TWI248941B - Selective cyclic peptides - Google Patents

Info

Publication number

TWI248941B

TWI248941B TW090121400A TW90121400A TWI248941B TW I248941 B TWI248941 B TW I248941B TW 090121400 A TW090121400 A TW 090121400A TW 90121400 A TW90121400 A TW 90121400A TW I248941 B TWI248941 B TW I248941B

Authority

TW

Taiwan

Prior art keywords

lys

hydrogen

asp

trp

arg

Prior art date

2000-08-30

Links

• Espacenet
• Global Dossier
• Discuss

• 102000001189 Cyclic Peptides Human genes 0.000 title description 10
• 108010069514 Cyclic Peptides Proteins 0.000 title description 10
• 150000001875 compounds Chemical class 0.000 claims abstract description 196
• 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 122
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 120
• 239000001257 hydrogen Substances 0.000 claims abstract description 119
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 88
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 81
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 58
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 52
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 36
• 150000003839 salts Chemical class 0.000 claims abstract description 28
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 20
• 230000000694 effects Effects 0.000 claims abstract description 19
• 208000008589 Obesity Diseases 0.000 claims abstract description 13
• 235000020824 obesity Nutrition 0.000 claims abstract description 13
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 12
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
• 229910052727 yttrium Inorganic materials 0.000 claims abstract description 5
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
• 150000002431 hydrogen Chemical group 0.000 claims abstract 20
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 290
• 229910001868 water Inorganic materials 0.000 claims description 178
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 161
• 238000000034 method Methods 0.000 claims description 76
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 42
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 39
• 239000011734 sodium Substances 0.000 claims description 30
• 108010092854 aspartyllysine Proteins 0.000 claims description 19
• OAMLVOVXNKILLQ-BQBZGAKWSA-N Asp-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O OAMLVOVXNKILLQ-BQBZGAKWSA-N 0.000 claims description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 10
• 229910052736 halogen Inorganic materials 0.000 claims description 10
• 150000002367 halogens Chemical class 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 239000000908 ammonium hydroxide Substances 0.000 claims description 9
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 229910052757 nitrogen Inorganic materials 0.000 claims description 9
• KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 8
• 229910052707 ruthenium Inorganic materials 0.000 claims description 8
• 230000001919 adrenal effect Effects 0.000 claims description 7
• XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical group C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims description 7
• YQNBKXUTWBRQCS-BVSLBCMMSA-N Phe-Arg-Trp Chemical compound C([C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)C1=CC=CC=C1 YQNBKXUTWBRQCS-BVSLBCMMSA-N 0.000 claims description 6
• 229910052708 sodium Inorganic materials 0.000 claims description 6
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
• 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 5
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
• 239000005711 Benzoic acid Substances 0.000 claims description 3
• 239000013543 active substance Substances 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• 108091008039 hormone receptors Proteins 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 229910052762 osmium Chemical group 0.000 claims description 3
• SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical group [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 3
• 230000002265 prevention Effects 0.000 claims description 3
• OABOXRPGTFRBFZ-IMJSIDKUSA-N Cys-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(O)=O OABOXRPGTFRBFZ-IMJSIDKUSA-N 0.000 claims 2
• 108010004073 cysteinylcysteine Proteins 0.000 claims 2
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims 2
• QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 claims 1
• 229940076279 serotonin Drugs 0.000 claims 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 1
• 102000004196 processed proteins & peptides Human genes 0.000 abstract description 29
• 102000001796 Melanocortin 4 receptors Human genes 0.000 abstract description 14
• 108010021436 Type 4 Melanocortin Receptor Proteins 0.000 abstract description 14
• 239000000556 agonist Substances 0.000 abstract description 6
• BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 abstract description 5
• 125000001475 halogen functional group Chemical group 0.000 abstract 2
• 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 451
• 235000019439 ethyl acetate Nutrition 0.000 description 223
• 238000006243 chemical reaction Methods 0.000 description 205
• 239000000243 solution Substances 0.000 description 159
• 239000000203 mixture Substances 0.000 description 155
• 239000011347 resin Substances 0.000 description 146
• 229920005989 resin Polymers 0.000 description 146
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 116
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 114
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 105
• 239000011541 reaction mixture Substances 0.000 description 105
• -1 5- Methoxy-2-aminotetrahydroanthracene-2-carboxylic acid Chemical compound 0.000 description 102
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 93
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 91
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 86
• 238000004128 high performance liquid chromatography Methods 0.000 description 81
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
• 235000001014 amino acid Nutrition 0.000 description 67
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
• 150000001413 amino acids Chemical class 0.000 description 66
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
• 239000010410 layer Substances 0.000 description 61
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 53
• 238000005859 coupling reaction Methods 0.000 description 53
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 52
• 238000005481 NMR spectroscopy Methods 0.000 description 52
• 239000002904 solvent Substances 0.000 description 52
• 239000012267 brine Substances 0.000 description 49
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 49
• 239000007787 solid Substances 0.000 description 49
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 47
• 230000008878 coupling Effects 0.000 description 46
• 238000010168 coupling process Methods 0.000 description 46
• 238000002360 preparation method Methods 0.000 description 46
• 239000000284 extract Substances 0.000 description 44
• 238000000746 purification Methods 0.000 description 44
• 239000012043 crude product Substances 0.000 description 41
• 239000002244 precipitate Substances 0.000 description 40
• 239000000872 buffer Substances 0.000 description 39
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 37
• 239000002253 acid Substances 0.000 description 37
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 36
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• 238000001914 filtration Methods 0.000 description 34
• 239000012442 inert solvent Substances 0.000 description 33
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 32
• 239000003921 oil Substances 0.000 description 31
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 30
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 30
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
• 125000006239 protecting group Chemical group 0.000 description 30
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
• 238000003818 flash chromatography Methods 0.000 description 29
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
• 239000002585 base Substances 0.000 description 28
• 239000000047 product Substances 0.000 description 28
• 239000000725 suspension Substances 0.000 description 28
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
• QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 25
• 238000007363 ring formation reaction Methods 0.000 description 25
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
• 239000000706 filtrate Substances 0.000 description 24
• ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 23
• 239000001099 ammonium carbonate Substances 0.000 description 23
• 235000012501 ammonium carbonate Nutrition 0.000 description 23
• UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 23
• 239000012044 organic layer Substances 0.000 description 23
• 238000010992 reflux Methods 0.000 description 23
• 229910052938 sodium sulfate Inorganic materials 0.000 description 23
• 235000011152 sodium sulphate Nutrition 0.000 description 23
• 238000010532 solid phase synthesis reaction Methods 0.000 description 23
• 238000004364 calculation method Methods 0.000 description 22
• 239000005457 ice water Substances 0.000 description 22
• 239000000463 material Substances 0.000 description 22
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 21
• 238000004440 column chromatography Methods 0.000 description 21
• NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 21
• 230000015572 biosynthetic process Effects 0.000 description 20
• 238000010586 diagram Methods 0.000 description 19
• 239000007789 gas Substances 0.000 description 19
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 18
• VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 18
• 229910052796 boron Inorganic materials 0.000 description 17
• 239000003153 chemical reaction reagent Substances 0.000 description 17
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
• 235000019341 magnesium sulphate Nutrition 0.000 description 17
• 238000003786 synthesis reaction Methods 0.000 description 17
• 238000005406 washing Methods 0.000 description 17
• QTWZCODKTSUZJN-LJAQVGFWSA-N (2s)-5-[[amino-[(2,2,5,7,8-pentamethyl-3,4-dihydrochromen-6-yl)sulfonylamino]methylidene]amino]-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)N[C@H](C(O)=O)CCCN=C(N)NS(=O)(=O)C(C(C)=C1C)=C(C)C2=C1OC(C)(C)CC2 QTWZCODKTSUZJN-LJAQVGFWSA-N 0.000 description 16
• DHBXNPKRAUYBTH-UHFFFAOYSA-N 1,1-ethanedithiol Chemical compound CC(S)S DHBXNPKRAUYBTH-UHFFFAOYSA-N 0.000 description 16
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 16
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
• 239000011521 glass Substances 0.000 description 16
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 16
• IHWDSEPNZDYMNF-UHFFFAOYSA-N 1H-indol-2-amine Chemical compound C1=CC=C2NC(N)=CC2=C1 IHWDSEPNZDYMNF-UHFFFAOYSA-N 0.000 description 15
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 15
• 238000003756 stirring Methods 0.000 description 15
• 238000004458 analytical method Methods 0.000 description 14
• 238000001816 cooling Methods 0.000 description 14
• 238000002953 preparative HPLC Methods 0.000 description 14
• 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 description 13
• BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 13
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
• 125000003277 amino group Chemical group 0.000 description 13
• 239000007864 aqueous solution Substances 0.000 description 13
• 239000007822 coupling agent Substances 0.000 description 13
• BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 13
• MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 13
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 12
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 238000009835 boiling Methods 0.000 description 12
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
• 239000010779 crude oil Substances 0.000 description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
• 239000000843 powder Substances 0.000 description 12
• 238000004809 thin layer chromatography Methods 0.000 description 12
• FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 11
• 239000000839 emulsion Substances 0.000 description 11
• 229920001184 polypeptide Polymers 0.000 description 11
• 241000894007 species Species 0.000 description 11
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
• 230000002378 acidificating effect Effects 0.000 description 10
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
• 235000015165 citric acid Nutrition 0.000 description 10
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
• 238000010265 fast atom bombardment Methods 0.000 description 10
• 238000006460 hydrolysis reaction Methods 0.000 description 10
• 238000000926 separation method Methods 0.000 description 10
• 239000002002 slurry Substances 0.000 description 10
• 239000007858 starting material Substances 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical compound NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 9
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
• 238000007605 air drying Methods 0.000 description 9
• 235000011114 ammonium hydroxide Nutrition 0.000 description 9
• 238000001514 detection method Methods 0.000 description 9
• 239000002243 precursor Substances 0.000 description 9
• 229910000029 sodium carbonate Inorganic materials 0.000 description 9
• COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 9
• WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 8
• 238000005160 1H NMR spectroscopy Methods 0.000 description 8
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 8
• 150000001241 acetals Chemical group 0.000 description 8
• 239000003054 catalyst Substances 0.000 description 8
• 239000003795 chemical substances by application Substances 0.000 description 8
• 239000013058 crude material Substances 0.000 description 8
• 230000007062 hydrolysis Effects 0.000 description 8
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