HU181885B

HU181885B - Process for producing benzo-, thieno- and pyrazolo-imidazo-diazepine derivatives

Process for producing benzo-, thieno- and pyrazolo-imidazo-diazepine derivatives Download PDF

Info

Publication number: HU181885B
Authority: HU; Hungary
Prior art keywords: formula; group; alkyl; phenyl; compounds
Prior art date: 1975-08-07

Application number

Other languages

English (en)

Spanish (es)

Hungarian (hu)

Inventor

Armin Walser

Rodney I Fryer

Original Assignee

Hoffmann La Roche

Priority date

1975-08-07

Filing date

1976-06-04

Publication date

1983-11-28

1976-06-04 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1983-11-28 Publication of HU181885B publication Critical patent/HU181885B/hu

Links

238000000034 method Methods 0.000 title claims abstract description 108
230000008569 process Effects 0.000 title claims abstract description 66
125000005605 benzo group Chemical group 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 285
125000000217 alkyl group Chemical group 0.000 claims abstract description 257
-1 mono-substituted phenyl Chemical group 0.000 claims abstract description 140
239000001257 hydrogen Substances 0.000 claims abstract description 99
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 99
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 88
238000002360 preparation method Methods 0.000 claims abstract description 63
125000004076 pyridyl group Chemical group 0.000 claims abstract description 39
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 12
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 210
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 179
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 134
239000002904 solvent Substances 0.000 claims description 62
150000002431 hydrogen Chemical class 0.000 claims description 53
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 46
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 40
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 36
125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 35
125000001424 substituent group Chemical group 0.000 claims description 35
229910052757 nitrogen Inorganic materials 0.000 claims description 33
150000003839 salts Chemical class 0.000 claims description 29
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 28
239000003054 catalyst Substances 0.000 claims description 25
125000004093 cyano group Chemical group *C#N 0.000 claims description 25
239000002253 acid Substances 0.000 claims description 24
ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 22
229910000564 Raney nickel Inorganic materials 0.000 claims description 18
239000007868 Raney catalyst Substances 0.000 claims description 17
OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 16
229910021529 ammonia Inorganic materials 0.000 claims description 16
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 14
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
206010029897 Obsessive thoughts Diseases 0.000 claims description 13
125000003545 alkoxy group Chemical group 0.000 claims description 12
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
229910052794 bromium Inorganic materials 0.000 claims description 12
229910052736 halogen Inorganic materials 0.000 claims description 12
125000001475 halogen functional group Chemical group 0.000 claims description 12
150000002367 halogens Chemical class 0.000 claims description 12
239000007858 starting material Substances 0.000 claims description 12
229910052783 alkali metal Inorganic materials 0.000 claims description 11
229910052801 chlorine Inorganic materials 0.000 claims description 11
WZNYKINYEPCGAZ-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC(C(O)=O)=C2CN=C1C1=CC=CC=C1F WZNYKINYEPCGAZ-UHFFFAOYSA-N 0.000 claims description 10
125000003282 alkyl amino group Chemical group 0.000 claims description 10
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
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 claims description 9
150000001204 N-oxides Chemical class 0.000 claims description 9
239000000460 chlorine Substances 0.000 claims description 9
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 8
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 8
150000001540 azides Chemical class 0.000 claims description 8
239000003795 chemical substances by application Substances 0.000 claims description 8
150000002148 esters Chemical class 0.000 claims description 8
239000012280 lithium aluminium hydride Substances 0.000 claims description 8
239000007800 oxidant agent Substances 0.000 claims description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 7
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 7
150000001412 amines Chemical class 0.000 claims description 7
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 7
239000003638 chemical reducing agent Substances 0.000 claims description 7
229940117975 chromium trioxide Drugs 0.000 claims description 7
WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 7
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 6
239000004480 active ingredient Substances 0.000 claims description 6
125000005236 alkanoylamino group Chemical group 0.000 claims description 6
229910052799 carbon Inorganic materials 0.000 claims description 6
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 6
HNDGEYCCZGRMTN-UHFFFAOYSA-N thieno[3,2-f:4,5-f]bis[1]benzothiophene Chemical group S1C2=CC=3SC=CC=3C=C2C2=C1C=C(SC=C1)C1=C2 HNDGEYCCZGRMTN-UHFFFAOYSA-N 0.000 claims description 6
GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 5
125000001309 chloro group Chemical group Cl* 0.000 claims description 5
230000018044 dehydration Effects 0.000 claims description 5
238000006297 dehydration reaction Methods 0.000 claims description 5
DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 5
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 4
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
125000005843 halogen group Chemical group 0.000 claims description 4
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
229910052740 iodine Inorganic materials 0.000 claims description 4
229910052698 phosphorus Inorganic materials 0.000 claims description 4
239000011574 phosphorus Substances 0.000 claims description 4
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
125000002252 acyl group Chemical group 0.000 claims description 3
125000004849 alkoxymethyl group Chemical group 0.000 claims description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
125000005518 carboxamido group Chemical group 0.000 claims description 3
239000003153 chemical reaction reagent Substances 0.000 claims description 3
150000004820 halides Chemical class 0.000 claims description 3
230000002140 halogenating effect Effects 0.000 claims description 3
230000007062 hydrolysis Effects 0.000 claims description 3
238000006460 hydrolysis reaction Methods 0.000 claims description 3
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
229910052744 lithium Inorganic materials 0.000 claims description 3
125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
150000002905 orthoesters Chemical class 0.000 claims description 3
239000001301 oxygen Substances 0.000 claims description 3
229910052760 oxygen Inorganic materials 0.000 claims description 3
239000008194 pharmaceutical composition Substances 0.000 claims description 3
CZPZWMPYEINMCF-UHFFFAOYSA-N propaneperoxoic acid Chemical compound CCC(=O)OO CZPZWMPYEINMCF-UHFFFAOYSA-N 0.000 claims description 3
125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
239000011701 zinc Substances 0.000 claims description 3
229910052725 zinc Inorganic materials 0.000 claims description 3
GGBODVPEUWQPFL-UHFFFAOYSA-N 1-[8-chloro-6-(2-chlorophenyl)-4h-imidazo[1,5-a][1,4]benzodiazepin-3-yl]ethanone Chemical compound CC(=O)C=1N=CN(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl GGBODVPEUWQPFL-UHFFFAOYSA-N 0.000 claims description 2
VUMCYGBPHCVIAY-UHFFFAOYSA-N 1H-1,2-benzodiazepine-3-carboxamide Chemical compound NC(=O)C1=NNc2ccccc2C=C1 VUMCYGBPHCVIAY-UHFFFAOYSA-N 0.000 claims description 2
SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
IMXWNWBXKWASOM-UHFFFAOYSA-N 3h-imidazo[1,5-a][1,4]diazepine Chemical class N1=CC=CN2CN=CC2=C1 IMXWNWBXKWASOM-UHFFFAOYSA-N 0.000 claims description 2
VEDQGLSZFGZSAO-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide Chemical compound NC(=O)C=1N=CN(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1F VEDQGLSZFGZSAO-UHFFFAOYSA-N 0.000 claims description 2
PWTKXZBPKIAZEH-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid Chemical compound OC(=O)C=1N=CN(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1F PWTKXZBPKIAZEH-UHFFFAOYSA-N 0.000 claims description 2
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 2
230000002378 acidificating effect Effects 0.000 claims description 2
125000004423 acyloxy group Chemical group 0.000 claims description 2
229910000102 alkali metal hydride Inorganic materials 0.000 claims description 2
150000008046 alkali metal hydrides Chemical class 0.000 claims description 2
150000004703 alkoxides Chemical class 0.000 claims description 2
125000005262 alkoxyamine group Chemical group 0.000 claims description 2
150000001350 alkyl halides Chemical class 0.000 claims description 2
230000001773 anti-convulsant effect Effects 0.000 claims description 2
125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
238000006698 hydrazinolysis reaction Methods 0.000 claims description 2
239000012336 iodinating agent Substances 0.000 claims description 2
239000003158 myorelaxant agent Substances 0.000 claims description 2
SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 claims description 2
238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
150000003335 secondary amines Chemical class 0.000 claims description 2
239000000932 sedative agent Substances 0.000 claims description 2
230000001624 sedative effect Effects 0.000 claims description 2
125000005907 alkyl ester group Chemical group 0.000 claims 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
FWHJGVYWXJSLPQ-UHFFFAOYSA-N C[S+]1C(N(C2)C(C(C3=CC=CC=C3Cl)=NC3)=CN2Cl)=C3C(C([O-])=O)=C1 Chemical compound C[S+]1C(N(C2)C(C(C3=CC=CC=C3Cl)=NC3)=CN2Cl)=C3C(C([O-])=O)=C1 FWHJGVYWXJSLPQ-UHFFFAOYSA-N 0.000 claims 1
PZQFZFREKLYPOJ-UHFFFAOYSA-N N1C=C(N=CC=C1)C(=O)N Chemical compound N1C=C(N=CC=C1)C(=O)N PZQFZFREKLYPOJ-UHFFFAOYSA-N 0.000 claims 1
YIHBFCSLYBATDM-UHFFFAOYSA-N N=1C=C(N=CC=2C=1SCC=2)C(=O)N Chemical compound N=1C=C(N=CC=2C=1SCC=2)C(=O)N YIHBFCSLYBATDM-UHFFFAOYSA-N 0.000 claims 1
229930006000 Sucrose Natural products 0.000 claims 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
125000005042 acyloxymethyl group Chemical group 0.000 claims 1
239000011230 binding agent Substances 0.000 claims 1
150000003857 carboxamides Chemical class 0.000 claims 1
235000014113 dietary fatty acids Nutrition 0.000 claims 1
239000003937 drug carrier Substances 0.000 claims 1
229930195729 fatty acid Natural products 0.000 claims 1
239000000194 fatty acid Substances 0.000 claims 1
150000004665 fatty acids Chemical class 0.000 claims 1
125000004970 halomethyl group Chemical group 0.000 claims 1
125000005059 halophenyl group Chemical group 0.000 claims 1
WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims 1
231100000252 nontoxic Toxicity 0.000 claims 1
230000003000 nontoxic effect Effects 0.000 claims 1
229910052697 platinum Inorganic materials 0.000 claims 1
239000000651 prodrug Substances 0.000 claims 1
229940002612 prodrug Drugs 0.000 claims 1
229960004793 sucrose Drugs 0.000 claims 1
125000004183 alkoxy alkyl group Chemical group 0.000 abstract 1
125000003710 aryl alkyl group Chemical group 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 636
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 288
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 268
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 234
239000000243 solution Substances 0.000 description 186
239000000203 mixture Substances 0.000 description 166
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 156
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 135
239000000047 product Substances 0.000 description 135
239000011541 reaction mixture Substances 0.000 description 125
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 111
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
238000006243 chemical reaction Methods 0.000 description 92
238000001953 recrystallisation Methods 0.000 description 92
239000013078 crystal Substances 0.000 description 80
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 78
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 72
239000000538 analytical sample Substances 0.000 description 62
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 61
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
239000000706 filtrate Substances 0.000 description 59
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 54
229960000583 acetic acid Drugs 0.000 description 54
238000003756 stirring Methods 0.000 description 52
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
238000010992 reflux Methods 0.000 description 43
239000000741 silica gel Substances 0.000 description 42
229910002027 silica gel Inorganic materials 0.000 description 42
239000007787 solid Substances 0.000 description 42
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 36
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 35
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
239000012362 glacial acetic acid Substances 0.000 description 32
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
150000002430 hydrocarbons Chemical group 0.000 description 29
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
238000002425 crystallisation Methods 0.000 description 28
230000008025 crystallization Effects 0.000 description 28
229930195733 hydrocarbon Natural products 0.000 description 28
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
239000012442 inert solvent Substances 0.000 description 27
238000002844 melting Methods 0.000 description 27
230000008018 melting Effects 0.000 description 27
229960004592 isopropanol Drugs 0.000 description 26
150000002170 ethers Chemical class 0.000 description 25
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 24
238000001816 cooling Methods 0.000 description 23
239000000155 melt Substances 0.000 description 22
LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 22
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 21
229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
235000017557 sodium bicarbonate Nutrition 0.000 description 21
229920002261 Corn starch Polymers 0.000 description 20
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 20
239000008120 corn starch Substances 0.000 description 20
239000005457 ice water Substances 0.000 description 20
239000012044 organic layer Substances 0.000 description 20
239000012074 organic phase Substances 0.000 description 20
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 20
239000000725 suspension Substances 0.000 description 19
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 18
229910052786 argon Inorganic materials 0.000 description 18
FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 18
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
229920006395 saturated elastomer Polymers 0.000 description 18
150000008280 chlorinated hydrocarbons Chemical class 0.000 description 17
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 16
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 16
239000008101 lactose Substances 0.000 description 16
229910000029 sodium carbonate Inorganic materials 0.000 description 16
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239000007788 liquid Substances 0.000 description 1
150000002739 metals Chemical class 0.000 description 1
WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 1
DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
FIVDZRLZHUUWGU-UHFFFAOYSA-N methyl 1-(acetyloxymethyl)-8-chloro-6-(2-chlorophenyl)-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=C(COC(C)=O)N(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl FIVDZRLZHUUWGU-UHFFFAOYSA-N 0.000 description 1
PQEYKXSDTLGGIB-UHFFFAOYSA-N methyl 1H-1,2-benzodiazepine-3-carboxylate Chemical compound N1N=C(C=CC2=C1C=CC=C2)C(=O)OC PQEYKXSDTLGGIB-UHFFFAOYSA-N 0.000 description 1
IRVDVEHZZSIHIA-UHFFFAOYSA-N methyl 1h-diazepine-7-carboxylate Chemical compound COC(=O)C1=CC=CC=NN1 IRVDVEHZZSIHIA-UHFFFAOYSA-N 0.000 description 1
QBRMDYGQWOCJKP-UHFFFAOYSA-N methyl 2-(7-chloro-5-phenyl-3H-1,4-benzodiazepin-2-yl)-2-hydroxyiminoacetate Chemical compound COC(C(C1=NC2=C(C(=NC1)C1=CC=CC=C1)C=C(C=C2)Cl)=NO)=O QBRMDYGQWOCJKP-UHFFFAOYSA-N 0.000 description 1
OLLFATJQDVODBO-UHFFFAOYSA-N methyl 2-[7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1,4-benzodiazepin-2-ylidene]acetate Chemical compound C12=CC(Cl)=CC=C2NC(=CC(=O)OC)CN=C1C1=CC=CC=C1Cl OLLFATJQDVODBO-UHFFFAOYSA-N 0.000 description 1
YFIFNBOUETYGFJ-UHFFFAOYSA-N methyl 8-chloro-1,4-dimethyl-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=C(C)N(C2=CC=C(Cl)C=C22)C=1C(C)N=C2C1=CC=CC=C1 YFIFNBOUETYGFJ-UHFFFAOYSA-N 0.000 description 1
AHQMAKCNWBYXKJ-UHFFFAOYSA-N methyl 8-chloro-1-methyl-6-phenyl-5,6-dihydro-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=C(C)N(C2=CC=C(Cl)C=C22)C=1CNC2C1=CC=CC=C1 AHQMAKCNWBYXKJ-UHFFFAOYSA-N 0.000 description 1
FSSHLALDVOGDHU-UHFFFAOYSA-N methyl 8-chloro-6-(2-chlorophenyl)-1-[2-(dimethylamino)ethyl]-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=C(CCN(C)C)N(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl FSSHLALDVOGDHU-UHFFFAOYSA-N 0.000 description 1
BYYNOPSGBFWEFQ-UHFFFAOYSA-N methyl 8-chloro-6-(2-chlorophenyl)-1-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(C=2C(=CC=CC=2)Cl)C2=CC(Cl)=CC=C2N2C1=C(C(=O)OC)N=C2C1=CC=CC=C1 BYYNOPSGBFWEFQ-UHFFFAOYSA-N 0.000 description 1
UHGMDABRGVKPBN-UHFFFAOYSA-N methyl 8-chloro-6-(2-chlorophenyl)-1-propan-2-yl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=C(C(C)C)N(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl UHGMDABRGVKPBN-UHFFFAOYSA-N 0.000 description 1
TXURVZAYCKHRGG-UHFFFAOYSA-N methyl 8-chloro-6-(2-chlorophenyl)-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=CN(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl TXURVZAYCKHRGG-UHFFFAOYSA-N 0.000 description 1
AUHFGWRAZMECLY-UHFFFAOYSA-N methyl 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=C(C)N(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1F AUHFGWRAZMECLY-UHFFFAOYSA-N 0.000 description 1
OJEYQCQPSBCODV-UHFFFAOYSA-N methyl 8-chloro-6-(2-fluorophenyl)-1-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(C=2C(=CC=CC=2)F)C2=CC(Cl)=CC=C2N2C1=C(C(=O)OC)N=C2C1=CC=CC=C1 OJEYQCQPSBCODV-UHFFFAOYSA-N 0.000 description 1
IBYDFFQUICRAIR-UHFFFAOYSA-N methyl 8-chloro-6-(2-fluorophenyl)-4-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=CN(C2=CC=C(Cl)C=C22)C=1C(C)N=C2C1=CC=CC=C1F IBYDFFQUICRAIR-UHFFFAOYSA-N 0.000 description 1
KCIMAXKRKBBLJK-UHFFFAOYSA-N methyl 8-chloro-6-phenyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound COC(=O)C=1N=CN(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1 KCIMAXKRKBBLJK-UHFFFAOYSA-N 0.000 description 1
RERNBTSGGCWFPT-UHFFFAOYSA-N methyl n-[8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbamate Chemical compound COC(=O)NC=1N=C(C)N(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1F RERNBTSGGCWFPT-UHFFFAOYSA-N 0.000 description 1
BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 description 1
125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
235000010755 mineral Nutrition 0.000 description 1
239000011707 mineral Substances 0.000 description 1
125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 1
WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 description 1
CLOCFUZWZQDXQH-UHFFFAOYSA-N n-(nitrosomethyl)-5-phenyl-3h-1,4-benzodiazepin-2-amine Chemical compound N=1CC(NCN=O)=NC2=CC=CC=C2C=1C1=CC=CC=C1 CLOCFUZWZQDXQH-UHFFFAOYSA-N 0.000 description 1
WAQXEXNGCAPWBE-UHFFFAOYSA-N n-(nitrosomethyl)-5-phenyl-3h-thieno[3,2-e][1,4]diazepin-2-amine Chemical compound N=1CC(NCN=O)=NC=2C=CSC=2C=1C1=CC=CC=C1 WAQXEXNGCAPWBE-UHFFFAOYSA-N 0.000 description 1
VXCCGNWORHEEDF-UHFFFAOYSA-N n-[7-chloro-5-(2-fluorophenyl)-3h-1,4-benzodiazepin-2-yl]-n-methylnitrous amide Chemical compound N=1CC(N(N=O)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F VXCCGNWORHEEDF-UHFFFAOYSA-N 0.000 description 1
FCQMSIWSMKWRQL-UHFFFAOYSA-N n-methyl-5-phenyl-3h-1,4-benzodiazepin-2-amine Chemical compound N=1CC(NC)=NC2=CC=CC=C2C=1C1=CC=CC=C1 FCQMSIWSMKWRQL-UHFFFAOYSA-N 0.000 description 1
230000007935 neutral effect Effects 0.000 description 1
KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
238000010899 nucleation Methods 0.000 description 1
238000007344 nucleophilic reaction Methods 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
239000002245 particle Substances 0.000 description 1
230000037361 pathway Effects 0.000 description 1
150000004965 peroxy acids Chemical class 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
229940100595 phenylacetaldehyde Drugs 0.000 description 1
125000003884 phenylalkyl group Chemical group 0.000 description 1
125000001639 phenylmethylene group Chemical group [H]C(=*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
230000000865 phosphorylative effect Effects 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
TZYFXTFNBJHONY-UHFFFAOYSA-M potassium;8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate;hydrate Chemical compound O.[K+].C12=CC(Cl)=CC=C2N2C(C)=NC(C([O-])=O)=C2CN=C1C1=CC=CC=C1F TZYFXTFNBJHONY-UHFFFAOYSA-M 0.000 description 1
239000000843 powder Substances 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
238000000746 purification Methods 0.000 description 1
239000012264 purified product Substances 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
238000006748 scratching Methods 0.000 description 1
230000002393 scratching effect Effects 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
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238000009987 spinning Methods 0.000 description 1
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238000010561 standard procedure Methods 0.000 description 1
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CMQCNTNASCDNGR-UHFFFAOYSA-N toluene;hydrate Chemical compound O.CC1=CC=CC=C1 CMQCNTNASCDNGR-UHFFFAOYSA-N 0.000 description 1
230000007704 transition Effects 0.000 description 1
238000001665 trituration Methods 0.000 description 1
JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
235000015112 vegetable and seed oil Nutrition 0.000 description 1
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238000005303 weighing Methods 0.000 description 1