁肽的方法 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103980358B (fr) |
| WO (1) | WO2015100876A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110191892A (zh) * | 2018-07-23 | 2019-08-30 | 深圳市健元医药科技有限公司 | 丙氨酸-赖氨酸-谷氨酸三肽衍生物及其应用 |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| SG11201503526UA (en) | 2012-12-21 | 2015-06-29 | Sanofi Sa | Dual glp1/gip or trigonal glp1/gip/glucagon agonists |
| WO2015086733A1 (fr) | 2013-12-13 | 2015-06-18 | Sanofi | Agonistes mixtes des récepteurs du glp-1/glucagon |
| WO2015086729A1 (fr) | 2013-12-13 | 2015-06-18 | Sanofi | Agonistes mixtes des récepteurs glp-1/gip |
| WO2015086728A1 (fr) | 2013-12-13 | 2015-06-18 | Sanofi | Analogues peptidiques de l'exendine 4 en tant qu'agonistes mixtes des récepteurs glp-1/gip |
| WO2015086730A1 (fr) | 2013-12-13 | 2015-06-18 | Sanofi | Analogues peptidiques de l'exendine 4 non acylés |
| TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑 |
| TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物 |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑 |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| CN104356224A (zh) * | 2014-10-24 | 2015-02-18 | 杭州阿德莱诺泰制药技术有限公司 | 一种制备萨摩鲁泰的方法 |
| CN105753964A (zh) * | 2014-12-16 | 2016-07-13 | 深圳翰宇药业股份有限公司 | 一种萨摩鲁肽的制备方法及其中间体 |
| CN104497130A (zh) * | 2014-12-30 | 2015-04-08 | 杭州华津药业股份有限公司 | 一种兰瑞肽的制备方法 |
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| AR105284A1 (es) * | 2015-07-10 | 2017-09-20 | Sanofi Sa | Derivados de exendina-4 como agonistas peptídicos duales específicos de los receptores de glp-1 / glucagón |
| EP3433267B1 (fr) | 2016-03-23 | 2022-08-24 | Bachem Holding AG | Procédé de préparation de peptides de type glucagon |
| CN110615836B (zh) * | 2018-06-20 | 2022-09-13 | 鲁南制药集团股份有限公司 | 一种利拉鲁肽的固相合成方法 |
| CN110845600B (zh) * | 2018-08-21 | 2022-12-27 | 鲁南制药集团股份有限公司 | 一种制备利拉鲁肽的方法 |
| EP3897570A1 (fr) | 2018-12-19 | 2021-10-27 | KRKA, d.d., Novo mesto | Composition pharmaceutique comprenant un analogue de glp -1 |
| CN109836368B (zh) * | 2019-03-14 | 2020-12-08 | 美药星（南京）制药有限公司 | 一种高纯度利拉鲁肽侧链的制备方法 |
| KR20210141600A (ko) * | 2019-03-19 | 2021-11-23 | 엔진 바이오사이언스 리미티드 | 글루카곤 유사 펩티드-1(glp-1) 수용체 작용제 및 이의 유사물의 제조 방법 |
| WO2021007703A1 (fr) * | 2019-07-12 | 2021-01-21 | Shanghai Space Peptides Pharmaceutical Co., Ltd. | Procédé de préparation de liraglutide par synthèse de peptides en phase solide |
| CN112279895B (zh) * | 2019-07-27 | 2023-03-14 | 深圳市健元医药科技有限公司 | 一种化学合成酸性多肽的制备方法 |
| CN110759990A (zh) * | 2019-10-31 | 2020-02-07 | 成都圣诺生物制药有限公司 | 一种利那鲁肽的制备方法 |
| CN110835369A (zh) * | 2019-12-02 | 2020-02-25 | 苏州天马医药集团天吉生物制药有限公司 | 一种合成利拉鲁肽的方法 |
| WO2021123228A1 (fr) | 2019-12-18 | 2021-06-24 | Krka, D.D., Novo Mesto | Composition pharmaceutique comprenant un analogue de glp-1 |
| CN111892650A (zh) * | 2020-07-06 | 2020-11-06 | 辽宁药联制药有限公司 | 一种利拉鲁肽固相合成方法 |
| EP4345104A1 (fr) | 2022-09-30 | 2024-04-03 | Bachem Holding AG | Procédé de préparation de liraglutide |
| CN116730902B (zh) * | 2023-08-07 | 2023-11-21 | 杭州湃肽生化科技有限公司 | 一种合成利拉鲁肽的方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043705A1 (fr) * | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | Derives de glp-1 tronques a l'extremite n-terminale |
| 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 |
| CN103275208A (zh) * | 2013-05-27 | 2013-09-04 | 成都圣诺生物制药有限公司 | 利拉鲁肽的制备方法 |
| 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 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-01-03 CN CN201410001671.XA patent/CN103980358B/zh active Active
- 2014-04-10 WO PCT/CN2014/075113 patent/WO2015100876A1/fr active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999043705A1 (fr) * | 1998-02-27 | 1999-09-02 | Novo Nordisk A/S | Derives de glp-1 tronques a l'extremite n-terminale |
| 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 |
| CN103275208A (zh) * | 2013-05-27 | 2013-09-04 | 成都圣诺生物制药有限公司 | 利拉鲁肽的制备方法 |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 降糖药艾塞那肽和利拉鲁肽的固相合成及艾塞那肽的药效学评价;张许;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20130715;E079-48 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110191892A (zh) * | 2018-07-23 | 2019-08-30 | 深圳市健元医药科技有限公司 | 丙氨酸-赖氨酸-谷氨酸三肽衍生物及其应用 |
| WO2020019128A1 (fr) * | 2018-07-23 | 2020-01-30 | 深圳市健元医药科技有限公司 | Dérivé de tripeptide alanine-lysine-glutamate et son utilisation |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103980358A (zh) | 2014-08-13 |
| WO2015100876A1 (fr) | 2015-07-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103980358B (zh) | 一种制备利拉鲁肽的方法 | |
| US11518794B2 (en) | Synthesis method for liraglutide with low racemate impurity | |
| EP3398960B1 (fr) | Procédé de préparation du semaglutide | |
| EP2757107B1 (fr) | Procédé de synthèse en phase solide de liraglutide | |
| CN102875665B (zh) | 一种合成利拉鲁肽的方法 | |
| CN103497245B (zh) | 一种合成胸腺法新的方法 | |
| AU2017372048B2 (en) | Synthesis of liraglutide | |
| CN104356224A (zh) | 一种制备萨摩鲁泰的方法 | |
| US20130289241A1 (en) | Method for preparing exenatide | |
| CN104017064B (zh) | 一种制备特立帕肽的方法 | |
| US20080287650A1 (en) | High purity peptides | |
| CN104650219A (zh) | 片段缩合制备利拉鲁肽的方法 | |
| CN103864918A (zh) | 一种利拉鲁肽的固相合成方法 | |
| KR20090023619A (ko) | 인슐린친화성 펩타이드 합성법 | |
| CN106986924A (zh) | 胃泌酸调节素（oxm）类似物及其应用 | |
| CN107022021A (zh) | 一种利拉鲁肽的固相合成法 | |
| CN106478805B (zh) | 一种glp-1衍生物的制备方法 | |
| CN104211801A (zh) | 一种制备利西拉来的方法 | |
| CN105968186B (zh) | 具有长效化作用的胰高血糖素(Glu)类似物及其应用 | |
| CN110615836B (zh) | 一种利拉鲁肽的固相合成方法 | |
| CN104428314A (zh) | 使用侧链锚接赖氨酸的胰岛素的固相肽合成 | |
| CN103992401B (zh) | 一种制备艾塞那肽的方法 | |
| CN104447963B (zh) | 一种制备阿肽地尔的方法 | |
| CN103204923B (zh) | 固相片段法制备卡培立肽 | |
| CN103880946B (zh) | 卡培立肽的制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant after: ADLAI NORTYE BIOPHARMA Co.,Ltd. Address before: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant before: HANGZHOU ADLAI NORTYE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Address after: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant after: HANGZHOU ADLAI NORTYE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Address before: 310018 Hangzhou economic and Technological Development Zone, Zhejiang, No. 6 Avenue, No. 452 Applicant before: Hangzhou Sinopep Pharmaceutical Inc. |
|
| COR | Change of bibliographic data | ||
| C14 | Grant of patent or utility model | ||
| 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: Preparation method of liraglutide Effective date of registration: 20170420 Granted publication date: 20160831 Pledgee: The Bank of Nanjing Limited by Share Ltd. of Hangzhou city Small and micro businesses franchise branch Pledgor: ADLAI NORTYE BIOPHARMA Co.,Ltd. Registration number: 2017330000031 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20171207 Granted publication date: 20160831 Pledgee: The Bank of Nanjing Limited by Share Ltd. of Hangzhou city Small and micro businesses franchise branch Pledgor: ADLAI NORTYE BIOPHARMA Co.,Ltd. Registration number: 2017330000031 |
|
| 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: Preparation method of liraglutide Effective date of registration: 20171214 Granted publication date: 20160831 Pledgee: The Bank of Nanjing Limited by Share Ltd. of Hangzhou city Small and micro businesses franchise branch Pledgor: ADLAI NORTYE BIOPHARMA Co.,Ltd. Registration number: 2017330000290 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20201014 Granted publication date: 20160831 Pledgee: The Bank of Nanjing Limited by Share Ltd. of Hangzhou city Small and micro businesses franchise branch Pledgor: ADLAI NORTYE BIOPHARMA Co.,Ltd. Registration number: 2017330000290 |