SG191840A1 - Compounds for the reduction of beta-amyloid production - Google Patents

Info

Publication number

SG191840A1

SG191840A1 SG2013051552A SG2013051552A SG191840A1 SG 191840 A1 SG191840 A1 SG 191840A1 SG 2013051552 A SG2013051552 A SG 2013051552A SG 2013051552 A SG2013051552 A SG 2013051552A SG 191840 A1 SG191840 A1 SG 191840A1

Authority

SG

Singapore

Prior art keywords

mmol

dihydro

cyclopenta

preparation

phenyl

Prior art date

2011-01-28

Links

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• Global Dossier
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• 150000001875 compounds Chemical class 0.000 title claims abstract description 226
• 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
• 230000009467 reduction Effects 0.000 title claims description 14
• 102000013455 Amyloid beta-Peptides Human genes 0.000 title 1
• 108010090849 Amyloid beta-Peptides Proteins 0.000 title 1
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 30
• 238000011282 treatment Methods 0.000 claims abstract description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims description 84
• 238000000034 method Methods 0.000 claims description 81
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 78
• 125000000217 alkyl group Chemical group 0.000 claims description 44
• 150000003839 salts Chemical class 0.000 claims description 42
• -1 hydroxy, methylamino Chemical group 0.000 claims description 39
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 39
• 125000001424 substituent group Chemical group 0.000 claims description 38
• 125000005843 halogen group Chemical group 0.000 claims description 34
• 239000001257 hydrogen Substances 0.000 claims description 32
• 125000003545 alkoxy group Chemical group 0.000 claims description 30
• 125000004076 pyridyl group Chemical group 0.000 claims description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 229910052757 nitrogen Inorganic materials 0.000 claims description 15
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
• 206010067889 Dementia with Lewy bodies Diseases 0.000 claims description 12
• 201000002832 Lewy body dementia Diseases 0.000 claims description 12
• 208000035475 disorder Diseases 0.000 claims description 12
• 208000005145 Cerebral amyloid angiopathy Diseases 0.000 claims description 11
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• 201000008319 inclusion body myositis Diseases 0.000 claims description 11
• 125000002560 nitrile group Chemical group 0.000 claims description 10
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 9
• 125000005842 heteroatom Chemical group 0.000 claims description 9
• 125000002950 monocyclic group Chemical group 0.000 claims description 9
• 125000002619 bicyclic group Chemical group 0.000 claims description 8
• 125000005879 dioxolanyl group Chemical group 0.000 claims description 8
• 201000010374 Down Syndrome Diseases 0.000 claims description 7
• 208000010877 cognitive disease Diseases 0.000 claims description 7
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 6
• 208000002780 macular degeneration Diseases 0.000 claims description 6
• 208000027061 mild cognitive impairment Diseases 0.000 claims description 6
• 241000124008 Mammalia Species 0.000 claims description 5
• 206010064930 age-related macular degeneration Diseases 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
• 125000001072 heteroaryl group Chemical group 0.000 claims description 4
• 125000003282 alkyl amino group Chemical group 0.000 claims description 3
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
• NJFIOBFAEKDSAX-UHFFFAOYSA-N 2-methoxy-4-[[7-(2-methoxyphenyl)-4-(methylamino)-6,7-dihydro-5h-cyclopenta[d]pyrimidin-2-yl]amino]benzonitrile Chemical compound N=1C=2C(C=3C(=CC=CC=3)OC)CCC=2C(NC)=NC=1NC1=CC=C(C#N)C(OC)=C1 NJFIOBFAEKDSAX-UHFFFAOYSA-N 0.000 claims description 2
• 206010028980 Neoplasm Diseases 0.000 claims description 2
• 125000003342 alkenyl group Chemical group 0.000 claims description 2
• 201000011510 cancer Diseases 0.000 claims description 2
• 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 2
• HPEAAAQYIBAHCB-UHFFFAOYSA-N 4-[[7-(4-chloro-2-fluorophenyl)-4-(methylamino)-6,7-dihydro-5h-cyclopenta[d]pyrimidin-2-yl]amino]-2-methoxybenzonitrile Chemical compound N=1C=2C(C=3C(=CC(Cl)=CC=3)F)CCC=2C(NC)=NC=1NC1=CC=C(C#N)C(OC)=C1 HPEAAAQYIBAHCB-UHFFFAOYSA-N 0.000 claims 1
• YHEMFEUAFNYLBN-UHFFFAOYSA-N 4-[[7-(4-fluorophenyl)-7-methyl-4-(methylamino)-5,6-dihydrocyclopenta[d]pyrimidin-2-yl]amino]-2-methoxybenzonitrile Chemical compound N=1C(C(CC2)(C)C=3C=CC(F)=CC=3)=C2C(NC)=NC=1NC1=CC=C(C#N)C(OC)=C1 YHEMFEUAFNYLBN-UHFFFAOYSA-N 0.000 claims 1
• DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 abstract description 7
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 508
• 238000002360 preparation method Methods 0.000 description 437
• 239000000543 intermediate Substances 0.000 description 337
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 293
• 239000000243 solution Substances 0.000 description 285
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 279
• 235000019439 ethyl acetate Nutrition 0.000 description 192
• 239000011541 reaction mixture Substances 0.000 description 191
• 239000002904 solvent Substances 0.000 description 144
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 142
• 238000005481 NMR spectroscopy Methods 0.000 description 139
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 134
• 230000002829 reductive effect Effects 0.000 description 126
• 239000000203 mixture Substances 0.000 description 115
• 238000004440 column chromatography Methods 0.000 description 108
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 107
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 100
• 239000007787 solid Substances 0.000 description 99
• 239000000741 silica gel Substances 0.000 description 95
• 229910002027 silica gel Inorganic materials 0.000 description 95
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 83
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 82
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 82
• 238000006243 chemical reaction Methods 0.000 description 81
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 80
• 239000012044 organic layer Substances 0.000 description 80
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 73
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
• 239000012267 brine Substances 0.000 description 64
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 64
• 239000012071 phase Substances 0.000 description 60
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 41
• 238000010992 reflux Methods 0.000 description 40
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 37
• 239000010410 layer Substances 0.000 description 36
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
• 239000007788 liquid Substances 0.000 description 34
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
• 229920006395 saturated elastomer Polymers 0.000 description 33
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 32
• 239000000284 extract Substances 0.000 description 32
• YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 32
• 238000000746 purification Methods 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
• 239000012043 crude product Substances 0.000 description 29
• 239000003795 chemical substances by application Substances 0.000 description 28
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 28
• 239000007864 aqueous solution Substances 0.000 description 27
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
• 238000003756 stirring Methods 0.000 description 24
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 22
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 22
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 21
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
• 239000000047 product Substances 0.000 description 20
• 238000003818 flash chromatography Methods 0.000 description 19
• VBBUFMFZDHLELS-UHFFFAOYSA-N n-(oxomethylidene)carbamoyl chloride Chemical compound ClC(=O)N=C=O VBBUFMFZDHLELS-UHFFFAOYSA-N 0.000 description 19
• 239000011734 sodium Substances 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• 239000012230 colorless oil Substances 0.000 description 17
• 229920000728 polyester Polymers 0.000 description 17
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
• 239000004202 carbamide Substances 0.000 description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
• 235000017557 sodium bicarbonate Nutrition 0.000 description 16
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 16
• ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 15
• ATWGDJMSPINOIM-UHFFFAOYSA-N 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical compound C1=CC(F)=CC=C1C1C(N=C(Cl)N=C2Cl)=C2CC1 ATWGDJMSPINOIM-UHFFFAOYSA-N 0.000 description 14
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 13
• NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 13
• 239000003921 oil Substances 0.000 description 13
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 239000000908 ammonium hydroxide Substances 0.000 description 12
• 239000003153 chemical reaction reagent Substances 0.000 description 12
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 12
• 235000019198 oils Nutrition 0.000 description 12
• 239000000843 powder Substances 0.000 description 12
• 239000000377 silicon dioxide Substances 0.000 description 12
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
• 230000015572 biosynthetic process Effects 0.000 description 11
• LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 11
• 238000009472 formulation Methods 0.000 description 11
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 11
• 238000006722 reduction reaction Methods 0.000 description 11
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
• JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 10
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 10
• BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• 238000004128 high performance liquid chromatography Methods 0.000 description 10
• KTDRJLRJAHBQDQ-UHFFFAOYSA-N 4-amino-2-methoxybenzonitrile Chemical compound COC1=CC(N)=CC=C1C#N KTDRJLRJAHBQDQ-UHFFFAOYSA-N 0.000 description 9
• 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 9
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 9
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 150000001412 amines Chemical class 0.000 description 9
• 230000003197 catalytic effect Effects 0.000 description 9
• 150000002431 hydrogen Chemical class 0.000 description 9
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 9
• 239000003826 tablet Substances 0.000 description 9
• IPFZARHKKQXZPN-UHFFFAOYSA-N 2,4-dichloro-7-phenyl-6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical compound C1CC=2C(Cl)=NC(Cl)=NC=2C1C1=CC=CC=C1 IPFZARHKKQXZPN-UHFFFAOYSA-N 0.000 description 8
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
• 239000004480 active ingredient Substances 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 8
• XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 8
• 150000002576 ketones Chemical class 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
• 238000002953 preparative HPLC Methods 0.000 description 8
• NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 8
• 239000000725 suspension Substances 0.000 description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
• SGLPRIIINMCHCW-UHFFFAOYSA-N 5h-pyrimidine-2,4-dione Chemical compound O=C1CC=NC(=O)N1 SGLPRIIINMCHCW-UHFFFAOYSA-N 0.000 description 7
• 239000002253 acid Substances 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
• 229910002091 carbon monoxide Inorganic materials 0.000 description 7
• 238000010511 deprotection reaction Methods 0.000 description 7
• 201000010099 disease Diseases 0.000 description 7
• 230000000694 effects Effects 0.000 description 7
• RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• CDDGNGVFPQRJJM-SCSAIBSYSA-N (3r)-3-fluoropyrrolidine Chemical compound F[C@@H]1CCNC1 CDDGNGVFPQRJJM-SCSAIBSYSA-N 0.000 description 6
• UJRHVRAGWATMET-UHFFFAOYSA-N 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical compound C1=CC(Cl)=CC=C1C1C(N=C(Cl)N=C2Cl)=C2CC1 UJRHVRAGWATMET-UHFFFAOYSA-N 0.000 description 6
• IBYKWGJCVSTIBW-UHFFFAOYSA-N 2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline Chemical compound C1=CC(F)=CC=C1C1C2=NC(Cl)=NC(Cl)=C2CCC1 IBYKWGJCVSTIBW-UHFFFAOYSA-N 0.000 description 6
• QUHVRXKSQHIZNV-UHFFFAOYSA-N 3,3-difluoroazetidine Chemical compound FC1(F)CNC1 QUHVRXKSQHIZNV-UHFFFAOYSA-N 0.000 description 6
• VDKRHQDYTOQEIB-UHFFFAOYSA-N 3-iodo-4,4-dimethoxyoxane Chemical compound COC1(OC)CCOCC1I VDKRHQDYTOQEIB-UHFFFAOYSA-N 0.000 description 6
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
• 229950000178 cyclopentobarbital Drugs 0.000 description 6
• GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 6
• 238000010438 heat treatment Methods 0.000 description 6
• 238000002514 liquid chromatography mass spectrum Methods 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 235000019341 magnesium sulphate Nutrition 0.000 description 6
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
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