CA2566085A1 - Ester linked macrolides useful for the treatment of microbial infections - Google Patents

Info

Publication number

CA2566085A1

CA2566085A1 CA002566085A CA2566085A CA2566085A1 CA 2566085 A1 CA2566085 A1 CA 2566085A1 CA 002566085 A CA002566085 A CA 002566085A CA 2566085 A CA2566085 A CA 2566085A CA 2566085 A1 CA2566085 A1 CA 2566085A1

Authority

CA

Canada

Prior art keywords

ethoxy

oxo

dihydro

propionyl

carboxy

Prior art date

2004-05-06

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 230000000813 microbial effect Effects 0.000 title claims abstract description 9
• 238000011282 treatment Methods 0.000 title claims description 16
• 208000015181 infectious disease Diseases 0.000 title claims description 8
• 239000003120 macrolide antibiotic agent Substances 0.000 title abstract description 11
• 229940041033 macrolides Drugs 0.000 title abstract description 6
• 150000002148 esters Chemical class 0.000 title description 13
• 238000000034 method Methods 0.000 claims abstract description 146
• 241000282414 Homo sapiens Species 0.000 claims abstract description 21
• 238000002360 preparation method Methods 0.000 claims abstract description 8
• 230000008569 process Effects 0.000 claims abstract description 7
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 7
• 230000000699 topical effect Effects 0.000 claims abstract description 7
• 241001465754 Metazoa Species 0.000 claims abstract description 6
• 238000011321 prophylaxis Methods 0.000 claims abstract description 6
• 230000009885 systemic effect Effects 0.000 claims abstract description 5
• 150000001875 compounds Chemical class 0.000 claims description 295
• 229960004099 azithromycin Drugs 0.000 claims description 154
• 229960003276 erythromycin Drugs 0.000 claims description 62
• 229910052739 hydrogen Inorganic materials 0.000 claims description 62
• 239000001257 hydrogen Substances 0.000 claims description 60
• 229960002626 clarithromycin Drugs 0.000 claims description 59
• 125000000623 heterocyclic group Chemical group 0.000 claims description 37
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 37
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 36
• 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 33
• 238000006243 chemical reaction Methods 0.000 claims description 33
• 229930006677 Erythromycin A Natural products 0.000 claims description 30
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 26
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
• 239000002253 acid Substances 0.000 claims description 20
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 18
• 239000003814 drug Substances 0.000 claims description 17
• 239000008194 pharmaceutical composition Substances 0.000 claims description 16
• 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 16
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical group 0.000 claims description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
• 125000003118 aryl group Chemical group 0.000 claims description 14
• 125000000217 alkyl group Chemical group 0.000 claims description 13
• 125000006239 protecting group Chemical group 0.000 claims description 13
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 11
• 239000003085 diluting agent Substances 0.000 claims description 11
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
• 125000004429 atom Chemical group 0.000 claims description 9
• 125000004122 cyclic group Chemical group 0.000 claims description 9
• 229910052731 fluorine Chemical group 0.000 claims description 9
• 239000011737 fluorine Chemical group 0.000 claims description 8
• 229910052757 nitrogen Inorganic materials 0.000 claims description 8
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims description 7
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
• 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 claims description 6
• 101000927076 Xenopus laevis Apoptosis regulator R11 Proteins 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 6
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
• 229910052770 Uranium Inorganic materials 0.000 claims description 5
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
• LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical group [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 4
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
• MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[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 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 3
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
• 125000001424 substituent group Chemical group 0.000 claims description 3
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
• 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 150000002431 hydrogen Chemical group 0.000 claims 9
• 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 2
• 239000000543 intermediate Substances 0.000 description 356
• 239000000203 mixture Substances 0.000 description 150
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 147
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 142
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 137
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 120
• 239000000243 solution Substances 0.000 description 115
• 239000000047 product Substances 0.000 description 112
• 229910001868 water Inorganic materials 0.000 description 106
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 80
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 67
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
• 235000019439 ethyl acetate Nutrition 0.000 description 63
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 62
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 53
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 52
• 239000011541 reaction mixture Substances 0.000 description 52
• -1 ester Chemical class 0.000 description 44
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
• 239000012044 organic layer Substances 0.000 description 40
• 239000002904 solvent Substances 0.000 description 40
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 32
• 230000002829 reductive effect Effects 0.000 description 32
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
• 239000002244 precipitate Substances 0.000 description 31
• 150000003839 salts Chemical class 0.000 description 29
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
• 238000004440 column chromatography Methods 0.000 description 26
• 238000004128 high performance liquid chromatography Methods 0.000 description 24
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
• 239000007787 solid Substances 0.000 description 23
• 238000005160 1H NMR spectroscopy Methods 0.000 description 22
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 22
• 239000010410 layer Substances 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 239000003480 eluent Substances 0.000 description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
• 229910000027 potassium carbonate Inorganic materials 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
• 239000000725 suspension Substances 0.000 description 19
• 239000007832 Na2SO4 Substances 0.000 description 18
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
• 239000003921 oil Substances 0.000 description 18
• 229910052938 sodium sulfate Inorganic materials 0.000 description 18
• 235000011152 sodium sulphate Nutrition 0.000 description 18
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 17
• 101150041968 CDC13 gene Proteins 0.000 description 17
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
• 239000012043 crude product Substances 0.000 description 17
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• 235000017557 sodium bicarbonate Nutrition 0.000 description 15
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
• 150000003254 radicals Chemical class 0.000 description 14
• 125000004432 carbon atom Chemical group C* 0.000 description 12
• 239000003795 chemical substances by application Substances 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 12
• 229910002027 silica gel Inorganic materials 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
• JYNZIOFUHBJABQ-UHFFFAOYSA-N allyl-{6-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-hexyl-}-methyl-amin Chemical compound C=1OC2=CC(OCCCCCCN(C)CC=C)=CC=C2C=1C1=CC=C(Br)C=C1 JYNZIOFUHBJABQ-UHFFFAOYSA-N 0.000 description 11
• 238000004587 chromatography analysis Methods 0.000 description 11
• 229910052760 oxygen Inorganic materials 0.000 description 11
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 10
• NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 10
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
• 235000019253 formic acid Nutrition 0.000 description 10
• 239000012453 solvate Substances 0.000 description 10
• 229960000583 acetic acid Drugs 0.000 description 9
• 239000007864 aqueous solution Substances 0.000 description 9
• 239000012267 brine Substances 0.000 description 9
• 229910052799 carbon Inorganic materials 0.000 description 9
• 125000001153 fluoro group Chemical group F* 0.000 description 9
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 9
• 239000000651 prodrug Substances 0.000 description 9
• 229940002612 prodrug Drugs 0.000 description 9
• 229910000104 sodium hydride Inorganic materials 0.000 description 9
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
• DTYLXDLAOLOTKT-UHFFFAOYSA-N 1,4-dihydroquinoline-3-carboxylic acid Chemical compound C1=CC=C2CC(C(=O)O)=CNC2=C1 DTYLXDLAOLOTKT-UHFFFAOYSA-N 0.000 description 8
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
• 239000002585 base Substances 0.000 description 8
• 238000009472 formulation Methods 0.000 description 8
• 229910052740 iodine Inorganic materials 0.000 description 8
• 229910000069 nitrogen hydride Inorganic materials 0.000 description 8
• 239000000843 powder Substances 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
• 238000005481 NMR spectroscopy Methods 0.000 description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
• POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 7
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
• 235000011181 potassium carbonates Nutrition 0.000 description 7
• 239000003826 tablet Substances 0.000 description 7
• RBIIKVXVYVANCQ-CUWPLCDZSA-N (2s,4s,5s)-5-amino-n-(3-amino-2,2-dimethyl-3-oxopropyl)-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-4-hydroxy-2-propan-2-ylhexanamide Chemical compound C1C(C)(C)N(C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)CC(=O)N1C1=CC=CC=C1Cl RBIIKVXVYVANCQ-CUWPLCDZSA-N 0.000 description 6
• ISPVACVJFUIDPD-UHFFFAOYSA-N 7-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid Chemical compound C12=CC(Cl)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 ISPVACVJFUIDPD-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-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
• 239000004480 active ingredient Substances 0.000 description 6
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
• 125000001309 chloro group Chemical group Cl* 0.000 description 6
• 239000000706 filtrate Substances 0.000 description 6
• 238000001914 filtration Methods 0.000 description 6
• 238000003818 flash chromatography Methods 0.000 description 6
• 239000001301 oxygen Substances 0.000 description 6
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
• GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 description 5
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
• 229920000858 Cyclodextrin Polymers 0.000 description 5
• 108091006629 SLC13A2 Proteins 0.000 description 5
• 229920002472 Starch Polymers 0.000 description 5
• 241000193996 Streptococcus pyogenes Species 0.000 description 5
• MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 5
• 239000002775 capsule Substances 0.000 description 5
• 239000001569 carbon dioxide Substances 0.000 description 5
• 229910002092 carbon dioxide Inorganic materials 0.000 description 5
• 229910052801 chlorine Inorganic materials 0.000 description 5
• 239000000460 chlorine Substances 0.000 description 5
• 239000006071 cream Substances 0.000 description 5
• 239000000796 flavoring agent Substances 0.000 description 5
• 150000002430 hydrocarbons Chemical group 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 239000012299 nitrogen atmosphere Substances 0.000 description 5
• 239000003960 organic solvent Substances 0.000 description 5
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
• 238000001556 precipitation Methods 0.000 description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
• 238000000746 purification Methods 0.000 description 5
• 239000007921 spray Substances 0.000 description 5
• 229940032147 starch Drugs 0.000 description 5
• 239000008107 starch Substances 0.000 description 5
• 235000019698 starch Nutrition 0.000 description 5
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 4
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• 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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• JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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• 238000005891 transamination reaction Methods 0.000 description 1
• 125000004665 trialkylsilyl group Chemical group 0.000 description 1
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• ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 1
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
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