CA2460947A1

CA2460947A1 - 6-o-carbamate-11,12-lacto-ketolide antimicrobials

6-o-carbamate-11,12-lacto-ketolide antimicrobials Download PDF

Info

Publication number: CA2460947A1
Authority: CA; Canada
Prior art keywords: mmol; compound; reference example; substituted; aryl
Prior art date: 2001-09-17
Legal status : Abandoned

Application number

CA002460947A

Other languages

English (en)

French (fr)

Inventor

Eugene B. Grant, Iii

Todd C. Henninger

Mark J. Macielag

Deodialsingh Guiadeen

Current Assignee

Janssen Pharmaceuticals Inc

Original Assignee

Individual

Priority date

2001-09-17

Filing date

2002-09-16

Publication date

2003-03-27

2002-09-16 Application filed by Individual filed Critical Individual

2003-03-27 Publication of CA2460947A1 publication Critical patent/CA2460947A1/en

Status Abandoned legal-status Critical Current

Links

239000003835 ketolide antibiotic agent Substances 0.000 title abstract description 6
239000004599 antimicrobial Substances 0.000 title abstract description 4
150000001875 compounds Chemical class 0.000 claims abstract description 199
-1 substituted Chemical class 0.000 claims description 85
238000000034 method Methods 0.000 claims description 56
239000000203 mixture Substances 0.000 claims description 56
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 43
125000001072 heteroaryl group Chemical group 0.000 claims description 33
229910052739 hydrogen Inorganic materials 0.000 claims description 32
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 31
239000001257 hydrogen Substances 0.000 claims description 28
125000003118 aryl group Chemical group 0.000 claims description 25
ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 24
125000000217 alkyl group Chemical group 0.000 claims description 24
125000001424 substituent group Chemical group 0.000 claims description 22
125000000304 alkynyl group Chemical group 0.000 claims description 17
150000003839 salts Chemical class 0.000 claims description 15
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
125000003107 substituted aryl group Chemical group 0.000 claims description 14
125000003342 alkenyl group Chemical group 0.000 claims description 13
229960003276 erythromycin Drugs 0.000 claims description 12
208000035143 Bacterial infection Diseases 0.000 claims description 10
208000022362 bacterial infectious disease Diseases 0.000 claims description 10
241000894006 Bacteria Species 0.000 claims description 9
125000000753 cycloalkyl group Chemical group 0.000 claims description 9
125000004432 carbon atom Chemical group C* 0.000 claims description 8
125000006239 protecting group Chemical group 0.000 claims description 8
239000008194 pharmaceutical composition Substances 0.000 claims description 7
125000003545 alkoxy group Chemical group 0.000 claims description 6
239000000651 prodrug Substances 0.000 claims description 6
229940002612 prodrug Drugs 0.000 claims description 6
239000003937 drug carrier Substances 0.000 claims description 4
150000002148 esters Chemical class 0.000 claims description 4
206010005940 Bone and joint infections Diseases 0.000 claims description 3
241000606768 Haemophilus influenzae Species 0.000 claims description 3
206010024971 Lower respiratory tract infections Diseases 0.000 claims description 3
208000032376 Lung infection Diseases 0.000 claims description 3
201000009906 Meningitis Diseases 0.000 claims description 3
206010035664 Pneumonia Diseases 0.000 claims description 3
206010057190 Respiratory tract infections Diseases 0.000 claims description 3
206010062255 Soft tissue infection Diseases 0.000 claims description 3
206010046306 Upper respiratory tract infection Diseases 0.000 claims description 3
230000008569 process Effects 0.000 claims description 3
208000020029 respiratory tract infectious disease Diseases 0.000 claims description 3
206010040872 skin infection Diseases 0.000 claims description 3
241000588655 Moraxella catarrhalis Species 0.000 claims description 2
241000191963 Staphylococcus epidermidis Species 0.000 claims description 2
125000004183 alkoxy alkyl group Chemical group 0.000 claims description 2
125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 2
230000003115 biocidal effect Effects 0.000 claims description 2
238000002156 mixing Methods 0.000 claims description 2
230000003287 optical effect Effects 0.000 claims description 2
125000004001 thioalkyl group Chemical group 0.000 claims description 2
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 6
125000006374 C2-C10 alkenyl group Chemical group 0.000 claims 3
241001478240 Coccus Species 0.000 claims 3
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims 1
125000005865 C2-C10alkynyl group Chemical group 0.000 claims 1
241000194033 Enterococcus Species 0.000 claims 1
239000003242 anti bacterial agent Substances 0.000 abstract description 10
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 291
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 258
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 199
239000000243 solution Substances 0.000 description 98
235000019439 ethyl acetate Nutrition 0.000 description 92
239000011541 reaction mixture Substances 0.000 description 85
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 80
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 78
AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 72
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 71
238000000746 purification Methods 0.000 description 69
239000012267 brine Substances 0.000 description 66
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 66
229910000030 sodium bicarbonate Inorganic materials 0.000 description 52
VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 48
238000004587 chromatography analysis Methods 0.000 description 47
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
238000010992 reflux Methods 0.000 description 44
229910017974 NH40H Inorganic materials 0.000 description 43
229910052681 coesite Inorganic materials 0.000 description 42
229910052906 cristobalite Inorganic materials 0.000 description 42
229910052682 stishovite Inorganic materials 0.000 description 42
229910052905 tridymite Inorganic materials 0.000 description 42
238000006243 chemical reaction Methods 0.000 description 39
239000006260 foam Substances 0.000 description 39
239000007787 solid Substances 0.000 description 37
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 35
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 33
239000002585 base Substances 0.000 description 33
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 29
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
239000002904 solvent Substances 0.000 description 24
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
238000003756 stirring Methods 0.000 description 19
150000003512 tertiary amines Chemical class 0.000 description 19
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
238000003818 flash chromatography Methods 0.000 description 18
239000012044 organic layer Substances 0.000 description 18
150000001299 aldehydes Chemical class 0.000 description 17
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 16
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
NMLYGLCBSFKJFI-UHFFFAOYSA-N 4-pyridin-2-ylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=N1 NMLYGLCBSFKJFI-UHFFFAOYSA-N 0.000 description 15
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 15
238000003786 synthesis reaction Methods 0.000 description 15
229960000549 4-dimethylaminophenol Drugs 0.000 description 14
JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 14
230000015572 biosynthetic process Effects 0.000 description 14
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
238000002360 preparation method Methods 0.000 description 14
QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 12
230000000694 effects Effects 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
229920006395 saturated elastomer Polymers 0.000 description 12
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
239000010410 layer Substances 0.000 description 11
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 10
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
239000002253 acid Substances 0.000 description 9
239000003054 catalyst Substances 0.000 description 9
125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 9
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 9
229910000027 potassium carbonate Inorganic materials 0.000 description 9
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
241001465754 Metazoa Species 0.000 description 8
230000000844 anti-bacterial effect Effects 0.000 description 8
NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
239000012442 inert solvent Substances 0.000 description 8
239000003921 oil Substances 0.000 description 8
235000019198 oils Nutrition 0.000 description 8
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
230000003647 oxidation Effects 0.000 description 8
238000007254 oxidation reaction Methods 0.000 description 8
229910000029 sodium carbonate Inorganic materials 0.000 description 8
229930006677 Erythromycin A Natural products 0.000 description 7
239000003153 chemical reaction reagent Substances 0.000 description 7
125000000623 heterocyclic group Chemical group 0.000 description 7
WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 7
239000000725 suspension Substances 0.000 description 7
XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 6
RLQBACIDRXTOLB-UHFFFAOYSA-N 2-(5-bromopyridin-3-yl)pyrimidine Chemical compound BrC1=CN=CC(C=2N=CC=CN=2)=C1 RLQBACIDRXTOLB-UHFFFAOYSA-N 0.000 description 6
LRWHPNRJCDEOMO-UHFFFAOYSA-N 3-pyridin-3-ylprop-2-ynal Chemical compound O=CC#CC1=CC=CN=C1 LRWHPNRJCDEOMO-UHFFFAOYSA-N 0.000 description 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
230000010933 acylation Effects 0.000 description 6
238000005917 acylation reaction Methods 0.000 description 6
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
239000003814 drug Substances 0.000 description 6
239000007788 liquid Substances 0.000 description 6
229910052760 oxygen Inorganic materials 0.000 description 6
230000035484 reaction time Effects 0.000 description 6
238000012360 testing method Methods 0.000 description 6
GRNOZCCBOFGDCL-UHFFFAOYSA-N 2,2,2-trichloroacetyl isocyanate Chemical compound ClC(Cl)(Cl)C(=O)N=C=O GRNOZCCBOFGDCL-UHFFFAOYSA-N 0.000 description 5
DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Chemical class CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
150000001241 acetals Chemical class 0.000 description 5
229910052736 halogen Inorganic materials 0.000 description 5
150000002367 halogens Chemical class 0.000 description 5
125000005842 heteroatom Chemical group 0.000 description 5
239000000463 material Substances 0.000 description 5
235000011181 potassium carbonates Nutrition 0.000 description 5
125000006413 ring segment Chemical group 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
LQHPKDJZDUACSS-UHFFFAOYSA-N (2,2,2-trichloroacetyl)carbamic acid Chemical compound OC(=O)NC(=O)C(Cl)(Cl)Cl LQHPKDJZDUACSS-UHFFFAOYSA-N 0.000 description 4
FRHRVQQUICVJDG-UHFFFAOYSA-M 1,3-dioxolan-2-ylmethyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)CC1OCCO1 FRHRVQQUICVJDG-UHFFFAOYSA-M 0.000 description 4
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
229910052799 carbon Inorganic materials 0.000 description 4
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 4
NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 4
150000003254 radicals Chemical class 0.000 description 4
239000011734 sodium Substances 0.000 description 4
238000005809 transesterification reaction Methods 0.000 description 4
HJBGZJMKTOMQRR-UHFFFAOYSA-N (3-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC(C=O)=C1 HJBGZJMKTOMQRR-UHFFFAOYSA-N 0.000 description 3
239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 description 3
ZQVYUASHVBAMNZ-ONEGZZNKSA-N (e)-3-(4-pyridin-2-ylphenyl)prop-2-enal Chemical compound C1=CC(/C=C/C=O)=CC=C1C1=CC=CC=N1 ZQVYUASHVBAMNZ-ONEGZZNKSA-N 0.000 description 3
JEHAVMYATWBTFS-NSCUHMNNSA-N (e)-3-quinolin-7-ylprop-2-enal Chemical compound C1=CC=NC2=CC(/C=C/C=O)=CC=C21 JEHAVMYATWBTFS-NSCUHMNNSA-N 0.000 description 3
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 3
UPCCKZGEKVVLHM-UHFFFAOYSA-N 2-fluoro-4-pyrimidin-2-ylbenzaldehyde Chemical compound C1=C(C=O)C(F)=CC(C=2N=CC=CN=2)=C1 UPCCKZGEKVVLHM-UHFFFAOYSA-N 0.000 description 3
SOSPMXMEOFGPIM-UHFFFAOYSA-N 3,5-dibromopyridine Chemical compound BrC1=CN=CC(Br)=C1 SOSPMXMEOFGPIM-UHFFFAOYSA-N 0.000 description 3
YHVUVJYEERGYNU-UHFFFAOYSA-N 4',8-Di-Me ether-5,7,8-Trihydroxy-3-(4-hydroxybenzyl)-4-chromanone Natural products COC1(C)CC(O)OC(C)C1O YHVUVJYEERGYNU-UHFFFAOYSA-N 0.000 description 3
BXNXTOLXLPQMHS-UHFFFAOYSA-N 4-pyrimidin-5-ylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CN=CN=C1 BXNXTOLXLPQMHS-UHFFFAOYSA-N 0.000 description 3
YOQRXZIMSKLRCY-UHFFFAOYSA-N 5-bromonicotinamide Chemical compound NC(=O)C1=CN=CC(Br)=C1 YOQRXZIMSKLRCY-UHFFFAOYSA-N 0.000 description 3
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
FIWILGQIZHDAQG-UHFFFAOYSA-N NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F Chemical compound NC1=C(C(=O)NCC2=CC=C(C=C2)OCC(F)(F)F)C=C(C(=N1)N)N1N=C(N=C1)C1(CC1)C(F)(F)F FIWILGQIZHDAQG-UHFFFAOYSA-N 0.000 description 3
239000007832 Na2SO4 Substances 0.000 description 3
101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 3
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
239000007983 Tris buffer Substances 0.000 description 3
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
125000002252 acyl group Chemical group 0.000 description 3
230000029936 alkylation Effects 0.000 description 3
238000005804 alkylation reaction Methods 0.000 description 3
229910021529 ammonia Inorganic materials 0.000 description 3
150000003934 aromatic aldehydes Chemical class 0.000 description 3
125000003710 aryl alkyl group Chemical group 0.000 description 3
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
229930008407 benzylideneacetone Natural products 0.000 description 3
230000002051 biphasic effect Effects 0.000 description 3
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