EA020853B1 - 3,4-замещенные пиперидиновые производные в качестве ингибиторов ренина - Google Patents

Info

Publication number

EA020853B1

EA020853B1 EA201071269A EA201071269A EA020853B1 EA 020853 B1 EA020853 B1 EA 020853B1 EA 201071269 A EA201071269 A EA 201071269A EA 201071269 A EA201071269 A EA 201071269A EA 020853 B1 EA020853 B1 EA 020853B1

Authority

EA

Eurasian Patent Office

Prior art keywords

methyl

optionally substituted

alkylene

equiv

solution

Prior art date

2008-05-05

Links

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• 239000002461 renin inhibitor Substances 0.000 title abstract description 10
• 229940086526 renin-inhibitors Drugs 0.000 title abstract description 10
• 150000003053 piperidines Chemical class 0.000 title 1
• 150000001875 compounds Chemical group 0.000 claims abstract description 375
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
• 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 8
• 201000006370 kidney failure Diseases 0.000 claims abstract description 8
• -1 atoms halogen Chemical class 0.000 claims description 215
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 111
• 238000000034 method Methods 0.000 claims description 104
• 150000002367 halogens Chemical class 0.000 claims description 100
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 88
• 125000006833 (C1-C5) alkylene group Chemical group 0.000 claims description 85
• 125000005843 halogen group Chemical group 0.000 claims description 78
• 229910052736 halogen Inorganic materials 0.000 claims description 70
• 229910052739 hydrogen Inorganic materials 0.000 claims description 64
• 229920006395 saturated elastomer Polymers 0.000 claims description 64
• 239000001257 hydrogen Substances 0.000 claims description 60
• 150000003839 salts Chemical class 0.000 claims description 45
• 125000000217 alkyl group Chemical group 0.000 claims description 24
• 125000003545 alkoxy group Chemical group 0.000 claims description 21
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 20
• 125000000623 heterocyclic group Chemical group 0.000 claims description 19
• 238000011282 treatment Methods 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 125000002947 alkylene group Chemical group 0.000 claims description 17
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 16
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
• 206010019280 Heart failures Diseases 0.000 claims description 13
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 12
• 201000010099 disease Diseases 0.000 claims description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 150000002431 hydrogen Chemical class 0.000 claims description 11
• 206010020772 Hypertension Diseases 0.000 claims description 10
• 125000002837 carbocyclic group Chemical group 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 125000005842 heteroatom Chemical group 0.000 claims description 10
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
• SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
• 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• 201000001320 Atherosclerosis Diseases 0.000 claims description 6
• 206010007559 Cardiac failure congestive Diseases 0.000 claims description 6
• 208000006029 Cardiomegaly Diseases 0.000 claims description 6
• 208000031229 Cardiomyopathies Diseases 0.000 claims description 6
• 206010018364 Glomerulonephritis Diseases 0.000 claims description 6
• 206010063897 Renal ischaemia Diseases 0.000 claims description 6
• 206010012601 diabetes mellitus Diseases 0.000 claims description 6
• 230000006806 disease prevention Effects 0.000 claims description 6
• 208000017169 kidney disease Diseases 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 125000002950 monocyclic group Chemical group 0.000 claims description 6
• 208000031225 myocardial ischemia Diseases 0.000 claims description 6
• 201000001119 neuropathy Diseases 0.000 claims description 6
• 230000007823 neuropathy Effects 0.000 claims description 6
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 6
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 6
• 230000036454 renin-angiotensin system Effects 0.000 claims description 6
• 208000037803 restenosis Diseases 0.000 claims description 6
• 208000019901 Anxiety disease Diseases 0.000 claims description 5
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 5
• 206010016654 Fibrosis Diseases 0.000 claims description 5
• 208000010412 Glaucoma Diseases 0.000 claims description 5
• 206010020571 Hyperaldosteronism Diseases 0.000 claims description 5
• 206010039710 Scleroderma Diseases 0.000 claims description 5
• 230000036506 anxiety Effects 0.000 claims description 5
• 208000010877 cognitive disease Diseases 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 230000004761 fibrosis Effects 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
• 239000003018 immunosuppressive agent Substances 0.000 claims description 5
• 201000001881 impotence Diseases 0.000 claims description 5
• 230000004410 intraocular pressure Effects 0.000 claims description 5
• 230000002980 postoperative effect Effects 0.000 claims description 5
• 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 5
• 208000005069 pulmonary fibrosis Diseases 0.000 claims description 5
• 238000001356 surgical procedure Methods 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• 206010007572 Cardiac hypertrophy Diseases 0.000 claims description 4
• 208000028698 Cognitive impairment Diseases 0.000 claims description 4
• 125000000304 alkynyl group Chemical group 0.000 claims description 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
• 206010038419 Renal colic Diseases 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 239000011737 fluorine Substances 0.000 claims description 2
• 229910052698 phosphorus Inorganic materials 0.000 claims description 2
• 201000002793 renal fibrosis Diseases 0.000 claims 4
• 229960003444 immunosuppressant agent Drugs 0.000 claims 3
• 230000002792 vascular Effects 0.000 claims 3
• 101100241486 Caenorhabditis elegans him-10 gene Proteins 0.000 claims 1
• 229940125721 immunosuppressive agent Drugs 0.000 claims 1
• 108090000623 proteins and genes Proteins 0.000 claims 1
• 125000003386 piperidinyl group Chemical class 0.000 abstract description 2
• 230000007211 cardiovascular event Effects 0.000 abstract 1
• 239000000243 solution Substances 0.000 description 428
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 301
• 150000001412 amines Chemical class 0.000 description 247
• 239000000706 filtrate Substances 0.000 description 236
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 208
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 207
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
• 239000007864 aqueous solution Substances 0.000 description 175
• 239000000284 extract Substances 0.000 description 168
• 239000000725 suspension Substances 0.000 description 147
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 142
• 239000012267 brine Substances 0.000 description 137
• 239000011541 reaction mixture Substances 0.000 description 132
• 238000000746 purification Methods 0.000 description 129
• 239000000203 mixture Substances 0.000 description 127
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 121
• 239000012043 crude product Substances 0.000 description 120
• 238000003818 flash chromatography Methods 0.000 description 112
• 239000003921 oil Substances 0.000 description 101
• 235000019198 oils Nutrition 0.000 description 100
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 85
• 239000010410 layer Substances 0.000 description 85
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 84
• 239000012230 colorless oil Substances 0.000 description 83
• 238000006243 chemical reaction Methods 0.000 description 78
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 75
• HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 70
• 239000000126 substance Substances 0.000 description 70
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 67
• 239000007787 solid Substances 0.000 description 63
• 238000002360 preparation method Methods 0.000 description 54
• 239000000460 chlorine Substances 0.000 description 49
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 48
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
• 239000007789 gas Substances 0.000 description 44
• 239000011734 sodium Substances 0.000 description 42
• 239000003039 volatile agent Substances 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 35
• 238000001914 filtration Methods 0.000 description 35
• 238000003756 stirring Methods 0.000 description 35
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 34
• 230000002152 alkylating effect Effects 0.000 description 31
• 239000012279 sodium borohydride Substances 0.000 description 31
• 229910000033 sodium borohydride Inorganic materials 0.000 description 31
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 30
• 239000003153 chemical reaction reagent Substances 0.000 description 29
• 239000007858 starting material Substances 0.000 description 29
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 29
• 229910052757 nitrogen Inorganic materials 0.000 description 26
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 25
• 238000004440 column chromatography Methods 0.000 description 24
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 23
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 150000002466 imines Chemical class 0.000 description 21
• 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 20
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 19
• 235000017557 sodium bicarbonate Nutrition 0.000 description 19
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 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
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
• 239000012298 atmosphere Substances 0.000 description 16
• 125000004432 carbon atom Chemical group C* 0.000 description 16
• 229910000104 sodium hydride Inorganic materials 0.000 description 16
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
• 238000005481 NMR spectroscopy Methods 0.000 description 15
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 15
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
• 101150026303 HEX1 gene Proteins 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 14
• 239000002904 solvent Substances 0.000 description 13
• FBAOFKFCKHJXRU-VOTSOKGWSA-N 2-[(e)-3-methoxyprop-1-enyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound COC\C=C\B1OC(C)(C)C(C)(C)O1 FBAOFKFCKHJXRU-VOTSOKGWSA-N 0.000 description 12
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 12
• 101000579218 Homo sapiens Renin Proteins 0.000 description 12
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 12
• 229910052799 carbon Inorganic materials 0.000 description 12
• 239000011777 magnesium Substances 0.000 description 12
• LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical class O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
• 235000019341 magnesium sulphate Nutrition 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• 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 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 10
• 239000012312 sodium hydride Substances 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 9
• 108090000783 Renin Proteins 0.000 description 9
• 125000003118 aryl group Chemical group 0.000 description 9
• AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 9
• 239000002198 insoluble material Substances 0.000 description 9
• 229910052749 magnesium Inorganic materials 0.000 description 9
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 8
• 239000008346 aqueous phase Substances 0.000 description 8
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 8
• OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 8
• 229910052740 iodine Inorganic materials 0.000 description 8
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 8
• 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 229910000029 sodium carbonate Inorganic materials 0.000 description 8
• 235000017550 sodium carbonate Nutrition 0.000 description 8
• 239000005541 ACE inhibitor Substances 0.000 description 7
• 102100028255 Renin Human genes 0.000 description 7
• 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• WVDDGKGOMKODPV-UHFFFAOYSA-N hydroxymethyl benzene Natural products OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 7
• 239000010502 orange oil Substances 0.000 description 7
• 229910052763 palladium Inorganic materials 0.000 description 7
• 239000000651 prodrug Substances 0.000 description 7
• 229940002612 prodrug Drugs 0.000 description 7
• 239000000741 silica gel Substances 0.000 description 7
• 229910002027 silica gel Inorganic materials 0.000 description 7
• DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 7
• 229940102001 zinc bromide Drugs 0.000 description 7
• CEVMYGZHEJSOHZ-UHFFFAOYSA-N 1-bromo-3-methoxypropane Chemical compound COCCCBr CEVMYGZHEJSOHZ-UHFFFAOYSA-N 0.000 description 6
• VFTIMBRSAGIHRD-UHFFFAOYSA-N 1-cyclopropyl-4-(1-methyl-2-oxopyridin-4-yl)piperidine-3-carboxamide Chemical compound O=C1N(C)C=CC(C2C(CN(CC2)C2CC2)C(N)=O)=C1 VFTIMBRSAGIHRD-UHFFFAOYSA-N 0.000 description 6
• FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 6
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
• 230000002051 biphasic effect Effects 0.000 description 6
• 239000000872 buffer Substances 0.000 description 6
• 150000001721 carbon Chemical group 0.000 description 6
• 238000001816 cooling Methods 0.000 description 6
• 239000006185 dispersion Substances 0.000 description 6
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
• KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
• 125000006239 protecting group Chemical group 0.000 description 6
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
• 238000003786 synthesis reaction Methods 0.000 description 6
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 5
• MHZGKXUYDGKKIU-UHFFFAOYSA-N Decylamine Chemical compound CCCCCCCCCCN MHZGKXUYDGKKIU-UHFFFAOYSA-N 0.000 description 5
• 235000019502 Orange oil Nutrition 0.000 description 5
• 238000004821 distillation Methods 0.000 description 5
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