JP2007522159A - テトラヒドロベンゾ［ｄ］アゼピン−２−オン誘導体および心臓血管疾患を処置するためのその使用 - Google Patents

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Publication number

JP2007522159A

JP2007522159A JP2006552501A JP2006552501A JP2007522159A JP 2007522159 A JP2007522159 A JP 2007522159A JP 2006552501 A JP2006552501 A JP 2006552501A JP 2006552501 A JP2006552501 A JP 2006552501A JP 2007522159 A JP2007522159 A JP 2007522159A

Authority

JP

Japan

Prior art keywords

alkyl

formula

compound

mmol

hydrogen

Prior art date

2004-02-10

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.)

Withdrawn

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• 208000024172 Cardiovascular disease Diseases 0.000 title abstract description 9
• DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical class O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 title abstract description 4
• HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical group C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 title abstract description 4
• 238000000034 method Methods 0.000 claims abstract description 83
• 238000004519 manufacturing process Methods 0.000 claims abstract description 12
• 239000003814 drug Substances 0.000 claims abstract description 11
• 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 10
• 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 9
• 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 8
• 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 8
• 238000002360 preparation method Methods 0.000 claims abstract description 7
• 208000037803 restenosis Diseases 0.000 claims abstract description 7
• 230000006806 disease prevention Effects 0.000 claims abstract description 6
• 208000028867 ischemia Diseases 0.000 claims abstract description 6
• 239000000126 substance Substances 0.000 claims abstract description 4
• 230000008569 process Effects 0.000 claims abstract description 3
• 150000001875 compounds Chemical class 0.000 claims description 201
• -1 hydroxy, amino, carboxyl Chemical group 0.000 claims description 64
• 239000002904 solvent Substances 0.000 claims description 40
• 150000003839 salts Chemical class 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 34
• 229910052739 hydrogen Inorganic materials 0.000 claims description 34
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 30
• 239000012453 solvate Substances 0.000 claims description 30
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 27
• 125000001424 substituent group Chemical group 0.000 claims description 27
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 20
• 241001465754 Metazoa Species 0.000 claims description 18
• 125000000623 heterocyclic group Chemical group 0.000 claims description 18
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
• 239000000460 chlorine Substances 0.000 claims description 14
• 229910052801 chlorine Inorganic materials 0.000 claims description 14
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
• 229910052731 fluorine Inorganic materials 0.000 claims description 10
• 239000011737 fluorine Substances 0.000 claims description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
• 230000002265 prevention Effects 0.000 claims description 10
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 9
• 239000012442 inert solvent Substances 0.000 claims description 9
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
• 239000002253 acid Substances 0.000 claims description 8
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
• 125000004043 oxo group Chemical group O=* 0.000 claims description 8
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
• 125000004429 atom Chemical group 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
• 125000005842 heteroatom Chemical group 0.000 claims description 6
• 150000002431 hydrogen Chemical class 0.000 claims description 6
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
• 230000009435 amidation Effects 0.000 claims description 5
• 238000007112 amidation reaction Methods 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
• 150000001735 carboxylic acids Chemical class 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
• GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 claims description 5
• 125000001624 naphthyl group Chemical group 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 229910052717 sulfur Inorganic materials 0.000 claims description 4
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
• 102000007592 Apolipoproteins Human genes 0.000 claims description 3
• 108010071619 Apolipoproteins Proteins 0.000 claims description 3
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 3
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 3
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 3
• 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
• 125000003545 alkoxy group Chemical group 0.000 claims description 3
• 239000003963 antioxidant agent Substances 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• 230000032050 esterification Effects 0.000 claims description 3
• 238000005886 esterification reaction Methods 0.000 claims description 3
• 230000007062 hydrolysis Effects 0.000 claims description 3
• 238000006460 hydrolysis reaction Methods 0.000 claims description 3
• 231100000252 nontoxic Toxicity 0.000 claims description 3
• 230000003000 nontoxic effect Effects 0.000 claims description 3
• 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
• 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 229940122502 Cholesterol absorption inhibitor Drugs 0.000 claims 1
• 230000003078 antioxidant effect Effects 0.000 claims 1
• 230000002757 inflammatory effect Effects 0.000 claims 1
• 201000010099 disease Diseases 0.000 abstract description 6
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 183
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 114
• 239000000243 solution Substances 0.000 description 101
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 67
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
• HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 58
• 239000000203 mixture Substances 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
• 239000012074 organic phase Substances 0.000 description 50
• 239000011541 reaction mixture Substances 0.000 description 46
• 238000005160 1H NMR spectroscopy Methods 0.000 description 45
• 229910052938 sodium sulfate Inorganic materials 0.000 description 45
• 235000011152 sodium sulphate Nutrition 0.000 description 45
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 44
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• 239000003480 eluent Substances 0.000 description 36
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• 238000006243 chemical reaction Methods 0.000 description 30
• 238000002953 preparative HPLC Methods 0.000 description 30
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
• 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 22
• 235000019253 formic acid Nutrition 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 125000004432 carbon atom Chemical group C* 0.000 description 21
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 20
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 16
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 239000002585 base Substances 0.000 description 15
• 238000004128 high performance liquid chromatography Methods 0.000 description 14
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 13
• 239000012071 phase Substances 0.000 description 13
• 229940031439 squalene Drugs 0.000 description 13
• YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 12
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 12
• 230000015572 biosynthetic process Effects 0.000 description 12
• PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 12
• TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
• 230000037396 body weight Effects 0.000 description 11
• 239000003826 tablet Substances 0.000 description 11
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
• 102100037997 Squalene synthase Human genes 0.000 description 10
• 239000008186 active pharmaceutical agent Substances 0.000 description 10
• 229940088679 drug related substance Drugs 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• 108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 description 9
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
• 239000008346 aqueous phase Substances 0.000 description 9
• 238000004587 chromatography analysis Methods 0.000 description 9
• 239000003112 inhibitor Substances 0.000 description 9
• 239000000741 silica gel Substances 0.000 description 9
• 229910002027 silica gel Inorganic materials 0.000 description 9
• 239000000725 suspension Substances 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
• DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 8
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
• 230000002829 reductive effect Effects 0.000 description 8
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 7
• 239000012300 argon atmosphere Substances 0.000 description 7
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
• 229910000024 caesium carbonate Inorganic materials 0.000 description 7
• 238000001816 cooling Methods 0.000 description 7
• ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 7
• 239000005457 ice water Substances 0.000 description 7
• 150000003254 radicals Chemical class 0.000 description 7
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
• 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 description 6
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
• 239000007983 Tris buffer Substances 0.000 description 6
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
• 238000003556 assay Methods 0.000 description 6
• 235000012000 cholesterol Nutrition 0.000 description 6
• CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
• CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
• BTUGGGLMQBJCBN-UHFFFAOYSA-N 1-iodo-2-methylpropane Chemical compound CC(C)CI BTUGGGLMQBJCBN-UHFFFAOYSA-N 0.000 description 5
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
• 150000001993 dienes Chemical class 0.000 description 5
• PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 5
• 229930195733 hydrocarbon Natural products 0.000 description 5
• 239000011630 iodine Substances 0.000 description 5
• 229910052740 iodine Inorganic materials 0.000 description 5
• 239000007788 liquid Substances 0.000 description 5
• 239000000047 product Substances 0.000 description 5
• 238000000825 ultraviolet detection Methods 0.000 description 5
• 238000010626 work up procedure Methods 0.000 description 5
• PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 4
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
• 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 4
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• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
• 239000007821 HATU Substances 0.000 description 4
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
• 241000700159 Rattus Species 0.000 description 4
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
• SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 4
• 150000002170 ethers Chemical class 0.000 description 4
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