NO329561B1

NO329561B1 - Forbindelser som er analoger av ET-743, farmasoytiske preparater som omfatter en slik forbindelse, og anvendelse av forbindelsene til fremstilling av farmasoytiske preparater for anvendelse ved behandling av tumorer

Forbindelser som er analoger av ET-743, farmasoytiske preparater som omfatter en slik forbindelse, og anvendelse av forbindelsene til fremstilling av farmasoytiske preparater for anvendelse ved behandling av tumorer Download PDF

Info

Publication number: NO329561B1
Authority: NO; Norway
Prior art keywords: alkyl; compound according; alkenyl; group; mmol
Prior art date: 1999-05-14

Application number

NO20025445A

Other languages

English (en)

Norwegian (no)

Other versions

NO20025445D0 (no

NO20025445L (no

Inventor

Carmen Cuevas

Ignacio Manzanares

Marta Perez

Maria Jesus Martin

Simon Munt

Alberto Rodriguez

Original Assignee

Pharma Mar Sa

Priority date

1999-05-14

Filing date

2002-11-14

Publication date

2010-11-15

1999-08-02 Priority claimed from GBGB9918178.6A external-priority patent/GB9918178D0/en

2000-05-15 Priority claimed from PCT/GB2000/001852 external-priority patent/WO2000069862A2/en

2002-11-14 Application filed by Pharma Mar Sa filed Critical Pharma Mar Sa

2002-11-14 Publication of NO20025445D0 publication Critical patent/NO20025445D0/no

2003-01-14 Publication of NO20025445L publication Critical patent/NO20025445L/no

2010-11-15 Publication of NO329561B1 publication Critical patent/NO329561B1/no

Links

150000001875 compounds Chemical class 0.000 title claims description 235
238000002360 preparation method Methods 0.000 title claims description 21
239000000825 pharmaceutical preparation Substances 0.000 title claims description 9
206010028980 Neoplasm Diseases 0.000 title claims description 8
PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 title description 24
229960000977 trabectedin Drugs 0.000 title description 17
XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 title description 12
239000008194 pharmaceutical composition Substances 0.000 title 1
-1 cinnamoyl Chemical group 0.000 claims description 118
125000004432 carbon atom Chemical group C* 0.000 claims description 80
125000000217 alkyl group Chemical group 0.000 claims description 46
125000003342 alkenyl group Chemical group 0.000 claims description 40
235000001014 amino acid Nutrition 0.000 claims description 32
229910052739 hydrogen Inorganic materials 0.000 claims description 31
125000003118 aryl group Chemical group 0.000 claims description 30
239000001257 hydrogen Substances 0.000 claims description 28
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 17
125000001072 heteroaryl group Chemical group 0.000 claims description 15
125000003710 aryl alkyl group Chemical group 0.000 claims description 14
150000001413 amino acids Chemical class 0.000 claims description 13
229910052760 oxygen Inorganic materials 0.000 claims description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 10
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims description 9
125000005842 heteroatom Chemical group 0.000 claims description 9
229910052757 nitrogen Inorganic materials 0.000 claims description 9
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
125000000753 cycloalkyl group Chemical group 0.000 claims description 8
ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
229910052717 sulfur Inorganic materials 0.000 claims description 8
COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 7
KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 7
KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 7
150000001944 cysteine derivatives Chemical class 0.000 claims description 7
COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 7
239000004474 valine Substances 0.000 claims description 7
239000004475 Arginine Substances 0.000 claims description 6
QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 6
QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 6
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 6
QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims description 6
235000004279 alanine Nutrition 0.000 claims description 6
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 6
235000018417 cysteine Nutrition 0.000 claims description 5
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 5
125000005018 aryl alkenyl group Chemical group 0.000 claims description 4
239000004305 biphenyl Substances 0.000 claims description 4
235000010290 biphenyl Nutrition 0.000 claims description 4
125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
125000001624 naphthyl group Chemical group 0.000 claims description 4
125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims description 3
125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
KTHDTJVBEPMMGL-VKHMYHEASA-N N-acetyl-L-alanine Chemical compound OC(=O)[C@H](C)NC(C)=O KTHDTJVBEPMMGL-VKHMYHEASA-N 0.000 claims description 2
150000003839 salts Chemical class 0.000 claims description 2
DNEIVOAPNFMSEC-NRFANRHFSA-N CC(C)(C)[Si](C)(C)N[C@@H](CSOCC1C(C=CC=C2)=C2C2=CC=CC=C12)C(O)=O Chemical compound CC(C)(C)[Si](C)(C)N[C@@H](CSOCC1C(C=CC=C2)=C2C2=CC=CC=C12)C(O)=O DNEIVOAPNFMSEC-NRFANRHFSA-N 0.000 claims 1
241000102542 Kara Species 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 784
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 525
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 336
235000019439 ethyl acetate Nutrition 0.000 description 332
239000000243 solution Substances 0.000 description 307
238000005481 NMR spectroscopy Methods 0.000 description 242
239000000460 chlorine Substances 0.000 description 219
239000011541 reaction mixture Substances 0.000 description 172
239000007787 solid Substances 0.000 description 155
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 146
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 141
239000012044 organic layer Substances 0.000 description 139
238000003818 flash chromatography Methods 0.000 description 135
229910004298 SiO 2 Inorganic materials 0.000 description 115
230000002829 reductive effect Effects 0.000 description 107
238000006243 chemical reaction Methods 0.000 description 106
239000002904 solvent Substances 0.000 description 104
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 102
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 95
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 93
229910000041 hydrogen chloride Inorganic materials 0.000 description 93
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 81
239000011734 sodium Substances 0.000 description 78
239000000203 mixture Substances 0.000 description 71
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 65
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 64
229910052938 sodium sulfate Inorganic materials 0.000 description 61
235000011152 sodium sulphate Nutrition 0.000 description 61
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 58
238000000034 method Methods 0.000 description 55
239000000543 intermediate Substances 0.000 description 52
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 51
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 50
238000012546 transfer Methods 0.000 description 50
229920006395 saturated elastomer Polymers 0.000 description 45
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 42
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
125000002887 hydroxy group Chemical group [H]O* 0.000 description 31
230000015572 biosynthetic process Effects 0.000 description 29
239000007858 starting material Substances 0.000 description 29
ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 27
JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 25
229960000549 4-dimethylaminophenol Drugs 0.000 description 25
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 25
101710134784 Agnoprotein Proteins 0.000 description 25
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical group O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 24
235000017557 sodium bicarbonate Nutrition 0.000 description 24
229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
229940024606 amino acid Drugs 0.000 description 23
239000012267 brine Substances 0.000 description 23
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
125000002252 acyl group Chemical group 0.000 description 21
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
229930190585 Saframycin Natural products 0.000 description 18
QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 18
230000008569 process Effects 0.000 description 18
238000000746 purification Methods 0.000 description 18
125000001424 substituent group Chemical group 0.000 description 16
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 15
239000012346 acetyl chloride Substances 0.000 description 15
125000006239 protecting group Chemical group 0.000 description 15
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
GKUZBRIJGIGFKC-UHFFFAOYSA-N Safracin B Natural products OC1C(N2C)CC3=CC(C)=C(OC)C(O)=C3C2C(C2)N1C(CNC(=O)C(C)N)C1=C2C(=O)C(C)=C(OC)C1=O GKUZBRIJGIGFKC-UHFFFAOYSA-N 0.000 description 14
GKUZBRIJGIGFKC-XPXFATIHSA-N antibiotic em 5519 Chemical compound C([C@@H](N1C)[C@@H]2O)C3=CC(C)=C(OC)C(O)=C3[C@H]1[C@H](C1)N2[C@@H](CNC(=O)[C@H](C)N)C2=C1C(=O)C(C)=C(OC)C2=O GKUZBRIJGIGFKC-XPXFATIHSA-N 0.000 description 14
238000004519 manufacturing process Methods 0.000 description 14
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 13
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
125000003277 amino group Chemical group 0.000 description 12
JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 12
239000012043 crude product Substances 0.000 description 12
125000004122 cyclic group Chemical group 0.000 description 12
239000003814 drug Substances 0.000 description 12
235000010633 broth Nutrition 0.000 description 11
229940079593 drug Drugs 0.000 description 11
238000000605 extraction Methods 0.000 description 11
239000000047 product Substances 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
150000001408 amides Chemical class 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 10
239000000284 extract Substances 0.000 description 10
SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 10
229910001868 water Inorganic materials 0.000 description 10
150000002367 halogens Chemical class 0.000 description 9
239000013067 intermediate product Substances 0.000 description 9
239000012074 organic phase Substances 0.000 description 9
229940117953 phenylisothiocyanate Drugs 0.000 description 9
239000012047 saturated solution Substances 0.000 description 9
238000003786 synthesis reaction Methods 0.000 description 9
QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 8
229930183496 Safracin Natural products 0.000 description 8
230000010933 acylation Effects 0.000 description 8
238000005917 acylation reaction Methods 0.000 description 8
239000012298 atmosphere Substances 0.000 description 8
JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 8
PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
229910052736 halogen Inorganic materials 0.000 description 8
125000000623 heterocyclic group Chemical group 0.000 description 8
239000002609 medium Substances 0.000 description 8
238000003756 stirring Methods 0.000 description 8
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 7
WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 7
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 7
125000003545 alkoxy group Chemical group 0.000 description 7
239000007864 aqueous solution Substances 0.000 description 7
DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 7
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
229910000024 caesium carbonate Inorganic materials 0.000 description 7
125000004093 cyano group Chemical group *C#N 0.000 description 7
239000012467 final product Substances 0.000 description 7
238000004128 high performance liquid chromatography Methods 0.000 description 7
238000006722 reduction reaction Methods 0.000 description 7
229930188681 renieramycin Natural products 0.000 description 7
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 7
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
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
229930195725 Mannitol Natural products 0.000 description 6
241000243142 Porifera Species 0.000 description 6
WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 6
230000002378 acidificating effect Effects 0.000 description 6
UMGDCJDMYOKAJW-UHFFFAOYSA-N aminothiocarboxamide Natural products NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
125000005110 aryl thio group Chemical group 0.000 description 6
239000000287 crude extract Substances 0.000 description 6
230000007062 hydrolysis Effects 0.000 description 6
238000006460 hydrolysis reaction Methods 0.000 description 6
239000010410 layer Substances 0.000 description 6
239000000594 mannitol Substances 0.000 description 6
235000010355 mannitol Nutrition 0.000 description 6
239000012071 phase Substances 0.000 description 6
229960005190 phenylalanine Drugs 0.000 description 6
230000009467 reduction Effects 0.000 description 6
JNEGMBHBUAJRSX-SHUHUVMISA-N saframycin a Chemical class C([C@H](N1C)[C@@H]2C#N)C(C(C(C)=C(OC)C3=O)=O)=C3[C@@H]1[C@H](C1)N2[C@@H](CNC(=O)C(C)=O)C2=C1C(=O)C(C)=C(OC)C2=O JNEGMBHBUAJRSX-SHUHUVMISA-N 0.000 description 6
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
239000000725 suspension Substances 0.000 description 6
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 6
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 5
ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 5
241000187389 Streptomyces lavendulae Species 0.000 description 5
229960003121 arginine Drugs 0.000 description 5
239000012300 argon atmosphere Substances 0.000 description 5
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