DE69926061T2 - Verfahren und zusammensetzungen zur peptidsynthese (t-20) - Google Patents
Verfahren und zusammensetzungen zur peptidsynthese (t-20) Download PDFInfo
- Publication number
- DE69926061T2 DE69926061T2 DE69926061T DE69926061T DE69926061T2 DE 69926061 T2 DE69926061 T2 DE 69926061T2 DE 69926061 T DE69926061 T DE 69926061T DE 69926061 T DE69926061 T DE 69926061T DE 69926061 T2 DE69926061 T2 DE 69926061T2
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- Germany
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- seq
- peptide
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- fmoc
- protected peptide
- Prior art date
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- Expired - Lifetime
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- 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 title claims abstract description 156
- 238000000034 method Methods 0.000 title claims abstract description 156
- 238000010647 peptide synthesis reaction Methods 0.000 title claims description 11
- 239000000203 mixture Substances 0.000 title description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 262
- 239000012634 fragment Substances 0.000 claims abstract description 156
- 108010033276 Peptide Fragments Proteins 0.000 claims abstract description 50
- 102000007079 Peptide Fragments Human genes 0.000 claims abstract description 50
- 238000002360 preparation method Methods 0.000 claims description 46
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
- 125000006239 protecting group Chemical group 0.000 claims description 34
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 31
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 230000008569 process Effects 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 230000004048 modification Effects 0.000 claims description 10
- 238000012986 modification Methods 0.000 claims description 10
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 65
- 230000015572 biosynthetic process Effects 0.000 abstract description 62
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 55
- 239000000543 intermediate Substances 0.000 abstract description 44
- 239000007790 solid phase Substances 0.000 abstract description 25
- 239000007791 liquid phase Substances 0.000 abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 411
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 241
- 239000011347 resin Substances 0.000 description 210
- 229920005989 resin Polymers 0.000 description 210
- 239000000243 solution Substances 0.000 description 161
- 239000007787 solid Substances 0.000 description 154
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 135
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 120
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 108
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 101
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 90
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 75
- 238000006243 chemical reaction Methods 0.000 description 65
- 238000004128 high performance liquid chromatography Methods 0.000 description 60
- 238000003828 vacuum filtration Methods 0.000 description 57
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 56
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 54
- 150000001413 amino acids Chemical class 0.000 description 54
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 53
- 239000000047 product Substances 0.000 description 51
- 238000011068 loading method Methods 0.000 description 50
- 230000014759 maintenance of location Effects 0.000 description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 44
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 43
- 238000012360 testing method Methods 0.000 description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 38
- 239000012071 phase Substances 0.000 description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- 238000003756 stirring Methods 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
- 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 29
- 238000012369 In process control Methods 0.000 description 29
- 238000010965 in-process control Methods 0.000 description 29
- 239000002904 solvent Substances 0.000 description 29
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000012299 nitrogen atmosphere Substances 0.000 description 23
- 150000001875 compounds Chemical class 0.000 description 22
- 239000000463 material Substances 0.000 description 22
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 21
- 238000013459 approach Methods 0.000 description 21
- 238000001514 detection method Methods 0.000 description 19
- -1 t-butyloxycarbonyl Chemical group 0.000 description 19
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- PGTKVMVZBBZCKQ-UHFFFAOYSA-N Fulvene Chemical compound C=C1C=CC=C1 PGTKVMVZBBZCKQ-UHFFFAOYSA-N 0.000 description 17
- 238000001035 drying Methods 0.000 description 17
- 239000000523 sample Substances 0.000 description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 125000000539 amino acid group Chemical group 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 16
- 239000000725 suspension Substances 0.000 description 15
- 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 14
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 238000001556 precipitation Methods 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000010511 deprotection reaction Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- ZYASLTYCYTYKFC-UHFFFAOYSA-N 9-methylidenefluorene Chemical compound C1=CC=C2C(=C)C3=CC=CC=C3C2=C1 ZYASLTYCYTYKFC-UHFFFAOYSA-N 0.000 description 12
- 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
- 238000004821 distillation Methods 0.000 description 11
- 238000010532 solid phase synthesis reaction Methods 0.000 description 11
- 238000010268 HPLC based assay Methods 0.000 description 10
- 239000006227 byproduct Substances 0.000 description 10
- 239000012535 impurity Substances 0.000 description 10
- 238000002955 isolation Methods 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 238000006114 decarboxylation reaction Methods 0.000 description 9
- 229910052740 iodine Inorganic materials 0.000 description 9
- 239000011630 iodine Substances 0.000 description 9
- 238000010926 purge Methods 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
- 238000001665 trituration Methods 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000008878 coupling Effects 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 230000004584 weight gain Effects 0.000 description 8
- 235000019786 weight gain Nutrition 0.000 description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 7
- 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 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 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
- 230000008961 swelling Effects 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
- OBSIQMZKFXFYLV-QMMMGPOBSA-N L-phenylalanine amide Chemical compound NC(=O)[C@@H](N)CC1=CC=CC=C1 OBSIQMZKFXFYLV-QMMMGPOBSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000003275 alpha amino acid group Chemical group 0.000 description 5
- 238000013329 compounding Methods 0.000 description 5
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- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 5
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- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 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 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
- 229910004373 HOAc Inorganic materials 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 4
- 238000006640 acetylation reaction Methods 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000012047 saturated solution Substances 0.000 description 4
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- 239000003930 superacid 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
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- 230000015556 catabolic process Effects 0.000 description 3
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- 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
- 230000002194 synthesizing effect Effects 0.000 description 3
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- 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
- 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- 108010075254 C-Peptide Proteins 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
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- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 2
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- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 2
- 125000001165 hydrophobic group Chemical group 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 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 2
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- 238000002953 preparative HPLC Methods 0.000 description 2
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- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 1
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 description 1
- WDGICUODAOGOMO-DHUJRADRSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-oxo-5-(tritylamino)pentanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)CC(=O)NC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 WDGICUODAOGOMO-DHUJRADRSA-N 0.000 description 1
- DYWUPCCKOVTCFZ-LBPRGKRZSA-N (2s)-2-amino-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=C(C[C@H](N)C(O)=O)C2=C1 DYWUPCCKOVTCFZ-LBPRGKRZSA-N 0.000 description 1
- PFRGGOIBYLYVKM-UHFFFAOYSA-N 15alpha-hydroxylup-20(29)-en-3-one Natural products CC(=C)C1CCC2(C)CC(O)C3(C)C(CCC4C5(C)CCC(=O)C(C)(C)C5CCC34C)C12 PFRGGOIBYLYVKM-UHFFFAOYSA-N 0.000 description 1
- 241001307241 Althaea Species 0.000 description 1
- 235000006576 Althaea officinalis Nutrition 0.000 description 1
- 101100189378 Caenorhabditis elegans pat-3 gene Proteins 0.000 description 1
- 101100232929 Caenorhabditis elegans pat-4 gene Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 101001094044 Mus musculus Solute carrier family 26 member 6 Proteins 0.000 description 1
- HDAXUHAUNCRXAE-UHFFFAOYSA-N N1CCCCC1.C(C1=CC=CC=C1)C1=CC=CC1=C Chemical compound N1CCCCC1.C(C1=CC=CC=C1)C1=CC=CC1=C HDAXUHAUNCRXAE-UHFFFAOYSA-N 0.000 description 1
- 108091081062 Repeated sequence (DNA) Proteins 0.000 description 1
- SOKRNBGSNZXYIO-UHFFFAOYSA-N Resinone Natural products CC(=C)C1CCC2(C)C(O)CC3(C)C(CCC4C5(C)CCC(=O)C(C)(C)C5CCC34C)C12 SOKRNBGSNZXYIO-UHFFFAOYSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 238000010420 art technique Methods 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 239000012468 concentrated sample Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- MBCZNRXYDIFUJF-UHFFFAOYSA-N fulvene;piperidine Chemical compound C=C1C=CC=C1.C1CCNCC1 MBCZNRXYDIFUJF-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003292 glue 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
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 235000001035 marshmallow Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- 230000009466 transformation Effects 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—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 |
| US45920 | 1998-03-23 | ||
| US09/071,877 US6015881A (en) | 1998-03-23 | 1998-05-01 | Methods and compositions for peptide synthesis |
| US71877 | 1998-05-01 | ||
| PCT/US1999/006230 WO1999048513A1 (en) | 1998-03-23 | 1999-03-22 | Methods and compositions for peptide synthesis |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69926061D1 DE69926061D1 (de) | 2005-08-11 |
| DE69926061T2 true DE69926061T2 (de) | 2006-06-01 |
Family
ID=26723345
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69926061T Expired - Lifetime DE69926061T2 (de) | 1998-03-23 | 1999-03-22 | Verfahren und zusammensetzungen zur peptidsynthese (t-20) |
Country Status (13)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| DE602004017057D1 (de) | 2003-12-31 | 2008-11-20 | Hoffmann La Roche | Verfahren und systeme zur rückgewinnung von peptiden |
| EP1701976A2 (en) * | 2003-12-31 | 2006-09-20 | F.Hoffmann-La Roche Ag | Peptide synthesis and deprotection with co-solvent |
| EP1701969B1 (en) | 2003-12-31 | 2007-10-24 | F.Hoffmann-La Roche Ag | Process for peptide synthesis using a reduced amount of deprotection agent |
| CA2592438C (en) * | 2004-12-30 | 2013-09-03 | F.Hoffmann-La Roche Ag | Synthesis of peptide t-20 using peptide intermediate fragments |
| CA2651070A1 (en) | 2006-05-03 | 2007-11-15 | Mallinckrodt Inc. | Composition and method for the release of protected peptides from a resin |
| WO2009014177A1 (ja) * | 2007-07-25 | 2009-01-29 | Ajinomoto Co., Inc. | ジベンゾフルベン誘導体の淘汰方法 |
| 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 |
| AU2008334783A1 (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 |
| US20110288235A1 (en) * | 2008-09-03 | 2011-11-24 | Scinopharm Taiwan Ltd. | Process for the Preparation of Pramlintide |
| AU2009288036A1 (en) * | 2008-09-03 | 2010-03-11 | 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 |
| CA3167047A1 (en) * | 2020-02-05 | 2021-08-12 | Martin D. Johnson | Three 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 |
Family Cites Families (8)
| 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 |
| US6479055B1 (en) * | 1993-06-07 | 2002-11-12 | Trimeris, Inc. | Methods for inhibition of membrane fusion-associated events, including respiratory syncytial virus transmission |
| EP0708659A4 (en) * | 1993-06-07 | 2000-08-23 | Genentech Inc | HIV ENVELOPE POLYPEPTIDE |
| US5464933A (en) * | 1993-06-07 | 1995-11-07 | Duke University | Synthetic peptide inhibitors of HIV transmission |
| JPH09502348A (ja) * | 1993-09-11 | 1997-03-11 | ポリムン・シエンティフィーク・イムノビオロギッシェ・フォルシュング・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | 遺伝学的に分岐したｈｉｖ−１株に対する中和抗体を誘導するペプチド |
| AU722895B2 (en) * | 1996-02-09 | 2000-08-10 | F. Hoffmann-La Roche Ag | Synthesis of VIP analog |
-
1999
- 1999-03-22 DE DE69926061T patent/DE69926061T2/de not_active Expired - Lifetime
- 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 CN CNB998064319A patent/CN100383158C/zh not_active Expired - Fee Related
- 1999-03-22 AU AU31097/99A patent/AU751358B2/en not_active Expired
- 1999-03-22 CA CA002324348A patent/CA2324348C/en not_active Expired - Lifetime
- 1999-03-22 ES ES99912802T patent/ES2245505T3/es not_active Expired - Lifetime
- 1999-03-22 AT AT99912802T patent/ATE299029T1/de active
- 1999-03-22 DK DK99912802T patent/DK1071442T3/da active
- 1999-03-22 BR BR9909018-0A patent/BR9909018A/pt not_active IP Right Cessation
- 1999-03-22 WO PCT/US1999/006230 patent/WO1999048513A1/en not_active Ceased
- 1999-03-22 JP JP2000537561A patent/JP4602547B2/ja not_active Expired - Fee Related
- 1999-03-23 TW TW088104562A patent/TWI233931B/zh not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU751358B2 (en) | 2002-08-15 |
| NZ507083A (en) | 2003-10-31 |
| ES2245505T3 (es) | 2006-01-01 |
| CN100383158C (zh) | 2008-04-23 |
| TWI233931B (en) | 2005-06-11 |
| AU3109799A (en) | 1999-10-18 |
| ATE299029T1 (de) | 2005-07-15 |
| WO1999048513A1 (en) | 1999-09-30 |
| JP4602547B2 (ja) | 2010-12-22 |
| JP2002507576A (ja) | 2002-03-12 |
| DK1071442T3 (da) | 2005-10-24 |
| CN1303299A (zh) | 2001-07-11 |
| EP1071442A4 (en) | 2002-06-05 |
| EP1071442B1 (en) | 2005-07-06 |
| EP1071442B9 (en) | 2006-01-18 |
| CA2324348A1 (en) | 1999-09-30 |
| EP1071442A1 (en) | 2001-01-31 |
| DE69926061D1 (de) | 2005-08-11 |
| CA2324348C (en) | 2006-03-14 |
| BR9909018A (pt) | 2001-10-16 |
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| 8364 | No opposition during term of opposition |