PT2049478E - N-fenilmetil-5-oxo-prolina-2-amidas substituídas como antagonistas do recetor p2x7 e seus métodos de utilização - Google Patents

Info

Publication number

PT2049478E

PT2049478E PT07787001T PT07787001T PT2049478E PT 2049478 E PT2049478 E PT 2049478E PT 07787001 T PT07787001 T PT 07787001T PT 07787001 T PT07787001 T PT 07787001T PT 2049478 E PT2049478 E PT 2049478E

Authority

PT

Portugal

Prior art keywords

methyl

oxoprolinamide

chloro

ethyl

phenyl

Prior art date

2006-07-06

Links

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• Global Dossier
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• 238000000034 method Methods 0.000 title description 107
• 101710189965 P2X purinoceptor 7 Proteins 0.000 title description 29
• 102100037602 P2X purinoceptor 7 Human genes 0.000 title description 29
• 239000002464 receptor antagonist Substances 0.000 title description 8
• 229940044551 receptor antagonist Drugs 0.000 title description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 138
• 150000001875 compounds Chemical class 0.000 claims description 121
• 239000007787 solid Substances 0.000 claims description 106
• -1 N - [(2-chloro-4-fluorophenyl) methyl] -1-cyclopentyl-5-oxoprolinamide hydrochloride N - [(2-chloro-4-fluorophenyl) methyl] -5-oxoprolinamide Chemical compound 0.000 claims description 96
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 67
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 64
• 150000003839 salts Chemical class 0.000 claims description 59
• 229910052739 hydrogen Inorganic materials 0.000 claims description 56
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 51
• 239000001257 hydrogen Substances 0.000 claims description 50
• 238000011282 treatment Methods 0.000 claims description 35
• 239000000126 substance Substances 0.000 claims description 33
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 28
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 28
• 208000002193 Pain Diseases 0.000 claims description 28
• 230000036407 pain Effects 0.000 claims description 27
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
• 125000005843 halogen group Chemical group 0.000 claims description 25
• 229910052731 fluorine Inorganic materials 0.000 claims description 24
• 150000002431 hydrogen Chemical class 0.000 claims description 24
• 229910052736 halogen Inorganic materials 0.000 claims description 23
• 150000002367 halogens Chemical class 0.000 claims description 23
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 20
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
• 239000011737 fluorine Substances 0.000 claims description 17
• YMNOJCVLDDTECB-NSHDSACASA-N (2s)-n-[(2,4-dichlorophenyl)methyl]-1-methyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=C(Cl)C=C1Cl YMNOJCVLDDTECB-NSHDSACASA-N 0.000 claims description 14
• VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims description 13
• 125000005002 aryl methyl group Chemical group 0.000 claims description 13
• 230000004770 neurodegeneration Effects 0.000 claims description 13
• 230000002265 prevention Effects 0.000 claims description 13
• 206010061218 Inflammation Diseases 0.000 claims description 12
• 239000000460 chlorine Substances 0.000 claims description 12
• 230000004054 inflammatory process Effects 0.000 claims description 12
• 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 11
• BJEMSIVBBUBXMZ-JTQLQIEISA-N (2s)-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-1-methyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=CC(C(F)(F)F)=C1Cl BJEMSIVBBUBXMZ-JTQLQIEISA-N 0.000 claims description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
• 125000004432 carbon atom Chemical group C* 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 10
• 208000004296 neuralgia Diseases 0.000 claims description 10
• 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
• 208000021722 neuropathic pain Diseases 0.000 claims description 10
• 206010065390 Inflammatory pain Diseases 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 208000024827 Alzheimer disease Diseases 0.000 claims description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 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
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• RHQHVNCBLRJDET-KRWDZBQOSA-N (2s)-1-benzyl-n-[(2-chloro-4-fluorophenyl)methyl]-5-oxopyrrolidine-2-carboxamide Chemical compound ClC1=CC(F)=CC=C1CNC(=O)[C@H]1N(CC=2C=CC=CC=2)C(=O)CC1 RHQHVNCBLRJDET-KRWDZBQOSA-N 0.000 claims description 6
• 125000006513 pyridinyl methyl group Chemical group 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 5
• 238000002560 therapeutic procedure Methods 0.000 claims description 5
• 208000009935 visceral pain Diseases 0.000 claims description 5
• SIHWHBDEWHCWCW-INIZCTEOSA-N (2s)-1-benzyl-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-5-oxopyrrolidine-2-carboxamide Chemical compound FC(F)(F)C1=CC=CC(CNC(=O)[C@H]2N(C(=O)CC2)CC=2C=CC=CC=2)=C1Cl SIHWHBDEWHCWCW-INIZCTEOSA-N 0.000 claims description 4
• RHFHPYKJKBCDEJ-ZDUSSCGKSA-N (2s)-n-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-4,4-dimethyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1C(C)(C)C(=O)N(CC)[C@@H]1C(=O)NCC1=CC=C(F)C=C1Cl RHFHPYKJKBCDEJ-ZDUSSCGKSA-N 0.000 claims description 4
• JAVGMSFCSADOCJ-NSHDSACASA-N (2s)-n-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-1-methyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=C(F)C=C1C(F)(F)F JAVGMSFCSADOCJ-NSHDSACASA-N 0.000 claims description 4
• 125000000217 alkyl group Chemical group 0.000 claims description 4
• VVWMBHKNRDAODD-CYBMUJFWSA-N (2s)-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-1,3,3-trimethyl-5-oxopyrrolidine-2-carboxamide Chemical compound CC1(C)CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=CC(C(F)(F)F)=C1Cl VVWMBHKNRDAODD-CYBMUJFWSA-N 0.000 claims description 3
• SRCBZZAEJSONIW-ZDUSSCGKSA-N (2s)-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-1-cyclobutyl-5-oxopyrrolidine-2-carboxamide Chemical compound FC(F)(F)C1=CC=CC(CNC(=O)[C@H]2N(C(=O)CC2)C2CCC2)=C1Cl SRCBZZAEJSONIW-ZDUSSCGKSA-N 0.000 claims description 3
• UMAJMKSSKVAUMP-LBPRGKRZSA-N (2s)-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-1-ethyl-4,4-dimethyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1C(C)(C)C(=O)N(CC)[C@@H]1C(=O)NCC1=CC=CC(C(F)(F)F)=C1Cl UMAJMKSSKVAUMP-LBPRGKRZSA-N 0.000 claims description 3
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
• 125000001153 fluoro group Chemical group F* 0.000 claims description 3
• 229910052757 nitrogen Inorganic materials 0.000 claims description 3
• FJYXQHJVIXPRFF-ZETCQYMHSA-N (2S)-1,2-dimethyl-5-oxopyrrolidine-2-carboxamide Chemical compound C[C@@]1(N(C(CC1)=O)C)C(=O)N FJYXQHJVIXPRFF-ZETCQYMHSA-N 0.000 claims description 2
• IEUBTQYUYPHSIV-LBPRGKRZSA-N (2s)-1-ethyl-n-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(CC)[C@@H]1C(=O)NCC1=CC=C(F)C=C1C(F)(F)F IEUBTQYUYPHSIV-LBPRGKRZSA-N 0.000 claims description 2
• QLFJNEQLOWARSQ-JTQLQIEISA-N (2s)-n-[(2,3-dichlorophenyl)methyl]-1-methyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=CC(Cl)=C1Cl QLFJNEQLOWARSQ-JTQLQIEISA-N 0.000 claims description 2
• ONGTZXPPNSRSHC-CYBMUJFWSA-N (2s)-n-[(2,4-dichlorophenyl)methyl]-1,3,3-trimethyl-5-oxopyrrolidine-2-carboxamide Chemical compound CC1(C)CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=C(Cl)C=C1Cl ONGTZXPPNSRSHC-CYBMUJFWSA-N 0.000 claims description 2
• BREZEOYXHXJAJA-ZDUSSCGKSA-N (2s)-n-[(2-chloro-6-methylphenyl)methyl]-1-ethyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(CC)[C@@H]1C(=O)NCC1=C(C)C=CC=C1Cl BREZEOYXHXJAJA-ZDUSSCGKSA-N 0.000 claims description 2
• KPYQTDDDXREZJU-ZDUSSCGKSA-N (2s)-n-[(2-cyanophenyl)methyl]-1-ethyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(CC)[C@@H]1C(=O)NCC1=CC=CC=C1C#N KPYQTDDDXREZJU-ZDUSSCGKSA-N 0.000 claims description 2
• WWFLDOWFLYUESZ-LBPRGKRZSA-N (2s)-n-[(4-bromo-2-fluorophenyl)methyl]-1-ethyl-5-oxopyrrolidine-2-carboxamide Chemical compound C1CC(=O)N(CC)[C@@H]1C(=O)NCC1=CC=C(Br)C=C1F WWFLDOWFLYUESZ-LBPRGKRZSA-N 0.000 claims description 2
• SELUVRPLQXSAEF-RLROJCQXSA-N (2s)-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-1,3-dimethyl-5-oxopyrrolidine-2-carboxamide Chemical compound CC1CC(=O)N(C)[C@@H]1C(=O)NCC1=CC=CC(C(F)(F)F)=C1Cl SELUVRPLQXSAEF-RLROJCQXSA-N 0.000 claims description 2
• AMWHFDCQJDIESP-AWEZNQCLSA-N (2s)-n-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]-1-cyclopentyl-5-oxopyrrolidine-2-carboxamide Chemical compound FC(F)(F)C1=CC=CC(CNC(=O)[C@H]2N(C(=O)CC2)C2CCCC2)=C1Cl AMWHFDCQJDIESP-AWEZNQCLSA-N 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
• XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims 1
• 235000018417 cysteine Nutrition 0.000 claims 1
• VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 claims 1
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
• 229910052721 tungsten Inorganic materials 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 348
• 239000000203 mixture Substances 0.000 description 299
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 150
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 117
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 110
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 99
• 239000000243 solution Substances 0.000 description 91
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 90
• 230000014759 maintenance of location Effects 0.000 description 85
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 78
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 77
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 70
• 239000003921 oil Substances 0.000 description 63
• 235000019198 oils Nutrition 0.000 description 63
• 239000002904 solvent Substances 0.000 description 62
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
• 239000012044 organic layer Substances 0.000 description 57
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 55
• 229920006395 saturated elastomer Polymers 0.000 description 54
• 238000003756 stirring Methods 0.000 description 53
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 48
• 239000010410 layer Substances 0.000 description 40
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 40
• 235000017557 sodium bicarbonate Nutrition 0.000 description 39
• 238000000746 purification Methods 0.000 description 37
• 238000004128 high performance liquid chromatography Methods 0.000 description 33
• 150000001412 amines Chemical class 0.000 description 32
• 239000012071 phase Substances 0.000 description 32
• 238000003818 flash chromatography Methods 0.000 description 27
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 25
• 229910052786 argon Inorganic materials 0.000 description 24
• 230000002209 hydrophobic effect Effects 0.000 description 24
• 230000015572 biosynthetic process Effects 0.000 description 22
• 238000006243 chemical reaction Methods 0.000 description 22
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 230000002829 reductive effect Effects 0.000 description 21
• 238000003786 synthesis reaction Methods 0.000 description 21
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
• 238000001914 filtration Methods 0.000 description 20
• 239000000377 silicon dioxide Substances 0.000 description 20
• 238000001704 evaporation Methods 0.000 description 19
• 230000008020 evaporation Effects 0.000 description 19
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• 239000002253 acid Substances 0.000 description 18
• 239000000463 material Substances 0.000 description 18
• CBKWAXKMZUULLO-UHFFFAOYSA-N (2-chloro-4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1Cl CBKWAXKMZUULLO-UHFFFAOYSA-N 0.000 description 17
• SHLYZEAOVWVTSW-BYPYZUCNSA-N (2s)-1-methyl-5-oxopyrrolidine-2-carboxylic acid Chemical compound CN1[C@H](C(O)=O)CCC1=O SHLYZEAOVWVTSW-BYPYZUCNSA-N 0.000 description 17
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 17
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 17
• AGWPBFFUIGQGJG-YFKPBYRVSA-N (2s)-1-ethyl-5-oxopyrrolidine-2-carboxylic acid Chemical compound CCN1[C@H](C(O)=O)CCC1=O AGWPBFFUIGQGJG-YFKPBYRVSA-N 0.000 description 16
• HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 16
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• 239000012267 brine Substances 0.000 description 15
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 15
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 14
• 238000001035 drying Methods 0.000 description 14
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
• 239000007858 starting material Substances 0.000 description 14
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 13
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
• 239000000284 extract Substances 0.000 description 13
• 238000010438 heat treatment Methods 0.000 description 13
• 238000010992 reflux Methods 0.000 description 13
• 239000011780 sodium chloride Substances 0.000 description 13
• 239000012312 sodium hydride Substances 0.000 description 13
• 229910000104 sodium hydride Inorganic materials 0.000 description 13
• 239000000725 suspension Substances 0.000 description 13
• IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 12
• GRFVQNWTQVWNBY-UHFFFAOYSA-N [2-chloro-3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1Cl GRFVQNWTQVWNBY-UHFFFAOYSA-N 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 239000012043 crude product Substances 0.000 description 12
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 12
• 238000002360 preparation method Methods 0.000 description 12
• 230000008569 process Effects 0.000 description 12
• 239000000047 product Substances 0.000 description 11
• 239000012279 sodium borohydride Substances 0.000 description 11
• 229910000033 sodium borohydride Inorganic materials 0.000 description 11
• 239000003643 water by type Substances 0.000 description 11
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 10
• 239000013058 crude material Substances 0.000 description 10
• 239000003814 drug Substances 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 9
• ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 9
• 235000019270 ammonium chloride Nutrition 0.000 description 9
• 238000010511 deprotection reaction Methods 0.000 description 9
• 238000001727 in vivo Methods 0.000 description 9
• 239000002244 precipitate Substances 0.000 description 9
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• 235000011152 sodium sulphate Nutrition 0.000 description 9
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• 238000005406 washing Methods 0.000 description 9
• WERLLDUWTMQVOS-ZETCQYMHSA-N (2s)-1-(2,2-dimethylpropyl)-5-oxopyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)CN1[C@H](C(O)=O)CCC1=O WERLLDUWTMQVOS-ZETCQYMHSA-N 0.000 description 8
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
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