JP5397959B2 - 置換ピロリジンアミド、それの製造方法、及び、それの薬剤としての使用 - Google Patents

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Publication number

JP5397959B2

JP5397959B2 JP2010500259A JP2010500259A JP5397959B2 JP 5397959 B2 JP5397959 B2 JP 5397959B2 JP 2010500259 A JP2010500259 A JP 2010500259A JP 2010500259 A JP2010500259 A JP 2010500259A JP 5397959 B2 JP5397959 B2 JP 5397959B2

Authority

JP

Japan

Prior art keywords

group

alkyl

atom

amino

methyl

Prior art date

2007-03-27

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.)

Expired - Fee Related

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• 238000000034 method Methods 0.000 title description 146
• 239000003814 drug Substances 0.000 title description 2
• 238000004519 manufacturing process Methods 0.000 title description 2
• 230000008569 process Effects 0.000 title description 2
• LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical class NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 title 1
• -1 methoxy, amino Chemical group 0.000 claims description 160
• 239000000203 mixture Substances 0.000 claims description 133
• 229910052801 chlorine Inorganic materials 0.000 claims description 72
• 150000001875 compounds Chemical class 0.000 claims description 65
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 60
• 125000001153 fluoro group Chemical group F* 0.000 claims description 56
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 52
• 239000000460 chlorine Chemical group 0.000 claims description 51
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 50
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 44
• 229910052799 carbon Inorganic materials 0.000 claims description 42
• 229910052731 fluorine Inorganic materials 0.000 claims description 38
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
• 125000003277 amino group Chemical group 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 34
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 32
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 30
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• 229910052717 sulfur Inorganic materials 0.000 claims description 28
• 150000001721 carbon Chemical group 0.000 claims description 26
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 24
• 125000000217 alkyl group Chemical group 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 22
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 22
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 22
• 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 claims description 21
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
• 125000005842 heteroatom Chemical group 0.000 claims description 20
• 125000004122 cyclic group Chemical group 0.000 claims description 18
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
• 125000004434 sulfur atom Chemical group 0.000 claims description 18
• 125000004432 carbon atom Chemical group C* 0.000 claims description 17
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 14
• 229910052794 bromium Inorganic materials 0.000 claims description 14
• 125000001072 heteroaryl group Chemical group 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 125000002619 bicyclic group Chemical group 0.000 claims description 13
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 12
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 12
• 229910052740 iodine Inorganic materials 0.000 claims description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical group C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
• 125000002950 monocyclic group Chemical group 0.000 claims description 11
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 10
• 125000006560 (C1-C5)alkylcarbonylamino group Chemical group 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 10
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
• 239000001301 oxygen Substances 0.000 claims description 10
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
• 125000002837 carbocyclic group Chemical group 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
• 125000003386 piperidinyl group Chemical group 0.000 claims description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
• 125000006599 (C1-C3) alkylaminocarbonylamino group Chemical group 0.000 claims description 6
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 6
• 125000002560 nitrile group Chemical group 0.000 claims description 6
• 125000004193 piperazinyl group Chemical group 0.000 claims description 6
• 239000011593 sulfur Substances 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 5
• 125000003545 alkoxy group Chemical group 0.000 claims description 5
• 125000000304 alkynyl group Chemical group 0.000 claims description 5
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000001174 sulfone group Chemical group 0.000 claims description 5
• 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 4
• 125000006562 (C1-C5) alkyloxycarbonylamino group Chemical group 0.000 claims description 4
• OYELEBBISJGNHJ-UHFFFAOYSA-N 1,3-oxazinan-2-one Chemical group O=C1NCCCO1 OYELEBBISJGNHJ-UHFFFAOYSA-N 0.000 claims description 4
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
• YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical group C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 4
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 4
• 125000002393 azetidinyl group Chemical group 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 4
• HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical group C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 claims description 4
• 239000011737 fluorine Substances 0.000 claims description 4
• 125000005843 halogen group Chemical group 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 150000002829 nitrogen Chemical class 0.000 claims description 4
• 125000003566 oxetanyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 4
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
• 125000003375 sulfoxide group Chemical group 0.000 claims description 4
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
• RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical group C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 4
• 125000002053 thietanyl group Chemical group 0.000 claims description 4
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical group OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 0.000 claims description 3
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 3
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
• 125000006556 (C1-C5) alkylsulphonyl group Chemical group 0.000 claims description 2
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
• 125000006091 1,3-dioxolane group Chemical group 0.000 claims description 2
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical group O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 2
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000004011 3 membered carbocyclic group Chemical group 0.000 claims description 2
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 2
• 125000006164 6-membered heteroaryl group Chemical group 0.000 claims description 2
• 125000006845 C1-5-alkyloxycarbonyl-C1-5-alkyl group Chemical group 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 2
• 125000005336 allyloxy group Chemical group 0.000 claims description 2
• 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 2
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 2
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
• YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical group O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 claims description 2
• PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
• 150000002825 nitriles Chemical class 0.000 claims description 2
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
• 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 claims description 2
• 125000004043 oxo group Chemical group O=* 0.000 claims description 2
• BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 2
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
• 238000001819 mass spectrum Methods 0.000 description 123
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 118
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
• 239000000243 solution Substances 0.000 description 65
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 63
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 57
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
• 239000012074 organic phase Substances 0.000 description 36
• 239000011541 reaction mixture Substances 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
• 229910052938 sodium sulfate Inorganic materials 0.000 description 30
• 235000011152 sodium sulphate Nutrition 0.000 description 30
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
• 239000003480 eluent Substances 0.000 description 23
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
• 239000013543 active substance Substances 0.000 description 21
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
• 125000006239 protecting group Chemical group 0.000 description 20
• 239000003643 water by type Substances 0.000 description 19
• 239000000741 silica gel Substances 0.000 description 18
• 229910002027 silica gel Inorganic materials 0.000 description 18
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
• 239000012043 crude product Substances 0.000 description 15
• 239000002904 solvent Substances 0.000 description 15
• 239000008346 aqueous phase Substances 0.000 description 14
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
• 238000002360 preparation method Methods 0.000 description 12
• 239000007821 HATU Substances 0.000 description 11
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 11
• 108090000190 Thrombin Proteins 0.000 description 11
• 239000002253 acid Substances 0.000 description 11
• 239000007864 aqueous solution Substances 0.000 description 11
• 238000003818 flash chromatography Methods 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• 229960004072 thrombin Drugs 0.000 description 11
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 239000003112 inhibitor Substances 0.000 description 10
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
• 238000004007 reversed phase HPLC Methods 0.000 description 10
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 230000008878 coupling Effects 0.000 description 9
• 238000010168 coupling process Methods 0.000 description 9
• 238000005859 coupling reaction Methods 0.000 description 9
• 239000012071 phase Substances 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• 230000005526 G1 to G0 transition Effects 0.000 description 8
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
• 229910021529 ammonia Inorganic materials 0.000 description 8
• 229910052796 boron Inorganic materials 0.000 description 8
• 239000003153 chemical reaction reagent Substances 0.000 description 8
• 229920006395 saturated elastomer Polymers 0.000 description 8
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
• 108010074860 Factor Xa Proteins 0.000 description 7
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
• 238000001514 detection method Methods 0.000 description 7
• 239000001257 hydrogen Substances 0.000 description 7
• 229910052739 hydrogen Inorganic materials 0.000 description 7
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
• 239000000758 substrate Substances 0.000 description 7
• 239000003826 tablet Substances 0.000 description 7
• DTRBIIDYMYVRNE-UHFFFAOYSA-N 1h-azepine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC=CN1 DTRBIIDYMYVRNE-UHFFFAOYSA-N 0.000 description 6
• FGKZKIVTRNULQO-UHFFFAOYSA-N 5-chloro-n-(4-methoxypyrrolidin-3-yl)thiophene-2-carboxamide Chemical compound COC1CNCC1NC(=O)C1=CC=C(Cl)S1 FGKZKIVTRNULQO-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
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 238000006243 chemical reaction Methods 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
• 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 6
• 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 5
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