TW202334113A

TW202334113A - 抗病毒化合物

抗病毒化合物 Download PDF

Info

Publication number: TW202334113A
Authority: TW; Taiwan
Prior art keywords: methyl; fluoro; chloro; acetyl; amino
Prior art date: 2021-12-09

Application number

TW111147190A

Other languages

English (en)

Chinese (zh)

Inventor

大衛艾德蒙

梁春根

貟紅英

張博

鄭秀芳

Original Assignee

瑞士商赫孚孟拉羅股份公司

Priority date

2021-12-09

Filing date

2022-12-08

Publication date

2023-09-01

2022-12-08 Application filed by 瑞士商赫孚孟拉羅股份公司 filed Critical 瑞士商赫孚孟拉羅股份公司

2023-09-01 Publication of TW202334113A publication Critical patent/TW202334113A/zh

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150000001875 compounds Chemical class 0.000 title claims abstract description 381
230000000840 anti-viral effect Effects 0.000 title 1
238000000034 method Methods 0.000 claims abstract description 117
238000004519 manufacturing process Methods 0.000 claims abstract description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 660
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 597
150000001412 amines Chemical class 0.000 claims description 294
229910052760 oxygen Inorganic materials 0.000 claims description 273
239000001301 oxygen Substances 0.000 claims description 262
-1 1-bicyclo[1.1.1]pentylmethyl Chemical group 0.000 claims description 206
150000003839 salts Chemical class 0.000 claims description 159
229910052739 hydrogen Inorganic materials 0.000 claims description 109
239000001257 hydrogen Substances 0.000 claims description 109
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 97
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 69
125000001072 heteroaryl group Chemical group 0.000 claims description 66
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 49
229910052799 carbon Inorganic materials 0.000 claims description 48
238000006243 chemical reaction Methods 0.000 claims description 46
150000001721 carbon Chemical group 0.000 claims description 43
239000000460 chlorine Substances 0.000 claims description 40
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 38
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 35
150000002431 hydrogen Chemical class 0.000 claims description 35
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 32
229910052801 chlorine Inorganic materials 0.000 claims description 32
125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 31
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 31
150000002367 halogens Chemical class 0.000 claims description 31
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 30
229910052731 fluorine Inorganic materials 0.000 claims description 30
239000011737 fluorine Substances 0.000 claims description 30
125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 29
229910052736 halogen Inorganic materials 0.000 claims description 29
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 27
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 25
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 23
125000000217 alkyl group Chemical group 0.000 claims description 22
125000004432 carbon atom Chemical group C* 0.000 claims description 20
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
125000001424 substituent group Chemical group 0.000 claims description 20
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 17
ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 16
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
125000006420 1-fluorocyclopropyl group Chemical group [H]C1([H])C([H])([H])C1(F)* 0.000 claims description 11
239000007822 coupling agent Substances 0.000 claims description 11
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 10
101800000504 3C-like protease Proteins 0.000 claims description 9
101800001016 Picornain 3C-like protease Proteins 0.000 claims description 9
101800000596 Probable picornain 3C-like protease Proteins 0.000 claims description 9
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
208000001528 Coronaviridae Infections Diseases 0.000 claims description 8
229940080818 propionamide Drugs 0.000 claims description 8
125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 7
239000003814 drug Substances 0.000 claims description 7
230000002255 enzymatic effect Effects 0.000 claims description 7
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
238000011282 treatment Methods 0.000 claims description 7
125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 claims description 6
125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
230000002401 inhibitory effect Effects 0.000 claims description 6
125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 claims description 6
125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
125000005915 C6-C14 aryl group Chemical group 0.000 claims description 5
125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
230000002265 prevention Effects 0.000 claims description 5
125000004076 pyridyl group Chemical group 0.000 claims description 5
125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 4
125000004429 atom Chemical group 0.000 claims description 4
125000001786 isothiazolyl group Chemical group 0.000 claims description 4
125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 4
125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
238000006467 substitution reaction Methods 0.000 claims description 4
125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 3
JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 claims description 3
239000013543 active substance Substances 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
125000004035 thiopropyl group Chemical group [H]SC([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
HJCUTNIGJHJGCF-UHFFFAOYSA-N acridan acid Natural products C1=CC=C2CC3=CC=CC=C3NC2=C1 HJCUTNIGJHJGCF-UHFFFAOYSA-N 0.000 claims description 2
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
BSEXNZMHLUMQKR-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1.NC(=O)C1CC1 BSEXNZMHLUMQKR-UHFFFAOYSA-N 0.000 claims 3
230000037429 base substitution Effects 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 198
229940042399 direct acting antivirals protease inhibitors Drugs 0.000 abstract description 2
239000000137 peptide hydrolase inhibitor Substances 0.000 abstract description 2
230000003612 virological effect Effects 0.000 abstract description 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 217
238000002360 preparation method Methods 0.000 description 207
239000000543 intermediate Substances 0.000 description 176
238000004949 mass spectrometry Methods 0.000 description 176
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 157
239000000243 solution Substances 0.000 description 134
235000019439 ethyl acetate Nutrition 0.000 description 106
238000005481 NMR spectroscopy Methods 0.000 description 95
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 82
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 78
239000007787 solid Substances 0.000 description 77
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 66
239000011541 reaction mixture Substances 0.000 description 63
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 63
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 63
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 52
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 52
239000007832 Na2SO4 Substances 0.000 description 51
229910052938 sodium sulfate Inorganic materials 0.000 description 51
235000011152 sodium sulphate Nutrition 0.000 description 51
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 50
239000003921 oil Substances 0.000 description 48
235000019198 oils Nutrition 0.000 description 48
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 46
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
239000002585 base Substances 0.000 description 44
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
239000012267 brine Substances 0.000 description 41
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 41
LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 39
KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 33
KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 33
VLKZOEOYAKHREP-UHFFFAOYSA-N methyl pentane Natural products CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
239000002904 solvent Substances 0.000 description 30
JSHXJPFZKBRLFU-JQWIXIFHSA-N (2s,3s)-3-methyl-2-(phenylmethoxycarbonylamino)pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 JSHXJPFZKBRLFU-JQWIXIFHSA-N 0.000 description 27
239000000741 silica gel Substances 0.000 description 27
229910002027 silica gel Inorganic materials 0.000 description 27
239000000706 filtrate Substances 0.000 description 26
239000012071 phase Substances 0.000 description 25
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
239000012074 organic phase Substances 0.000 description 24
239000000725 suspension Substances 0.000 description 22
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
239000012044 organic layer Substances 0.000 description 21
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
239000012230 colorless oil Substances 0.000 description 19
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 19
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 18
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
238000003818 flash chromatography Methods 0.000 description 18
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 18
230000002441 reversible effect Effects 0.000 description 18
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 17
GQZXNSPRSGFJLY-UHFFFAOYSA-N hydroxyphosphanone Chemical compound OP=O GQZXNSPRSGFJLY-UHFFFAOYSA-N 0.000 description 17
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239000007821 HATU Substances 0.000 description 16
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 16
230000000670 limiting effect Effects 0.000 description 16
239000011734 sodium Substances 0.000 description 16
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 15
239000002253 acid Substances 0.000 description 14
VZJVRCWSIVAASQ-SFOWXEAESA-N (2R)-2-chloro-2-fluoroacetyl chloride Chemical compound F[C@H](Cl)C(Cl)=O VZJVRCWSIVAASQ-SFOWXEAESA-N 0.000 description 13
125000000753 cycloalkyl group Chemical group 0.000 description 13
125000005843 halogen group Chemical group 0.000 description 13
PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical group CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 12
229960000549 4-dimethylaminophenol Drugs 0.000 description 12
150000007530 organic bases Chemical class 0.000 description 12
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 12
238000002953 preparative HPLC Methods 0.000 description 12
125000006413 ring segment Chemical group 0.000 description 12
KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 11
241000711573 Coronaviridae Species 0.000 description 11
239000008346 aqueous phase Substances 0.000 description 11
238000004808 supercritical fluid chromatography Methods 0.000 description 11
RWFNAAZDBOSSIY-YCLXABBFSA-N (1r,2s,5s)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid;hydrochloride Chemical compound Cl.C1N[C@H](C(O)=O)[C@H]2C(C)(C)[C@H]21 RWFNAAZDBOSSIY-YCLXABBFSA-N 0.000 description 10
241001678559 COVID-19 virus Species 0.000 description 10
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 10
239000007858 starting material Substances 0.000 description 10
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 9
241000315672 SARS coronavirus Species 0.000 description 9
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
150000002148 esters Chemical class 0.000 description 9
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 9
QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 description 8
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
229940024606 amino acid Drugs 0.000 description 8
235000001014 amino acid Nutrition 0.000 description 8
150000001413 amino acids Chemical class 0.000 description 8
229910052757 nitrogen Inorganic materials 0.000 description 8
238000000746 purification Methods 0.000 description 8
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 7
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 7
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239000012043 crude product Substances 0.000 description 7
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125000006239 protecting group Chemical group 0.000 description 7
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208000024891 symptom Diseases 0.000 description 7
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
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125000005914 C6-C14 aryloxy group Chemical group 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
239000002671 adjuvant Substances 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 6
150000001728 carbonyl compounds Chemical class 0.000 description 6
AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 6
208000035475 disorder Diseases 0.000 description 6
238000002347 injection Methods 0.000 description 6
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BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
125000002950 monocyclic group Chemical group 0.000 description 6
125000000719 pyrrolidinyl group Chemical group 0.000 description 6
238000000926 separation method Methods 0.000 description 6
239000000377 silicon dioxide Substances 0.000 description 6
229910052717 sulfur Inorganic materials 0.000 description 6
BDNWSJQJILLEBS-YFKPBYRVSA-N (2s)-4,4-dimethylpyrrolidine-2-carboxylic acid Chemical compound CC1(C)CN[C@H](C(O)=O)C1 BDNWSJQJILLEBS-YFKPBYRVSA-N 0.000 description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 5
AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 5
238000001816 cooling Methods 0.000 description 5
238000005859 coupling reaction Methods 0.000 description 5
XRILGDCLXWSSHU-UHFFFAOYSA-N methyl 3-azabicyclo[3.1.0]hexane-2-carboxylate Chemical compound COC(=O)C1NCC2CC12 XRILGDCLXWSSHU-UHFFFAOYSA-N 0.000 description 5
239000012299 nitrogen atmosphere Substances 0.000 description 5
235000019260 propionic acid Nutrition 0.000 description 5
DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Chemical compound OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 5
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 5
238000003756 stirring Methods 0.000 description 5
238000003786 synthesis reaction Methods 0.000 description 5
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