AU751358B2 - Methods and compositions for peptide synthesis - Google Patents
Methods and compositions for peptide synthesis Download PDFInfo
- Publication number
- AU751358B2 AU751358B2 AU31097/99A AU3109799A AU751358B2 AU 751358 B2 AU751358 B2 AU 751358B2 AU 31097/99 A AU31097/99 A AU 31097/99A AU 3109799 A AU3109799 A AU 3109799A AU 751358 B2 AU751358 B2 AU 751358B2
- Authority
- AU
- Australia
- Prior art keywords
- seq
- peptide
- formula
- fmoc
- chain protected
- 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.)
- Expired
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- 238000000034 method Methods 0.000 title claims abstract description 180
- 238000010647 peptide synthesis reaction Methods 0.000 title description 11
- 239000000203 mixture Substances 0.000 title description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 334
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 claims abstract description 143
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 84
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 83
- 108010033276 Peptide Fragments Proteins 0.000 claims abstract description 47
- 102000007079 Peptide Fragments Human genes 0.000 claims abstract description 47
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 59
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 230000004048 modification Effects 0.000 claims description 15
- 238000012986 modification Methods 0.000 claims description 15
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 4
- 239000012634 fragment Substances 0.000 abstract description 148
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 68
- 239000000543 intermediate Substances 0.000 abstract description 48
- 239000007790 solid phase Substances 0.000 abstract description 25
- 239000007791 liquid phase Substances 0.000 abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 482
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 252
- 229920005989 resin Polymers 0.000 description 218
- 239000011347 resin Substances 0.000 description 218
- 239000000243 solution Substances 0.000 description 162
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 159
- 239000007787 solid Substances 0.000 description 152
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 147
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 116
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 114
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 97
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 96
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 92
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 84
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 78
- 150000001413 amino acids Chemical group 0.000 description 72
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 67
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 65
- 229940024606 amino acid Drugs 0.000 description 63
- 238000004128 high performance liquid chromatography Methods 0.000 description 62
- 238000005859 coupling reaction Methods 0.000 description 60
- 235000001014 amino acid Nutrition 0.000 description 58
- 238000003828 vacuum filtration Methods 0.000 description 56
- 238000011068 loading method Methods 0.000 description 53
- 239000000047 product Substances 0.000 description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
- 230000014759 maintenance of location Effects 0.000 description 48
- 239000000463 material Substances 0.000 description 47
- 238000002360 preparation method Methods 0.000 description 47
- 238000010168 coupling process Methods 0.000 description 46
- 238000003756 stirring Methods 0.000 description 45
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 44
- 230000008878 coupling Effects 0.000 description 43
- 229910052757 nitrogen Inorganic materials 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- 238000012360 testing method Methods 0.000 description 39
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 37
- 235000019441 ethanol Nutrition 0.000 description 36
- 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 description 34
- 239000012071 phase Substances 0.000 description 34
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 31
- 239000002002 slurry Substances 0.000 description 31
- 239000002904 solvent Substances 0.000 description 29
- 238000003776 cleavage reaction Methods 0.000 description 28
- 230000007017 scission Effects 0.000 description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 27
- 238000012369 In process control Methods 0.000 description 27
- 238000010965 in-process control Methods 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 26
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 24
- ZYASLTYCYTYKFC-UHFFFAOYSA-N 9-methylidenefluorene Chemical compound C1=CC=C2C(=C)C3=CC=CC=C3C2=C1 ZYASLTYCYTYKFC-UHFFFAOYSA-N 0.000 description 23
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 238000013459 approach Methods 0.000 description 21
- 238000001514 detection method Methods 0.000 description 21
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
- 238000010511 deprotection reaction Methods 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 230000008569 process Effects 0.000 description 18
- 238000000746 purification Methods 0.000 description 17
- 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 16
- 125000000539 amino acid group Chemical group 0.000 description 16
- 239000012298 atmosphere Substances 0.000 description 16
- 125000006239 protecting group Chemical group 0.000 description 16
- 239000000523 sample Substances 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- -1 T-butyloxycarbonyl Chemical group 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000001556 precipitation Methods 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- 238000001665 trituration Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012535 impurity Substances 0.000 description 12
- 238000010532 solid phase synthesis reaction Methods 0.000 description 12
- PGTKVMVZBBZCKQ-UHFFFAOYSA-N Fulvene Chemical compound C=C1C=CC=C1 PGTKVMVZBBZCKQ-UHFFFAOYSA-N 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 230000004584 weight gain Effects 0.000 description 11
- 235000019786 weight gain Nutrition 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 9
- 238000010268 HPLC based assay Methods 0.000 description 9
- 229910052740 iodine Inorganic materials 0.000 description 9
- 239000011630 iodine Substances 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 238000010926 purge Methods 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 8
- 238000006114 decarboxylation reaction Methods 0.000 description 8
- 238000002955 isolation Methods 0.000 description 8
- 229960004592 isopropanol Drugs 0.000 description 8
- 239000012299 nitrogen atmosphere Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 230000008961 swelling Effects 0.000 description 8
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 238000013019 agitation Methods 0.000 description 7
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 7
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- MGHMWKZOLAAOTD-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(1h-indol-3-yl)propanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)NC(C(=O)O)CC1=CNC2=CC=CC=C12 MGHMWKZOLAAOTD-UHFFFAOYSA-N 0.000 description 5
- 229910004373 HOAc Inorganic materials 0.000 description 5
- OBSIQMZKFXFYLV-QMMMGPOBSA-N L-phenylalanine amide Chemical compound NC(=O)[C@@H](N)CC1=CC=CC=C1 OBSIQMZKFXFYLV-QMMMGPOBSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 230000005587 bubbling Effects 0.000 description 5
- MBCZNRXYDIFUJF-UHFFFAOYSA-N fulvene;piperidine Chemical compound C=C1C=CC=C1.C1CCNCC1 MBCZNRXYDIFUJF-UHFFFAOYSA-N 0.000 description 5
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 5
- 238000012856 packing Methods 0.000 description 5
- 230000006340 racemization Effects 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- MJZMSEWWBGCBFM-UHFFFAOYSA-N 2-(2-acetamidopropanoylamino)propanoic acid Chemical compound OC(=O)C(C)NC(=O)C(C)NC(C)=O MJZMSEWWBGCBFM-UHFFFAOYSA-N 0.000 description 4
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000002835 absorbance Methods 0.000 description 4
- 125000003368 amide group Chemical group 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000001143 conditioned effect Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
- 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 4
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 238000006640 acetylation reaction Methods 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 230000008021 deposition Effects 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- IZZWJPQHPPRVLP-UHFFFAOYSA-N hexane;2-methoxy-2-methylpropane Chemical compound CCCCCC.COC(C)(C)C IZZWJPQHPPRVLP-UHFFFAOYSA-N 0.000 description 3
- 125000001165 hydrophobic group Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- UYCAUPASBSROMS-AWQJXPNKSA-M sodium;2,2,2-trifluoroacetate Chemical compound [Na+].[O-][13C](=O)[13C](F)(F)F UYCAUPASBSROMS-AWQJXPNKSA-M 0.000 description 3
- 239000003930 superacid Substances 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 2
- JAUKCFULLJFBFN-VWLOTQADSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoic acid Chemical compound C1=CC(OC(C)(C)C)=CC=C1C[C@@H](C(O)=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 JAUKCFULLJFBFN-VWLOTQADSA-N 0.000 description 2
- KSDTXRUIZMTBNV-INIZCTEOSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)butanedioic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)O)C(O)=O)C3=CC=CC=C3C2=C1 KSDTXRUIZMTBNV-INIZCTEOSA-N 0.000 description 2
- OIOAKXPMBIZAHL-LURJTMIESA-N (2s)-2-azaniumyl-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoate Chemical compound CC(C)(C)OC(=O)CC[C@H](N)C(O)=O OIOAKXPMBIZAHL-LURJTMIESA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- LXAVCFDWHMZCJH-UHFFFAOYSA-N 2-[4-(hydroxymethyl)-3-methoxyphenoxy]butanoic acid Chemical compound CCC(C(O)=O)OC1=CC=C(CO)C(OC)=C1 LXAVCFDWHMZCJH-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- 238000012935 Averaging Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
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- 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
-
- 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
- Y02P20/582—Recycling of unreacted starting or intermediate materials
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/045,920 US6281331B1 (en) | 1998-03-23 | 1998-03-23 | Methods and compositions for peptide synthesis |
| US09/045920 | 1998-03-23 | ||
| US09/071,877 US6015881A (en) | 1998-03-23 | 1998-05-01 | Methods and compositions for peptide synthesis |
| US09/071877 | 1998-05-01 | ||
| PCT/US1999/006230 WO1999048513A1 (en) | 1998-03-23 | 1999-03-22 | Methods and compositions for peptide synthesis |
Publications (2)
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|---|---|
| AU3109799A AU3109799A (en) | 1999-10-18 |
| AU751358B2 true AU751358B2 (en) | 2002-08-15 |
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| EP (1) | EP1071442B9 (enExample) |
| JP (1) | JP4602547B2 (enExample) |
| CN (1) | CN100383158C (enExample) |
| AT (1) | ATE299029T1 (enExample) |
| AU (1) | AU751358B2 (enExample) |
| BR (1) | BR9909018A (enExample) |
| CA (1) | CA2324348C (enExample) |
| DE (1) | DE69926061T2 (enExample) |
| DK (1) | DK1071442T3 (enExample) |
| ES (1) | ES2245505T3 (enExample) |
| NZ (1) | NZ507083A (enExample) |
| TW (1) | TWI233931B (enExample) |
| WO (1) | WO1999048513A1 (enExample) |
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| US6281331B1 (en) * | 1998-03-23 | 2001-08-28 | Trimeris, Inc. | Methods and compositions for peptide synthesis |
| US6469136B1 (en) * | 1999-07-07 | 2002-10-22 | Trimeris, Inc. | Methods and composition for peptide synthesis |
| ES2525317T3 (es) | 2001-06-15 | 2014-12-22 | F. Hoffmann-La Roche Ag | Producción recombinante de inhibidores de la fusión antivirales peptídicos |
| AU2003257467B2 (en) * | 2002-07-24 | 2008-02-28 | F. Hoffmann-La Roche Ag | Pegylated T20 polypeptide |
| ATE410437T1 (de) | 2003-12-31 | 2008-10-15 | Hoffmann La Roche | Verfahren und systeme zur rückgewinnung von peptiden |
| WO2005063799A2 (en) * | 2003-12-31 | 2005-07-14 | F.Hoffmann-La Roche Ag | Peptide synthesis and deprotection with co-solvent |
| DE602004009710T2 (de) | 2003-12-31 | 2008-08-07 | F. Hoffmann-La Roche Ag | Verfahren zur peptidsynthese unter verwendung einer reduzierten menge an entschützungsmittel |
| DE602005017188D1 (de) * | 2004-12-30 | 2009-11-26 | Hoffmann La Roche | Synthese des peptides t-20 aus peptidfragmenten als zwischenprodukte |
| CA2651070A1 (en) | 2006-05-03 | 2007-11-15 | Mallinckrodt Inc. | Composition and method for the release of protected peptides from a resin |
| EP2181983A4 (en) * | 2007-07-25 | 2013-01-02 | Ajinomoto Kk | METHOD FOR THE SELECTIVE REMOVAL OF A DIBENZOFULVENE DERIVATIVE |
| JP5473925B2 (ja) * | 2007-10-27 | 2014-04-16 | コーデン ファーマ コロラド インコーポレイテッド | 固相および溶液相の組み合わせ技法を使用するインスリン分泌性ペプチドの合成 |
| WO2009074483A2 (en) * | 2007-12-11 | 2009-06-18 | F. Hoffmann-La Roche Ag | Insulinotropic peptide synthesis using solid and solution phase combination techniques |
| EP2322498B1 (en) * | 2008-08-06 | 2014-04-16 | Ajinomoto Co., Inc. | Processes for removing dibenzofulvene |
| EP2349307B1 (en) * | 2008-09-03 | 2015-03-04 | ScinoPharm Taiwan, Ltd. | Process for making bivalirudin |
| US20110288235A1 (en) * | 2008-09-03 | 2011-11-24 | Scinopharm Taiwan Ltd. | Process for the Preparation of Pramlintide |
| WO2011095989A2 (en) * | 2010-02-04 | 2011-08-11 | Matrix Laboratories Ltd | An improved process for the preparation of enfuvirtide |
| PL219569B1 (pl) * | 2010-02-19 | 2015-05-29 | Peptaderm Spółka Z Ograniczoną Odpowiedzialnością | Cykliczne tetrapeptydy i ich zastosowanie |
| CN103374054B (zh) * | 2012-04-28 | 2014-12-24 | 上海第一生化药业有限公司 | 一步法固相合成多肽的方法 |
| GB201315335D0 (en) | 2013-08-29 | 2013-10-09 | Of Singapore | Amino diacids containing peptide modifiers |
| EP4100417A2 (en) * | 2020-02-05 | 2022-12-14 | Eli Lilly and Company | Resin reactors in series peptide synthesizer |
| CN114315957B (zh) * | 2021-12-30 | 2023-07-07 | 深圳瑞德林生物技术有限公司 | 一种多肽的制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1987007616A1 (en) * | 1986-06-12 | 1987-12-17 | Biogen N.V. | Peptides involved in the pathogenesis of hiv infection |
| US4787222A (en) * | 1986-11-24 | 1988-11-29 | Novatek Medical Inc. | Combination lock for blood identification system |
| US5444044A (en) * | 1992-03-26 | 1995-08-22 | New York Blood Center | Synthetic polypeptides as inhibitors of HIV-1 |
| US5464933A (en) * | 1993-06-07 | 1995-11-07 | Duke University | Synthetic peptide inhibitors of HIV transmission |
| US6479055B1 (en) * | 1993-06-07 | 2002-11-12 | Trimeris, Inc. | Methods for inhibition of membrane fusion-associated events, including respiratory syncytial virus transmission |
| CA2164505A1 (en) * | 1993-06-07 | 1994-12-22 | Phillip W. Berman | Hiv envelope polypeptides |
| RU2181379C2 (ru) * | 1993-09-11 | 2002-04-20 | Полимун Сайентифик Иммунобиологише Форшунг ГмбХ | Пептид (варианты) и способ его производства, фармацевтическое средство, антитело и способ его производства |
| KR100493795B1 (ko) * | 1996-02-09 | 2005-09-09 | 에프. 호프만-라 로슈 아게 | 혈관활성장펩타이드유사체의합성방법 |
-
1999
- 1999-03-22 ES ES99912802T patent/ES2245505T3/es not_active Expired - Lifetime
- 1999-03-22 DE DE69926061T patent/DE69926061T2/de not_active Expired - Lifetime
- 1999-03-22 CA CA002324348A patent/CA2324348C/en not_active Expired - Lifetime
- 1999-03-22 JP JP2000537561A patent/JP4602547B2/ja not_active Expired - Fee Related
- 1999-03-22 EP EP99912802A patent/EP1071442B9/en not_active Expired - Lifetime
- 1999-03-22 NZ NZ507083A patent/NZ507083A/en not_active IP Right Cessation
- 1999-03-22 WO PCT/US1999/006230 patent/WO1999048513A1/en not_active Ceased
- 1999-03-22 CN CNB998064319A patent/CN100383158C/zh not_active Expired - Fee Related
- 1999-03-22 BR BR9909018-0A patent/BR9909018A/pt not_active IP Right Cessation
- 1999-03-22 AT AT99912802T patent/ATE299029T1/de active
- 1999-03-22 DK DK99912802T patent/DK1071442T3/da active
- 1999-03-22 AU AU31097/99A patent/AU751358B2/en not_active Expired
- 1999-03-23 TW TW088104562A patent/TWI233931B/zh not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002507576A (ja) | 2002-03-12 |
| CA2324348A1 (en) | 1999-09-30 |
| CA2324348C (en) | 2006-03-14 |
| CN1303299A (zh) | 2001-07-11 |
| EP1071442A1 (en) | 2001-01-31 |
| AU3109799A (en) | 1999-10-18 |
| EP1071442B1 (en) | 2005-07-06 |
| ES2245505T3 (es) | 2006-01-01 |
| WO1999048513A1 (en) | 1999-09-30 |
| DE69926061D1 (de) | 2005-08-11 |
| CN100383158C (zh) | 2008-04-23 |
| NZ507083A (en) | 2003-10-31 |
| DE69926061T2 (de) | 2006-06-01 |
| TWI233931B (en) | 2005-06-11 |
| EP1071442B9 (en) | 2006-01-18 |
| BR9909018A (pt) | 2001-10-16 |
| JP4602547B2 (ja) | 2010-12-22 |
| ATE299029T1 (de) | 2005-07-15 |
| EP1071442A4 (en) | 2002-06-05 |
| DK1071442T3 (da) | 2005-10-24 |
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