CA2682012A1 - Substituted pyrrolidinamides, manufacturing and use thereof as medicaments - Google Patents

Info

Publication number

CA2682012A1

CA2682012A1 CA002682012A CA2682012A CA2682012A1 CA 2682012 A1 CA2682012 A1 CA 2682012A1 CA 002682012 A CA002682012 A CA 002682012A CA 2682012 A CA2682012 A CA 2682012A CA 2682012 A1 CA2682012 A1 CA 2682012A1

Authority

CA

Canada

Prior art keywords

group

alkyl

denotes

methyl

amino

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 239000003814 drug Substances 0.000 title claims description 6
• 238000004519 manufacturing process Methods 0.000 title description 3
• LCDCPQHFCOBUEF-UHFFFAOYSA-N pyrrolidine-1-carboxamide Chemical class NC(=O)N1CCCC1 LCDCPQHFCOBUEF-UHFFFAOYSA-N 0.000 title description 3
• -1 pyrrolidine amides Chemical class 0.000 claims abstract description 215
• 239000000203 mixture Substances 0.000 claims abstract description 129
• 150000003839 salts Chemical class 0.000 claims abstract description 41
• 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 abstract description 21
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 14
• 238000000034 method Methods 0.000 claims description 211
• 229910052801 chlorine Inorganic materials 0.000 claims description 127
• 239000000460 chlorine Chemical group 0.000 claims description 125
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 109
• 150000001875 compounds Chemical class 0.000 claims description 71
• 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 53
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
• 229910052799 carbon Inorganic materials 0.000 claims description 44
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 40
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 38
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
• 125000001153 fluoro group Chemical group F* 0.000 claims description 34
• 229910052757 nitrogen Inorganic materials 0.000 claims description 34
• 229910052731 fluorine Inorganic materials 0.000 claims description 32
• 229910052794 bromium Inorganic materials 0.000 claims description 30
• 150000001721 carbon Chemical group 0.000 claims description 28
• 229910052760 oxygen Inorganic materials 0.000 claims description 28
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 26
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 26
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 26
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 26
• 239000001301 oxygen Substances 0.000 claims description 26
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 25
• 239000011737 fluorine Substances 0.000 claims description 23
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 20
• 125000005842 heteroatom Chemical group 0.000 claims description 20
• 239000001257 hydrogen Substances 0.000 claims description 19
• 229910052739 hydrogen Inorganic materials 0.000 claims description 19
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
• 125000000217 alkyl group Chemical group 0.000 claims description 18
• 125000004429 atom Chemical group 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
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 16
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 16
• 125000004432 carbon atom Chemical group C* 0.000 claims description 15
• 125000004122 cyclic group Chemical class 0.000 claims description 14
• 125000001424 substituent group Chemical group 0.000 claims description 14
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 13
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 13
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 12
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
• 125000001072 heteroaryl group Chemical group 0.000 claims description 12
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 11
• 239000012634 fragment Substances 0.000 claims description 11
• 125000006560 (C1-C5)alkylcarbonylamino group Chemical group 0.000 claims description 10
• 239000005864 Sulphur Substances 0.000 claims description 10
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 10
• 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 10
• 125000002950 monocyclic group Chemical group 0.000 claims description 10
• 239000000126 substance Substances 0.000 claims description 10
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 9
• 108010074860 Factor Xa Proteins 0.000 claims description 9
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
• 125000002837 carbocyclic group Chemical group 0.000 claims description 8
• HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 8
• LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 229910052740 iodine Inorganic materials 0.000 claims description 8
• 150000002825 nitriles Chemical class 0.000 claims description 8
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
• 230000002401 inhibitory effect Effects 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 6
• 125000006561 (C1-C5) alkylsulphonylamino group Chemical group 0.000 claims description 6
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
• 125000001174 sulfone group Chemical group 0.000 claims description 6
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
• 125000006599 (C1-C3) alkylaminocarbonylamino group Chemical group 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
• NQPJDJVGBDHCAD-UHFFFAOYSA-N 1,3-diazinan-2-one Chemical compound OC1=NCCCN1 NQPJDJVGBDHCAD-UHFFFAOYSA-N 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
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
• ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 claims description 4
• DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 4
• YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 4
• 125000003342 alkenyl group Chemical group 0.000 claims description 4
• 125000000304 alkynyl group Chemical group 0.000 claims description 4
• 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 4
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 4
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 claims description 4
• 125000002534 ethynyl group Chemical group [H]C#C* 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
• AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 4
• RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
• RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 claims description 4
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 4
• 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 3
• 239000003085 diluting agent Substances 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
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
• 125000006562 (C1-C5) alkyloxycarbonylamino group Chemical group 0.000 claims description 2
• 125000006715 (C1-C5) alkylthio group Chemical group 0.000 claims description 2
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 2
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
• WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 2
• RPAJWWXZIQJVJF-UHFFFAOYSA-N 2,4-dichloro-6-(3,5-dichloro-2-hydroxyphenyl)sulfinylphenol Chemical compound OC1=C(Cl)C=C(Cl)C=C1S(=O)C1=CC(Cl)=CC(Cl)=C1O RPAJWWXZIQJVJF-UHFFFAOYSA-N 0.000 claims description 2
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound 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
• 108010022999 Serine Proteases Proteins 0.000 claims description 2
• 102000012479 Serine Proteases Human genes 0.000 claims description 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 125000005336 allyloxy group Chemical group 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000002619 bicyclic group Chemical group 0.000 claims description 2
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
• YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound 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
• 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 compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 2
• 229920002554 vinyl polymer Polymers 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims 2
• 125000006845 C1-5-alkyloxycarbonyl-C1-5-alkyl group Chemical group 0.000 claims 1
• 150000007522 mineralic acids Chemical class 0.000 abstract description 4
• 150000007524 organic acids Chemical class 0.000 abstract description 4
• 235000005985 organic acids Nutrition 0.000 abstract description 4
• 238000001819 mass spectrum Methods 0.000 description 123
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 121
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
• VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 107
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 66
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 65
• 239000000243 solution Substances 0.000 description 63
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 49
• 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 44
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
• 229910052938 sodium sulfate Inorganic materials 0.000 description 33
• 235000011152 sodium sulphate Nutrition 0.000 description 33
• 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 26
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 26
• 125000006239 protecting group Chemical group 0.000 description 23
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
• 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
• 239000003643 water by type Substances 0.000 description 19
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
• 239000000741 silica gel Substances 0.000 description 18
• 229910002027 silica gel Inorganic materials 0.000 description 18
• 239000002904 solvent Substances 0.000 description 16
• 239000012043 crude product Substances 0.000 description 15
• 239000008346 aqueous phase Substances 0.000 description 14
• 238000002360 preparation method Methods 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 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
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• 108090000190 Thrombin Proteins 0.000 description 11
• 239000002253 acid Substances 0.000 description 11
• 230000015572 biosynthetic process Effects 0.000 description 11
• 230000000694 effects Effects 0.000 description 11
• 238000003818 flash chromatography Methods 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
• 239000002585 base Substances 0.000 description 10
• 238000001816 cooling Methods 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
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-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
• 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
• 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
• 239000003112 inhibitor Substances 0.000 description 8
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
• 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 7
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
• 239000002775 capsule Substances 0.000 description 7
• 238000001514 detection method Methods 0.000 description 7
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
• 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
• 230000010933 acylation Effects 0.000 description 6
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