CN114685613A - Preparation method of terlipressin impurity Q - Google Patents
Preparation method of terlipressin impurity Q Download PDFInfo
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- CN114685613A CN114685613A CN202011583895.8A CN202011583895A CN114685613A CN 114685613 A CN114685613 A CN 114685613A CN 202011583895 A CN202011583895 A CN 202011583895A CN 114685613 A CN114685613 A CN 114685613A
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- resin
- tfa
- impurity
- lysate
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- 239000012535 impurity Substances 0.000 title claims abstract description 36
- 108010010056 Terlipressin Proteins 0.000 title claims abstract description 30
- BENFXAYNYRLAIU-QSVFAHTRSA-N terlipressin Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CN)CSSC1 BENFXAYNYRLAIU-QSVFAHTRSA-N 0.000 title claims abstract description 30
- 229960003813 terlipressin Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 16
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 59
- 229920001184 polypeptide Polymers 0.000 claims abstract description 36
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims abstract description 9
- 239000012043 crude product Substances 0.000 claims abstract description 7
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 6
- 239000011630 iodine Substances 0.000 claims abstract description 6
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 229920005989 resin Polymers 0.000 claims description 37
- 239000011347 resin Substances 0.000 claims description 37
- 239000012634 fragment Substances 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 239000006166 lysate Substances 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 230000009089 cytolysis Effects 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- ROUFCTKIILEETD-UHFFFAOYSA-N 5-nitro-2-[(5-nitropyridin-2-yl)disulfanyl]pyridine Chemical compound N1=CC([N+](=O)[O-])=CC=C1SSC1=CC=C([N+]([O-])=O)C=N1 ROUFCTKIILEETD-UHFFFAOYSA-N 0.000 claims description 11
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 11
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims description 7
- -1 HBTU Chemical compound 0.000 claims description 7
- 150000001413 amino acids Chemical group 0.000 claims description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 7
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 6
- CSMYOORPUGPKAP-IBGZPJMESA-N (2r)-3-(acetamidomethylsulfanyl)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CSCNC(=O)C)C(O)=O)C3=CC=CC=C3C2=C1 CSMYOORPUGPKAP-IBGZPJMESA-N 0.000 claims description 5
- ZPGDWQNBZYOZTI-SFHVURJKSA-N (2s)-1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-SFHVURJKSA-N 0.000 claims description 5
- 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 claims description 5
- UMRUUWFGLGNQLI-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 UMRUUWFGLGNQLI-QFIPXVFZSA-N 0.000 claims description 5
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 5
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 claims description 5
- FBKUOPULLUJMOC-UHFFFAOYSA-N 2-[[2-(9h-fluoren-9-ylmethoxycarbonylamino)acetyl]amino]acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 FBKUOPULLUJMOC-UHFFFAOYSA-N 0.000 claims description 5
- FZTIWOBQQYPTCJ-UHFFFAOYSA-N 4-[4-(4-carboxyphenyl)phenyl]benzoic acid Chemical group C1=CC(C(=O)O)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(O)=O)C=C1 FZTIWOBQQYPTCJ-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
- 230000005526 G1 to G0 transition Effects 0.000 claims description 4
- 239000007821 HATU Substances 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 238000010828 elution Methods 0.000 claims description 4
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- JDDWRLPTKIOUOF-UHFFFAOYSA-N 9h-fluoren-9-ylmethyl n-[[4-[2-[bis(4-methylphenyl)methylamino]-2-oxoethoxy]phenyl]-(2,4-dimethoxyphenyl)methyl]carbamate Chemical compound COC1=CC(OC)=CC=C1C(C=1C=CC(OCC(=O)NC(C=2C=CC(C)=CC=2)C=2C=CC(C)=CC=2)=CC=1)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JDDWRLPTKIOUOF-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims 4
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 238000010532 solid phase synthesis reaction Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 31
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 5
- 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 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YDJXDYKQMRNUSA-UHFFFAOYSA-N tri(propan-2-yl)silane Chemical compound CC(C)[SiH](C(C)C)C(C)C YDJXDYKQMRNUSA-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- KLBPUVPNPAJWHZ-UMSFTDKQSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UMSFTDKQSA-N 0.000 description 3
- XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 3
- 229920003180 amino resin Polymers 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 2
- 229930003268 Vitamin C Natural products 0.000 description 2
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- XKUKSGPZAADMRA-UHFFFAOYSA-N glycyl-glycyl-glycine Chemical compound NCC(=O)NCC(=O)NCC(O)=O XKUKSGPZAADMRA-UHFFFAOYSA-N 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 2
- 235000019154 vitamin C Nutrition 0.000 description 2
- 239000011718 vitamin C Substances 0.000 description 2
- LOBUWFUSGOYXQX-DHUJRADRSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(4-methoxyphenyl)-diphenylmethyl]sulfanylpropanoic acid Chemical compound C1=CC(OC)=CC=C1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)SC[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 LOBUWFUSGOYXQX-DHUJRADRSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical class C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- HPZAJRPYUIHDIN-BZSNNMDCSA-N Cys-Tyr-Phe Chemical compound C1=CC=C(C=C1)C[C@@H](C(=O)O)NC(=O)[C@H](CC2=CC=C(C=C2)O)NC(=O)[C@H](CS)N HPZAJRPYUIHDIN-BZSNNMDCSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- MINZLORERLNSPP-ACZMJKKPSA-N Gln-Asn-Cys Chemical compound C(CC(=O)N)[C@@H](C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CS)C(=O)O)N MINZLORERLNSPP-ACZMJKKPSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- ABSSTGUCBCDKMU-UWVGGRQHSA-N Pro-Lys-Gly Chemical compound NCCCC[C@@H](C(=O)NCC(O)=O)NC(=O)[C@@H]1CCCN1 ABSSTGUCBCDKMU-UWVGGRQHSA-N 0.000 description 1
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000001595 contractor effect Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 108010060199 cysteinylproline Proteins 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108010067216 glycyl-glycyl-glycine Proteins 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N nmp n-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 108010091858 peptide Q Proteins 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention relates to the technical field of polypeptide synthesis, and particularly relates to a preparation method of terlipressin impurity Q. The method comprises the steps of firstly synthesizing two polypeptide segments I and two polypeptide segments II with good stability, then carrying out disulfide bond exchange between SH of a Cys residue at the 4 th position of the C end of a polypeptide segment and SNpys or SPyr of a Cys residue at the 4 th position of the C end of a polypeptide segment through condensation reaction to form a first pair of disulfide bonds, and forming a second pair of disulfide bonds while removing Acm protecting groups of Cys through iodine oxidation reaction. Experiments show that the terlipressin impurity Q obtained by the preparation method has high purity and less impurities, and the purity of a crude product can reach over 75 percent.
Description
Technical Field
The invention relates to the technical field of polypeptide synthesis, and particularly relates to a preparation method of terlipressin impurity Q.
Background
Terlipressin (Terlipessin) is an artificially synthesized analogue of hormone secreted by the posterior pituitary, can be hydrolyzed by enzyme in a human body to generate vasopressin which has a contraction effect on smooth muscle, and is mainly used for treating esophageal variceal bleeding clinically. The peptide sequence is as follows:
terlipressin can generate an impurity Q in the preparation and storage processes, thereby affecting the safety of the medicine. In the process of developing the terlipressin production process, a reference substance of impurity Q needs to be prepared for the study of the product quality thereof.
The peptide sequence of impurity Q is as follows:
at present, a large number of documents in the prior art report the preparation method of terlipressin, but no report is made on the preparation of impurity Q.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing terlipressin impurity Q.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of terlipressin impurity Q, which comprises the following steps:
step 1: synthesizing peptide resin which is coupled with a resin carrier at the C end of the amino acid sequence shown in SEQ ID NO. 1, is coupled with an Acm protecting group on the side chain of the Cys at the 4 th position and is coupled with Trt or Mmt protecting group on the side chain of the Cys at the 9 th position according to the sequence from the C end to the N end;
and 2, step: under the action of a lysis solution 1, the peptide resin in the step 1 is lysed to obtain a polypeptide fragment I;
and step 3: under the action of a lysis solution 2, the peptide resin in the step 1 is lysed to obtain a second polypeptide fragment;
and 4, step 4: mixing the polypeptide fragment I and the polypeptide fragment II, and sequentially carrying out condensation reaction and iodine oxidation reaction to obtain a terlipressin impurity Q crude product;
the lysate 1 comprises a capture agent and TFA;
the lysate 2 comprises a mixture of a capture agent, TFA and DTDP, or a mixture of a capture agent, TFA and DTNP;
in the lysis solution 1 and the lysis solution 2, the capture agent is PhSMe, PhOH and H2One or more of O, TIS and PhOMe.
The polypeptide fragment I and the polypeptide fragment II synthesized by the method have good stability, the SH of the 4 th Cys residue at the C end of the polypeptide fragment and the SNpys or SPyr of the 4 th Cys residue at the C end of the polypeptide fragment are subjected to disulfide bond exchange to form a first pair of disulfide bonds, and a second pair of disulfide bonds are formed while the Acm protecting group of Cys is removed through iodine oxidation reaction, so that the oxidation efficiency is high, and impurities are few.
In the invention, the resin carrier is amino resin. In some embodiments, the amino resin comprises Rink Amide resin, Rink Amide AM resin, Rink Amide MBHA resin. The substitution degree of the amino resin is preferably 0.1-1.0 mmol/g.
In some embodiments, step 1 is specifically:
step 1-1: coupling Fmoc-Gly-OH with a resin carrier, and removing Fmoc protecting groups to obtain Fmoc-Gly-resin;
step 1-2: according to the amino acid sequence shown in SEQ ID NO. 1, the following protected amino acids are coupled on Fmoc-Gly-resin from the C end to the N end in sequence: Fmoc-L-Lys (Boc) -OH, Fmoc-L-Pro-OH, Fmoc-L-Cys (Trt or Mmt) -OH, Fmoc-L-Asn (Trt) -OH, Fmoc-L-Gln (Trt) -OH, Fmoc-L-Phe-OH, Fmoc-L-Tyr (tBu) -OH, Fmoc-L-Cys (Acm) -OH, Fmoc-Gly-Gly-OH and Boc-Gly-OH to obtain peptide resin.
In the invention, a kaiser method is used for detecting and judging whether the reaction of the coupling amino acid in the step 1 is complete, if the resin is colorless and transparent, the reaction is complete; if the resin develops color, the reaction is not complete, and the above operation needs to be repeated for two shots. The judgment standard is suitable for detecting and judging the reaction endpoint by a kaiser method in subsequent contents.
In some embodiments, the Fmoc-protecting group removal agent is a 20% by volume piperidine solution. Wherein, the solvent of the piperidine solution is one or more of NMP, THF, DCM and DMF.
In some embodiments, the coupling agent is selected from any one of the following combinations:
a combination of DIC and HOBT, a combination of DIC and HOAT, a combination of HBTU, HOBT and DIPEA, a combination of HATU, HOAT and DIPEA, or a combination of PyBOP, HOBT and DIPEA.
In some embodiments, the lysate 1 comprises TFA and H2O。
The lysis solution 2 comprises TFA and H2O and DTDP, or TFA, H2O and DTNP.
In some embodiments, in lysate 1 and lysate 2, the capture agent is H2O。
The lysate 1 consists of TFA and H2And (C) O. In some embodiments, lysate 1 is composed of TFA and H in a 95:5 by volume ratio2And (C) O.
The lysate 2 is composed of TFA and H2O and DTDP, or TFA, H2O and DTNP. In some embodiments, lysate 2 is composed of 95:5:5 volume to mass ratio of TFA, H2O and DTDP, or TFA and H with the volume mass ratio of 95:5:52O and DTNP.
In some embodiments, the condensation reaction is carried out in the presence of acetic acid solution and acetonitrile; the temperature of the condensation reaction is room temperature, and the reaction time is 1 h.
In the preparation method provided by the invention, the step of HPLC purification is also included in the process of obtaining the crude product of terlipressin impurity Q.
The conditions for HPLC purification were:
octadecylsilane chemically bonded silica is used as a stationary phase, 0.2% acetic acid solution is used as a mobile phase A phase, methanol is used as a mobile phase B phase, the detection wavelength is 280nm, and gradient elution is carried out.
The method comprises the steps of firstly synthesizing two polypeptide segments I and two polypeptide segments II with good stability, then carrying out disulfide bond exchange between SH of a Cys residue at the 4 th position of the C end of a polypeptide segment and SNpys or SPyr of a Cys residue at the 4 th position of the C end of a polypeptide segment through condensation reaction to form a first pair of disulfide bonds, and forming a second pair of disulfide bonds while removing Acm protecting groups of Cys through iodine oxidation reaction. Experiments show that the terlipressin impurity Q obtained by the preparation method has high purity and less impurities, and the purity of a crude product can reach over 75 percent.
Drawings
FIG. 1 shows a flow diagram of a process for the preparation of terlipressin impurity Q of the present invention;
FIG. 2 shows a chromatogram of polypeptide fragment one;
FIG. 3 shows a chromatogram of polypeptide fragment two;
FIG. 4 chromatogram of crude peptide of terlipressin impurity Q;
FIG. 5 shows a chromatogram of the fine peptide of terlipressin impurity Q;
FIG. 6 mass spectrum of terlipressin impurity Q;
figure 7 shows a process flow diagram of comparative example 1.
Detailed Description
The invention provides a preparation method of terlipressin impurity Q. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The test materials adopted by the invention are all common commercial products and can be purchased in the market.
In the present invention, the meanings of English abbreviations are shown in Table 1.
TABLE 1
Abbreviations and English | Means of |
HOAt | 1-hydroxy-7-azobenzotriazol |
DIPCDI | Diisopropylcarbodiimide |
HOBt | 1-hydroxybenzotriazoles |
HATU | 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate |
HBTU | benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate |
DIPEA | N, N-diisopropylethylamine |
PyBOP | Benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphates |
DMF | N, N-dimethylformamide |
NMP | N-methyl pyrrolidone |
THF | Tetrahydrofuran (THF) |
DCM | Methylene dichloride |
TFA | Trifluoroacetic acid |
PhSMe | Phenylmethyl sulfide |
PhOH | Phenol and its preparation |
PhOMe | Phenylmethyl ether |
TIS | Tri-isopropyl silane |
DTDP | 2,2' -dithiodipyridine |
DTNP | 2,2' -dithiobis (5-nitropyridine) |
The invention provides a method for preparing terlipressin impurity Q, wherein a synthetic route is shown as figure 1, and the method specifically comprises the following steps:
1. coupling Fmoc-Gly-OH, Fmoc-L-Lys (Boc) -OH, Fmoc-L-Pro-OH, Fmoc-L-Cys (Trt) -OH or Fmoc-L-Cys (Mmt) -OH, Fmoc-L-Asn (Trt) -OH, Fmoc-L-Gln (Trt) -OH, Fmoc-L-Phe-OH, Fmoc-L-Tyr (tBu) -OH, Fmoc-L-Cys (Acm) -OH, Fmoc-Gly-Gly-OH and Boc-Gly-OH to the resin in sequence, the resin can be Rink Amide resin, Rink Amide AM resin or Rink Amide MBHA resin, and the condensing agent can be selected from DIC/HOBT, DIC/HOAT, HBTU/HOBT/DIPEA, HATU/HOAT/DIPEA or PyBOP/HOBT/DIPEA.
2. And (3) cracking the peptide resin by adopting a trifluoroacetic acid solution containing a capture agent to obtain a polypeptide fragment I. Wherein the capture agent is PhSMe, PhOH, H2One or more of O, TIS and PhOMe, and preferably, the lysis solution is TFA H2O=95:5(v/v)。
3. The peptide resin is cracked by DTDP or DTNP/trifluoroacetic acid solution containing catching agent to obtain fragment II, wherein the catching agent is PhSMe, PhOH, H2One or more of O, TIS and PhOMe, and preferably, the lysis solution is TFA H2O DTDP or TFA H2O:DTNP=95:5:5(ml/ml/g)。
4. And (3) carrying out condensation reaction on the polypeptide fragment I and the fragment II to form a first pair of disulfide bonds, and carrying out iodine oxidation to form a second pair of disulfide bonds, so as to obtain a terlipressin impurity Q crude product.
In the invention, a step of HPLC purification is also included after the crude product of terlipressin impurity Q is obtained.
The conditions for HPLC purification were:
octadecylsilane chemically bonded silica is used as a stationary phase, 0.2% acetic acid solution is used as a mobile phase A phase, methanol is used as a mobile phase B phase, the detection wavelength is 280nm, and gradient elution is carried out.
The invention is further illustrated by the following examples:
EXAMPLE 1 Synthesis of polypeptide fragment one
Weighing 16.7g Rink Amide resin (substitution degree is 0.60mmol/g, scale is 10mmol), DMF swelling resin for 30 minutes, pumping out resin, and DMF washing for 2 times. 20% piperidine/DMF solution was added for Fmoc protection removal, the reaction was stirred at room temperature for 10 minutes, the resin was drained and the procedure was repeated once and then washed 6 times with DMF. Weighing 8.92g (30mmol) of Fmoc-Gly-OH, 4.86g (36mmol) of HOBT and 60ml of DMF, stirring to dissolve the mixture to be clear, adding DIPCDI5.63ml (36mmol) under ice bath for activation, adding the mixture into resin, reacting for 2 hours at room temperature, and detecting whether the reaction is complete by a kaiser method, wherein if the resin is colorless and transparent, the reaction is complete; if the resin develops color, the reaction is not complete, and the above operation needs to be repeated for two shots. The judgment standard is suitable for detecting and judging the reaction endpoint by a kaiser method in subsequent contents. The above steps of Fmoc-L-Lys (Boc) -OH, Fmoc-L-Pro-OH, Fmoc-L-Cys (Trt) -OH, Fmoc-L-Asn (Trt) -OH, Fmoc-L-Gln (Trt) -OH, Fmoc-L-Phe-OH, Fmoc-L-Tyr (tBu) -OH, Fmoc-L-Cys (Acm) -OH, Fmoc-Gly-Gly-OH and Boc-Gly-OH were repeated, followed by 3 DMF washes, 3 dichloromethane washes, methanol shrinkage, and vacuum drying to obtain 37g of peptide resin.
The peptide resin was taken and added to the lysate (TFA: H) at a ratio of 10ml/g2O-90: 5), stirring at room temperature for 2 hours, filtering, pouring the filtrate into frozen anhydrous ether for precipitation, centrifuging, washing with anhydrous ether for 3 times, and drying in vacuum to obtain 15.6g of polypeptide fragment with the purity of 89.29%. The chromatogram is shown in fig. 2, and the chromatogram data of typical characteristic peaks are shown in table 2.
TABLE 2
EXAMPLE 2 Synthesis of polypeptide fragment two
The peptide resin of example 1 was taken and added to a lysis solution (TFA: H) at a ratio of 10ml/g2DTDP (90: 5:5) at room temperature, stirring and reacting for 2 hours, filtering, pouring the filtrate into frozen anhydrous ether for precipitation, centrifuging, washing for 3 times by the anhydrous ether, and drying in vacuum to obtain the polypeptide fragment II 16.9g with the purity of 88.05%.
EXAMPLE 3 Synthesis of polypeptide fragment two
The peptide resin of example 1 was taken and added to a lysis solution (TFA: H) at a ratio of 10ml/g2DTNP (90: 5:5) at room temperature, stirring and reacting for 2 hours, filtering, pouring the filtrate into frozen anhydrous ether for precipitation, centrifuging, washing for 3 times by the anhydrous ether, and drying in vacuum to obtain the polypeptide fragment II 17.4g with the purity of 86.43%. The chromatogram is shown in fig. 3, and the chromatogram data of typical characteristic peaks are shown in table 3.
TABLE 3
Example 4 Synthesis of terlipressin impurity Q
Weighing 15.6g of the first polypeptide fragment and 16.9g of the second polypeptide fragment obtained in the example 2, adding 200ml of 2N acetic acid solution and acetonitrile respectively, reacting at room temperature for 1 hour, and monitoring by HPLC that the reaction is complete; adding 16L of purified water into the solution, diluting to 1mg/ml, weighing 3.8g (15mmol) of iodine, adding 50ml of methanol for dissolving, slowly dropwise adding the solution into the solution, reacting for 1 hour at room temperature, monitoring the reaction by HPLC (high performance liquid chromatography), and adding vitamin C to terminate the reaction, thus obtaining a crude peptide solution of the impurity Q, wherein the purity is 77.48%. The chromatogram is shown in fig. 4, and the chromatogram data of typical characteristic peaks are shown in table 4.
TABLE 4
Example 5 Synthesis of terlipressin impurity Q
Weighing 15.6g of the first polypeptide fragment and 17.4g of the second polypeptide fragment obtained in the example 3, adding 200ml of 2N acetic acid solution and acetonitrile respectively, reacting at room temperature for 1 hour, and monitoring by HPLC that the reaction is complete; adding 16L of purified water into the solution, diluting to 1mg/ml, weighing 3.8g (15mmol) of iodine, adding 50ml of methanol for dissolving, slowly dropwise adding the solution into the solution, reacting for 1 hour at room temperature, monitoring the reaction by HPLC (high performance liquid chromatography), and adding vitamin C to terminate the reaction, thus obtaining a crude peptide solution of the impurity Q with the purity of 75.56%.
EXAMPLE 6 preparation of Terlipressin impurity, Fine peptide Q
Taking the crude peptide solution of the impurity Q obtained in the embodiment 4, preparing and purifying by using a high performance liquid chromatograph, taking octadecylsilane chemically bonded silica as a stationary phase, taking a 0.2% acetic acid solution as a mobile phase A phase and taking methanol as a mobile phase B phase, monitoring the wavelength at 280nm, performing gradient elution to collect a target peak fraction, concentrating and freeze-drying to obtain 9.8g of impurity Q refined peptide, wherein the total yield is 40%, the purity is 97.43%, and the mass spectrum conforms to the theory. The chromatogram is shown in FIG. 5, the mass spectrum is shown in FIG. 6, and the chromatogram data of typical characteristic peaks are shown in Table 5.
TABLE 5
Injection | RT | Area | %Area | Height | |
1 | 1 | 15.259 | 54688 | 0.29 | 7930 |
2 | 1 | 15.787 | 193009 | 1.03 | 27300 |
3 | 1 | 15.982 | 35899 | 0.19 | 5573 |
4 | 1 | 16.569 | 18222186 | 97.43 | 1946683 |
5 | 1 | 17.668 | 39646 | 0.21 | 2889 |
6 | 1 | 21.216 | 157446 | 0.84 | 15930 |
Comparative example 1
Referring to the procedure of example 1, Rink Amide resin was selected and coupled with Fmoc-Gly-OH, Fmoc-L-Lys (Boc) -OH, Fmoc-L-Pro-OH, Fmoc-L-Cys (Acm) -OH, Fmoc-L-Asn (Trt) -OH, Fmoc-L-Gln (Trt) -OH, Fmoc-L-Phe-OH, Fmoc-L-Tyr (tBu) -OH, Fmoc-L-Cys (Trt) -OH, Fmoc-Gly-Gly-OH and Boc-Gly-OH in this order. Cleavage solution (TFA: H)2O-90: 5) cleavage of the peptide resin to give fragment III, lysate (TFA: H)2DTNP ═ 90:5:5) cleavage of the peptide resin gave fragment four. Referring to the procedure of example 5, coupling of fragments three and four did not yield the desired product, which was instead terlipressin, and the process flow diagram is shown in FIG. 7.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.
Sequence listing
<110> Shenzhen Hanyu pharmaceutical stockings Limited
<120> preparation method of terlipressin impurity Q
<130> S20P2484
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 12
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<400> 1
Gly Gly Gly Cys Tyr Phe Gln Asn Cys Pro Lys Gly
1 5 10
Claims (10)
1. A method for preparing terlipressin impurity Q, which is characterized by comprising the following steps:
step 1: synthesizing peptide resin with a resin carrier coupled to the C end of an amino acid sequence shown in SEQ ID NO. 1, an Acm protecting group coupled to the side chain of the 4 th Cys and a Trt or Mmt protecting group coupled to the side chain of the 9 th Cys according to the sequence from the C end to the N end;
step 2: under the action of a lysis solution 1, the peptide resin in the step 1 is lysed to obtain a polypeptide fragment I;
and step 3: under the action of a lysis solution 2, the peptide resin in the step 1 is lysed to obtain a second polypeptide fragment;
and 4, step 4: mixing the polypeptide fragment I and the polypeptide fragment II, and sequentially carrying out condensation reaction and iodine oxidation reaction to obtain a terlipressin impurity Q crude product;
the lysate 1 comprises a capture agent and TFA;
the lysate 2 comprises a mixture of a capture agent, TFA and DTDP, or a mixture of a capture agent, TFA and DTNP;
in the lysate 1 and the lysate 2, the capture agent is PhSMe, PhOH or H2One or more of O, TIS and PhOMe.
2. The method according to claim 1, wherein the resin carrier is Rink Amide resin, Rink Amide AM resin, or Rink Amide MBHA resin.
3. The method according to claim 1, wherein the step 1 is:
step 1-1: solid-phase synthesis of Fmoc-Gly-resin;
step 1-2: according to the amino acid sequence shown in SEQ ID NO. 1, the following protected amino acids are coupled on Fmoc-Gly-resin from the C end to the N end in sequence: Fmoc-L-Lys (Boc) -OH, Fmoc-L-Pro-OH, Fmoc-L-Cys (Trt or Mmt) -OH, Fmoc-L-Asn (Trt) -OH, Fmoc-L-Gln (Trt) -OH, Fmoc-L-Phe-OH, Fmoc-L-Tyr (tBu) -OH, Fmoc-L-Cys (Acm) -OH, Fmoc-Gly-Gly-OH and Boc-Gly-OH.
4. The method according to claim 3, wherein the Fmoc protecting group removing agent is a piperidine solution with a volume percentage of 20%; the solvent of the piperidine solution is one or more of NMP, THF, DCM and DMF.
5. The process of claim 3, wherein the coupling agent is selected from the group consisting of DIC and HOBT, DIC and HOAT, HBTU, HOBT and DIPEA, HATU, HOAT and DIPEA, PyBOP, HOBT and DIPEA.
6. The method according to claim 1, wherein the lysate 1 comprises TFA and H2O; the lysis solution 2 comprises TFA and H2O and DTDP, or TFA, H2O and DTNP.
7. The method according to claim 5, wherein the lysate 1 is composed of TFA and H at a volume ratio of 95:52O composition;
the lysate 2 is composed of TFA and H with the volume-mass ratio of ml/ml/g of 95:5:52O and DTDP composition, or volume massTFA, H in a ratio of 95:5:52O and DTNP.
8. The production method according to claim 1, wherein the condensation reaction is carried out in the presence of an acetic acid solution and acetonitrile; the temperature of the condensation reaction is room temperature, and the reaction time is 1 h.
9. The process of claim 1, further comprising a step of HPLC purification after obtaining crude terlipressin impurity Q.
10. The method of claim 9, wherein the conditions for HPLC purification are:
octadecylsilane chemically bonded silica is used as a stationary phase, 0.2% acetic acid solution is used as a mobile phase A phase, methanol is used as a mobile phase B phase, the detection wavelength is 280nm, and gradient elution is carried out.
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CN103675138A (en) * | 2013-12-10 | 2014-03-26 | 深圳翰宇药业股份有限公司 | Ultra-high performance liquid chromatogram detection method for terlipressin and impurities thereof |
CN104371008A (en) * | 2014-10-15 | 2015-02-25 | 兰州大学 | Method for preparing terlipressin by virtue of fragment condensation |
CN105367627A (en) * | 2014-08-29 | 2016-03-02 | 安徽工程大学 | Method for preparing terlipressin |
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CN103675138A (en) * | 2013-12-10 | 2014-03-26 | 深圳翰宇药业股份有限公司 | Ultra-high performance liquid chromatogram detection method for terlipressin and impurities thereof |
CN105367627A (en) * | 2014-08-29 | 2016-03-02 | 安徽工程大学 | Method for preparing terlipressin |
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