HRP990396A2 - NITROGEN CONTAINING HETEROBICYCLES AS FACTOR Xa INHIBITORS - Google Patents

Info

Publication number

HRP990396A2

HRP990396A2 HR990396A HRP990396A HRP990396A2 HR P990396 A2 HRP990396 A2 HR P990396A2 HR 990396 A HR990396 A HR 990396A HR P990396 A HRP990396 A HR P990396A HR P990396 A2 HRP990396 A2 HR P990396A2

Authority

HR

Croatia

Prior art keywords

biphen

alkyl

trifluoromethyl

dihydropyrazolo

methyl

Prior art date

1998-12-23

Links

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• 229910052757 nitrogen Inorganic materials 0.000 title claims description 71
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 title description 26
• 229940123583 Factor Xa inhibitor Drugs 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims description 261
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 164
• -1 methylenedioxy Chemical group 0.000 claims description 153
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 86
• 229910052760 oxygen Inorganic materials 0.000 claims description 71
• 229910052717 sulfur Inorganic materials 0.000 claims description 71
• 238000000034 method Methods 0.000 claims description 61
• 125000005842 heteroatom Chemical group 0.000 claims description 57
• 150000003839 salts Chemical class 0.000 claims description 55
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 50
• 229910052799 carbon Inorganic materials 0.000 claims description 49
• 102100022631 Glutamate receptor ionotropic, NMDA 2C Human genes 0.000 claims description 48
• 108091008646 testicular receptors Proteins 0.000 claims description 48
• 229920006395 saturated elastomer Polymers 0.000 claims description 41
• 125000000623 heterocyclic group Chemical group 0.000 claims description 38
• 108020002076 NR2 subfamily Proteins 0.000 claims description 36
• 125000000217 alkyl group Chemical group 0.000 claims description 36
• 125000002837 carbocyclic group Chemical group 0.000 claims description 33
• 229910052739 hydrogen Inorganic materials 0.000 claims description 33
• 229910052794 bromium Inorganic materials 0.000 claims description 30
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 28
• 229910052731 fluorine Inorganic materials 0.000 claims description 28
• 229910052740 iodine Inorganic materials 0.000 claims description 28
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 28
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 26
• 229910052801 chlorine Inorganic materials 0.000 claims description 25
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
• 125000004076 pyridyl group Chemical group 0.000 claims description 20
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 20
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 19
• 125000004429 atom Chemical group 0.000 claims description 18
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 16
• 125000003118 aryl group Chemical group 0.000 claims description 15
• 125000002541 furyl group Chemical group 0.000 claims description 14
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 14
• 108020004021 3-ketosteroid receptors Proteins 0.000 claims description 12
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
• 125000002883 imidazolyl group Chemical group 0.000 claims description 11
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 10
• 125000001544 thienyl group Chemical group 0.000 claims description 10
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
• 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 claims description 9
• 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 9
• 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 9
• 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 claims description 9
• 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 9
• 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 claims description 9
• 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 claims description 9
• 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 claims description 9
• 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 claims description 9
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 9
• 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
• 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 9
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 9
• 125000001041 indolyl group Chemical group 0.000 claims description 9
• 125000005438 isoindazolyl group Chemical group 0.000 claims description 9
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 9
• 125000002757 morpholinyl group Chemical group 0.000 claims description 9
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 9
• 125000002971 oxazolyl group Chemical group 0.000 claims description 9
• 125000004193 piperazinyl group Chemical group 0.000 claims description 9
• 125000003386 piperidinyl group Chemical group 0.000 claims description 9
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 9
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 9
• 125000000335 thiazolyl group Chemical group 0.000 claims description 9
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 8
• 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 claims description 8
• 108020000002 NR3 subfamily Proteins 0.000 claims description 8
• 125000002947 alkylene group Chemical group 0.000 claims description 8
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 8
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
• 230000009424 thromboembolic effect Effects 0.000 claims description 8
• 125000001425 triazolyl group Chemical group 0.000 claims description 8
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
• 229910052727 yttrium Inorganic materials 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 7
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
• 125000004434 sulfur atom Chemical group 0.000 claims description 7
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 6
• 239000003814 drug Substances 0.000 claims description 6
• 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 5
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 5
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 5
• 125000004104 aryloxy group Chemical group 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 4
• XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 4
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 claims description 4
• 125000003971 isoxazolinyl group Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
• ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims description 2
• 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
• 230000002265 prevention Effects 0.000 claims description 2
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000004523 tetrazol-1-yl group Chemical group N1(N=NN=C1)* 0.000 claims description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 366
• 239000000243 solution Substances 0.000 description 212
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 203
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 200
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 187
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 163
• 235000019439 ethyl acetate Nutrition 0.000 description 150
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
• 238000006243 chemical reaction Methods 0.000 description 125
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 113
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 104
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 100
• 235000019341 magnesium sulphate Nutrition 0.000 description 100
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 96
• 239000000203 mixture Substances 0.000 description 82
• 239000007787 solid Substances 0.000 description 79
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 69
• 238000005160 1H NMR spectroscopy Methods 0.000 description 66
• 239000012267 brine Substances 0.000 description 62
• 239000000741 silica gel Substances 0.000 description 62
• 229910002027 silica gel Inorganic materials 0.000 description 62
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 62
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 59
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 58
• 239000000047 product Substances 0.000 description 57
• 230000002829 reductive effect Effects 0.000 description 57
• 238000000746 purification Methods 0.000 description 51
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
• 238000007792 addition Methods 0.000 description 49
• 239000000543 intermediate Substances 0.000 description 48
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 48
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 48
• 125000002619 bicyclic group Chemical group 0.000 description 47
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 45
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 45
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
• 238000010992 reflux Methods 0.000 description 45
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
• 238000003756 stirring Methods 0.000 description 41
• LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 38
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
• 239000002585 base Substances 0.000 description 34
• 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 34
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 32
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 239000011541 reaction mixture Substances 0.000 description 32
• 150000002148 esters Chemical group 0.000 description 30
• 230000002441 reversible effect Effects 0.000 description 30
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 28
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 27
• 238000002953 preparative HPLC Methods 0.000 description 27
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 26
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 26
• 239000010410 layer Substances 0.000 description 26
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 26
• 235000017557 sodium bicarbonate Nutrition 0.000 description 26
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
• 239000012266 salt solution Substances 0.000 description 25
• 229910000027 potassium carbonate Inorganic materials 0.000 description 24
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 22
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 22
• 239000002904 solvent Substances 0.000 description 22
• 230000015572 biosynthetic process Effects 0.000 description 21
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 21
• 238000010511 deprotection reaction Methods 0.000 description 21
• 238000010438 heat treatment Methods 0.000 description 21
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
• 235000010288 sodium nitrite Nutrition 0.000 description 19
• 238000004587 chromatography analysis Methods 0.000 description 18
• 238000002360 preparation method Methods 0.000 description 18
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
• FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Substances O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 18
• QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 18
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 17
• 229960000583 acetic acid Drugs 0.000 description 17
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
• 150000002576 ketones Chemical group 0.000 description 16
• 239000000651 prodrug Substances 0.000 description 16
• 229940002612 prodrug Drugs 0.000 description 16
• 230000009467 reduction Effects 0.000 description 16
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 15
• 150000001721 carbon Chemical group 0.000 description 15
• 238000006722 reduction reaction Methods 0.000 description 15
• 239000000377 silicon dioxide Substances 0.000 description 15
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 14
• 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 14
• 150000001540 azides Chemical class 0.000 description 14
• 239000003153 chemical reaction reagent Substances 0.000 description 14
• 238000007254 oxidation reaction Methods 0.000 description 14
• 235000011181 potassium carbonates Nutrition 0.000 description 14
• 239000000126 substance Substances 0.000 description 14
• 125000001424 substituent group Chemical group 0.000 description 14
• 125000001302 tertiary amino group Chemical group 0.000 description 14
• 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 13
• 108010074860 Factor Xa Proteins 0.000 description 13
• 235000019253 formic acid Nutrition 0.000 description 13
• 238000004128 high performance liquid chromatography Methods 0.000 description 13
• 230000003647 oxidation Effects 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 239000002253 acid Substances 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 12
• 125000004093 cyano group Chemical group *C#N 0.000 description 12
• 150000004820 halides Chemical class 0.000 description 12
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 12
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 11
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 11
• 150000001299 aldehydes Chemical class 0.000 description 11
• 238000009833 condensation Methods 0.000 description 11
• 230000005494 condensation Effects 0.000 description 11
• 239000006260 foam Substances 0.000 description 11
• 238000004007 reversed phase HPLC Methods 0.000 description 11
• DGUWACLYDSWXRZ-UHFFFAOYSA-N (2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C=O DGUWACLYDSWXRZ-UHFFFAOYSA-N 0.000 description 10
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 10
• JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 description 10
• 229960001171 acetohydroxamic acid Drugs 0.000 description 10
• 239000012954 diazonium Substances 0.000 description 10
• 238000003818 flash chromatography Methods 0.000 description 10
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
• 239000012044 organic layer Substances 0.000 description 10
• 235000015320 potassium carbonate Nutrition 0.000 description 10
• 150000003217 pyrazoles Chemical class 0.000 description 10
• 239000012279 sodium borohydride Substances 0.000 description 10
• 229910000033 sodium borohydride Inorganic materials 0.000 description 10
• 150000003852 triazoles Chemical class 0.000 description 10
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 9
• 125000000524 functional group Chemical group 0.000 description 9
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