HRP20040653A2 - Aza-arylpiperazines - Google Patents

Info

Publication number

HRP20040653A2

HRP20040653A2 HR20040653A HRP20040653A HRP20040653A2 HR P20040653 A2 HRP20040653 A2 HR P20040653A2 HR 20040653 A HR20040653 A HR 20040653A HR P20040653 A HRP20040653 A HR P20040653A HR P20040653 A2 HRP20040653 A2 HR P20040653A2

Authority

HR

Croatia

Prior art keywords

methyl

triaza

fluorene

hexahydro

tert

Prior art date

2002-01-29

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 claims description 297
• -1 hydroxyalkoxyalkyl Chemical group 0.000 claims description 118
• 238000000034 method Methods 0.000 claims description 109
• 206010012601 diabetes mellitus Diseases 0.000 claims description 72
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 66
• 125000000217 alkyl group Chemical group 0.000 claims description 64
• 238000011282 treatment Methods 0.000 claims description 55
• 239000001257 hydrogen Substances 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 51
• 229940086609 Lipase inhibitor Drugs 0.000 claims description 37
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 33
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 32
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
• 238000006243 chemical reaction Methods 0.000 claims description 29
• AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 28
• 239000003814 drug Substances 0.000 claims description 27
• 229960001243 orlistat Drugs 0.000 claims description 26
• 208000035475 disorder Diseases 0.000 claims description 25
• 150000003839 salts Chemical class 0.000 claims description 25
• 238000004519 manufacturing process Methods 0.000 claims description 21
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
• 229940079593 drug Drugs 0.000 claims description 19
• 208000008589 Obesity Diseases 0.000 claims description 18
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 18
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 235000020824 obesity Nutrition 0.000 claims description 18
• 125000006239 protecting group Chemical group 0.000 claims description 18
• 230000009467 reduction Effects 0.000 claims description 18
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
• 230000002265 prevention Effects 0.000 claims description 16
• 238000011321 prophylaxis Methods 0.000 claims description 16
• 150000002148 esters Chemical class 0.000 claims description 15
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 15
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
• 125000001188 haloalkyl group Chemical group 0.000 claims description 13
• 229910052736 halogen Inorganic materials 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 13
• 201000001421 hyperglycemia Diseases 0.000 claims description 13
• 208000002249 Diabetes Complications Diseases 0.000 claims description 12
• 206010012655 Diabetic complications Diseases 0.000 claims description 12
• 206010022489 Insulin Resistance Diseases 0.000 claims description 12
• 208000016222 Pancreatic disease Diseases 0.000 claims description 12
• 150000003431 steroids Chemical class 0.000 claims description 12
• 150000001721 carbon Chemical group 0.000 claims description 11
• 229910052799 carbon Inorganic materials 0.000 claims description 11
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000005080 alkoxycarbonylalkenyl group Chemical group 0.000 claims description 8
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• 230000003542 behavioural effect Effects 0.000 claims description 8
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
• 241000282414 Homo sapiens Species 0.000 claims description 7
• 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 claims description 7
• 201000010064 diabetes insipidus Diseases 0.000 claims description 7
• 201000010099 disease Diseases 0.000 claims description 7
• 239000012453 solvate Substances 0.000 claims description 7
• VFLUBEQSNNICTK-WCABBAIRSA-N (1s)-1-[(5ar,9r)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazin-2-yl]ethanol Chemical compound C1NC[C@@H](C)N2C3=NC([C@@H](O)C)=CC=C3C[C@@H]21 VFLUBEQSNNICTK-WCABBAIRSA-N 0.000 claims description 6
• RWHZKUHKJJABFU-VXNVDRBHSA-N (5ar,9r)-2-bromo-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(Br)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 RWHZKUHKJJABFU-VXNVDRBHSA-N 0.000 claims description 6
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
• 208000018522 Gastrointestinal disease Diseases 0.000 claims description 5
• 208000015114 central nervous system disease Diseases 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
• YCGIBRPJFAKJEZ-MWLCHTKSSA-N (5ar,9r)-2,9-dimethyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(C)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 YCGIBRPJFAKJEZ-MWLCHTKSSA-N 0.000 claims description 4
• LJRLAJVWAFFRLV-IAQYHMDHSA-N (5ar,9r)-2-(cyclopropylmethoxymethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C([C@@H]1CNC[C@H](N1C1=N2)C)C1=CC=C2COCC1CC1 LJRLAJVWAFFRLV-IAQYHMDHSA-N 0.000 claims description 4
• IACZCHZSSZAVGU-VXNVDRBHSA-N (5ar,9r)-2-(difluoromethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(C(F)F)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 IACZCHZSSZAVGU-VXNVDRBHSA-N 0.000 claims description 4
• PYJAIOOKUMKWAJ-LDYMZIIASA-N (5ar,9r)-2-(fluoromethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(CF)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 PYJAIOOKUMKWAJ-LDYMZIIASA-N 0.000 claims description 4
• AUVNCNYPOJVIRZ-BXKDBHETSA-N (5ar,9r)-2-(methoxymethyl)-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC(COC)=CC=C3C[C@@H]21 AUVNCNYPOJVIRZ-BXKDBHETSA-N 0.000 claims description 4
• HBPFKRQLQBROKQ-TYNCELHUSA-N (5ar,9r)-2-[(1s)-1-(cyclopropylmethoxy)ethyl]-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound O([C@@H](C)C=1N=C2N3[C@H](C)CNC[C@H]3CC2=CC=1)CC1CC1 HBPFKRQLQBROKQ-TYNCELHUSA-N 0.000 claims description 4
• OZKJKXGCRKEWKL-NTZNESFSSA-N (5ar,9r)-2-[(1s)-1-ethoxyethyl]-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC([C@H](C)OCC)=CC=C3C[C@@H]21 OZKJKXGCRKEWKL-NTZNESFSSA-N 0.000 claims description 4
• SAODIZUAXCAGTK-JFGNBEQYSA-N (5ar,9r)-2-[(1s)-1-methoxyethyl]-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1NC[C@@H](C)N2C3=NC([C@H](C)OC)=CC=C3C[C@@H]21 SAODIZUAXCAGTK-JFGNBEQYSA-N 0.000 claims description 4
• PKOPGQYFQBKBPB-VXNVDRBHSA-N (5ar,9r)-2-chloro-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(Cl)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 PKOPGQYFQBKBPB-VXNVDRBHSA-N 0.000 claims description 4
• ZRNVRGJQVCODRO-BXKDBHETSA-N (5ar,9r)-2-cyclopropyl-9-methyl-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C([C@@H]1CNC[C@H](N1C1=N2)C)C1=CC=C2C1CC1 ZRNVRGJQVCODRO-BXKDBHETSA-N 0.000 claims description 4
• CTPWPURTEYFXDP-VXNVDRBHSA-N (5ar,9r)-9-methyl-2-(trifluoromethyl)-5,5a,6,7,8,9-hexahydropyrido[1,2]pyrrolo[4,5-a]pyrazine Chemical compound C1=C(C(F)(F)F)N=C2N3[C@H](C)CNC[C@H]3CC2=C1 CTPWPURTEYFXDP-VXNVDRBHSA-N 0.000 claims description 4
• GVCOTWGEKWXLPZ-SECBINFHSA-N (9r)-2,9-dimethyl-6,7,8,9-tetrahydropyrido[3,4]pyrrolo[3,5-a]pyrazine Chemical compound C1=C(C)N=C2N3[C@H](C)CNCC3=CC2=C1 GVCOTWGEKWXLPZ-SECBINFHSA-N 0.000 claims description 4
• MMOQJRSPKZSHHF-SSDOTTSWSA-N (9r)-2-chloro-5,9-dimethyl-6,7,8,9-tetrahydropyrido[3,4]pyrrolo[3,5-a]pyrazine Chemical compound C1=C(Cl)N=C2N3[C@H](C)CNCC3=C(C)C2=C1 MMOQJRSPKZSHHF-SSDOTTSWSA-N 0.000 claims description 4
• 102000056834 5-HT2 Serotonin Receptors Human genes 0.000 claims description 4
• 108091005479 5-HT2 receptors Proteins 0.000 claims description 4
• 206010001488 Aggression Diseases 0.000 claims description 4
• 208000000103 Anorexia Nervosa Diseases 0.000 claims description 4
• 208000019901 Anxiety disease Diseases 0.000 claims description 4
• 208000020925 Bipolar disease Diseases 0.000 claims description 4
• 208000032841 Bulimia Diseases 0.000 claims description 4
• 206010006550 Bulimia nervosa Diseases 0.000 claims description 4
• 206010012289 Dementia Diseases 0.000 claims description 4
• 208000030814 Eating disease Diseases 0.000 claims description 4
• 208000019454 Feeding and Eating disease Diseases 0.000 claims description 4
• 206010019233 Headaches Diseases 0.000 claims description 4
• 206010022773 Intracranial pressure increased Diseases 0.000 claims description 4
• 208000026139 Memory disease Diseases 0.000 claims description 4
• 201000009906 Meningitis Diseases 0.000 claims description 4
• 208000019695 Migraine disease Diseases 0.000 claims description 4
• 208000027626 Neurocognitive disease Diseases 0.000 claims description 4
• 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 4
• 208000002193 Pain Diseases 0.000 claims description 4
• 206010036618 Premenstrual syndrome Diseases 0.000 claims description 4
• 208000028017 Psychotic disease Diseases 0.000 claims description 4
• 201000001880 Sexual dysfunction Diseases 0.000 claims description 4
• 206010041250 Social phobia Diseases 0.000 claims description 4
• 208000006011 Stroke Diseases 0.000 claims description 4
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 4
• 125000005081 alkoxyalkoxyalkyl group Chemical group 0.000 claims description 4
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
• 208000025748 atypical depressive disease Diseases 0.000 claims description 4
• 235000014632 disordered eating Nutrition 0.000 claims description 4
• 206010013663 drug dependence Diseases 0.000 claims description 4
• 206010014599 encephalitis Diseases 0.000 claims description 4
• 206010015037 epilepsy Diseases 0.000 claims description 4
• 125000004692 haloalkylcarbonyl group Chemical group 0.000 claims description 4
• 231100000869 headache Toxicity 0.000 claims description 4
• 208000014674 injury Diseases 0.000 claims description 4
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
• 230000004770 neurodegeneration Effects 0.000 claims description 4
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
• 208000022821 personality disease Diseases 0.000 claims description 4
• 201000000484 premenstrual tension Diseases 0.000 claims description 4
• 208000020016 psychiatric disease Diseases 0.000 claims description 4
• 201000000980 schizophrenia Diseases 0.000 claims description 4
• 231100000872 sexual dysfunction Toxicity 0.000 claims description 4
• 201000002859 sleep apnea Diseases 0.000 claims description 4
• 208000019116 sleep disease Diseases 0.000 claims description 4
• 230000008733 trauma Effects 0.000 claims description 4
• 208000007848 Alcoholism Diseases 0.000 claims description 3
• 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 3
• 210000003169 central nervous system Anatomy 0.000 claims description 3
• 238000003776 cleavage reaction Methods 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
• 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
• 206010027599 migraine Diseases 0.000 claims description 3
• 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 3
• 229910052757 nitrogen Inorganic materials 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 230000007017 scission Effects 0.000 claims description 3
• 208000011117 substance-related disease Diseases 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 2
• 239000013543 active substance Substances 0.000 claims description 2
• 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 2
• 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 6
• 208000012902 Nervous system disease Diseases 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 257
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 174
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 171
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 120
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 112
• 239000000243 solution Substances 0.000 description 93
• 235000019439 ethyl acetate Nutrition 0.000 description 87
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• 229940093499 ethyl acetate Drugs 0.000 description 85
• 239000000543 intermediate Substances 0.000 description 85
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 80
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 66
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
• 239000000047 product Substances 0.000 description 56
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
• 239000000741 silica gel Substances 0.000 description 43
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• 235000011121 sodium hydroxide Nutrition 0.000 description 43
• 239000000203 mixture Substances 0.000 description 42
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 41
• 239000003480 eluent Substances 0.000 description 41
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 40
• 235000019341 magnesium sulphate Nutrition 0.000 description 40
• 239000002904 solvent Substances 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
• 239000012230 colorless oil Substances 0.000 description 35
• 239000007787 solid Substances 0.000 description 35
• 238000004128 high performance liquid chromatography Methods 0.000 description 34
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 30
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
• 239000012044 organic layer Substances 0.000 description 27
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 24
• 239000005695 Ammonium acetate Substances 0.000 description 24
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
• 235000019257 ammonium acetate Nutrition 0.000 description 24
• 229940043376 ammonium acetate Drugs 0.000 description 24
• 230000002349 favourable effect Effects 0.000 description 23
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• 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 20
• CYOSGVOYQOPWKY-VXNVDRBHSA-N (5ar,9r)-2-bromo-9-methyl-5a,6,8,9-tetrahydro-5h-pyrido[1,2]pyrrolo[4,5-a]pyrazine-7-carboxylic acid Chemical class C1=C(Br)N=C2N3[C@H](C)CN(C(O)=O)C[C@H]3CC2=C1 CYOSGVOYQOPWKY-VXNVDRBHSA-N 0.000 description 19
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 19
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• 239000002585 base Substances 0.000 description 19
• 238000004587 chromatography analysis Methods 0.000 description 19
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• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• 239000002253 acid Substances 0.000 description 18
• 229910052740 iodine Inorganic materials 0.000 description 18
• 239000000460 chlorine Substances 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
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• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
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• 238000006722 reduction reaction Methods 0.000 description 14
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
• 238000010992 reflux Methods 0.000 description 13
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
• 230000002829 reductive effect Effects 0.000 description 12
• 235000017557 sodium bicarbonate Nutrition 0.000 description 12
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• 238000010998 test method Methods 0.000 description 1
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