KR20230154789A

KR20230154789A - 헤테로고리 메탄온 화합물 및 그의 아자-비시클로 중간체의 제조 공정

헤테로고리 메탄온 화합물 및 그의 아자-비시클로 중간체의 제조 공정 Download PDF

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Publication number: KR20230154789A
Authority: KR; South Korea
Prior art keywords: formula; compound; group; manufacturing process; reaction
Prior art date: 2020-11-06
Legal status : Pending

Application number

KR1020237018659A

Other languages

English (en)

Korean (ko)

Inventor

크리스티안 그루겔

토비아스 웨델

Original Assignee

액티노젠 메디컬 리미티드

Priority date

2020-11-06

Filing date

2021-11-05

Publication date

2023-11-09

2020-11-06 Priority claimed from AU2020904060A external-priority patent/AU2020904060A0/en

2021-11-05 Application filed by 액티노젠 메디컬 리미티드 filed Critical 액티노젠 메디컬 리미티드

2023-11-09 Publication of KR20230154789A publication Critical patent/KR20230154789A/ko

Status Pending legal-status Critical Current

Links

-1 heterocyclic methanone compounds Chemical class 0.000 title claims abstract description 176
238000000034 method Methods 0.000 title claims abstract description 96
230000008569 process Effects 0.000 title claims abstract description 76
239000000543 intermediate Substances 0.000 title abstract description 13
150000001875 compounds Chemical class 0.000 claims abstract description 295
238000006243 chemical reaction Methods 0.000 claims description 173
238000005859 coupling reaction Methods 0.000 claims description 95
239000000203 mixture Substances 0.000 claims description 81
239000003153 chemical reaction reagent Substances 0.000 claims description 80
150000003839 salts Chemical class 0.000 claims description 73
125000000217 alkyl group Chemical group 0.000 claims description 62
230000008878 coupling Effects 0.000 claims description 61
238000010168 coupling process Methods 0.000 claims description 61
238000004519 manufacturing process Methods 0.000 claims description 50
150000001408 amides Chemical class 0.000 claims description 40
125000004452 carbocyclyl group Chemical group 0.000 claims description 40
125000000623 heterocyclic group Chemical group 0.000 claims description 40
125000002950 monocyclic group Chemical group 0.000 claims description 31
125000002619 bicyclic group Chemical group 0.000 claims description 29
238000003747 Grignard reaction Methods 0.000 claims description 28
229910052739 hydrogen Inorganic materials 0.000 claims description 26
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
239000000654 additive Substances 0.000 claims description 25
125000006242 amine protecting group Chemical group 0.000 claims description 25
239000001257 hydrogen Substances 0.000 claims description 25
229910052736 halogen Inorganic materials 0.000 claims description 24
150000002367 halogens Chemical class 0.000 claims description 24
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 21
229910052751 metal Inorganic materials 0.000 claims description 20
239000002184 metal Substances 0.000 claims description 20
125000001188 haloalkyl group Chemical group 0.000 claims description 19
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 18
125000001424 substituent group Chemical group 0.000 claims description 18
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
150000001718 carbodiimides Chemical class 0.000 claims description 16
SNUSZUYTMHKCPM-UHFFFAOYSA-N 1-hydroxypyridin-2-one Chemical group ON1C=CC=CC1=O SNUSZUYTMHKCPM-UHFFFAOYSA-N 0.000 claims description 15
150000002148 esters Chemical group 0.000 claims description 15
239000002253 acid Substances 0.000 claims description 14
239000012535 impurity Substances 0.000 claims description 13
125000006239 protecting group Chemical group 0.000 claims description 13
BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 12
230000000996 additive effect Effects 0.000 claims description 12
BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 12
125000003118 aryl group Chemical group 0.000 claims description 11
239000003125 aqueous solvent Substances 0.000 claims description 9
150000002923 oximes Chemical class 0.000 claims description 9
150000001204 N-oxides Chemical class 0.000 claims description 8
150000008054 sulfonate salts Chemical class 0.000 claims description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 6
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 6
238000005660 chlorination reaction Methods 0.000 claims description 6
125000001072 heteroaryl group Chemical group 0.000 claims description 6
239000011630 iodine Substances 0.000 claims description 6
229910052740 iodine Inorganic materials 0.000 claims description 6
238000007127 saponification reaction Methods 0.000 claims description 6
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
CNEFRTDDIMNTHC-UHFFFAOYSA-N 2-cyano-2-hydroxyiminoacetic acid Chemical compound ON=C(C#N)C(O)=O CNEFRTDDIMNTHC-UHFFFAOYSA-N 0.000 claims description 4
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
125000002877 alkyl aryl group Chemical group 0.000 claims description 4
LCFXLZAXGXOXAP-DAXSKMNVSA-N ethyl (2z)-2-cyano-2-hydroxyiminoacetate Chemical group CCOC(=O)C(=N/O)\C#N LCFXLZAXGXOXAP-DAXSKMNVSA-N 0.000 claims description 4
CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 3
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 2
BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 claims description 2
RDWDVLFMPFUBDV-PXMDEAMVSA-N [(e)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-tripyrrolidin-1-ylphosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(O/N=C(C(=O)OCC)\C#N)N1CCCC1 RDWDVLFMPFUBDV-PXMDEAMVSA-N 0.000 claims description 2
GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims description 2
HOAYEIDTOTYMMW-UHFFFAOYSA-M potassium 2-cyano-2-hydroxyiminoacetate Chemical compound [K+].ON=C(C(=O)[O-])C#N HOAYEIDTOTYMMW-UHFFFAOYSA-M 0.000 claims description 2
QQXLDOJGLXJCSE-UHFFFAOYSA-N N-methylnortropinone Natural products C1C(=O)CC2CCC1N2C QQXLDOJGLXJCSE-UHFFFAOYSA-N 0.000 claims 1
125000000815 N-oxide group Chemical group 0.000 claims 1
QQXLDOJGLXJCSE-KNVOCYPGSA-N Tropinone Natural products C1C(=O)C[C@H]2CC[C@@H]1N2C QQXLDOJGLXJCSE-KNVOCYPGSA-N 0.000 claims 1
LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims 1
230000015572 biosynthetic process Effects 0.000 abstract description 38
238000003786 synthesis reaction Methods 0.000 abstract description 33
MMZFGTAMARVHAF-RTHVDDQRSA-N [(1S,5R)-3-hydroxy-3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-8-yl]-[5-(1H-pyrazol-4-yl)thiophen-3-yl]methanone Chemical compound OC1(C[C@@H]2CC[C@H](C1)N2C(=O)c1csc(c1)-c1cn[nH]c1)c1ncccn1 MMZFGTAMARVHAF-RTHVDDQRSA-N 0.000 abstract description 11
PJUIJVYORNIHSN-UHFFFAOYSA-N OC1(C=C(C2=CNN=C2)SC1)C(N1C2CCCC1CC2)=O Chemical class OC1(C=C(C2=CNN=C2)SC1)C(N1C2CCCC1CC2)=O PJUIJVYORNIHSN-UHFFFAOYSA-N 0.000 abstract description 2
235000002639 sodium chloride Nutrition 0.000 description 76
239000002904 solvent Substances 0.000 description 59
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 49
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
238000004128 high performance liquid chromatography Methods 0.000 description 35
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
239000000243 solution Substances 0.000 description 30
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 25
239000011541 reaction mixture Substances 0.000 description 24
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 22
239000002585 base Substances 0.000 description 21
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
238000002360 preparation method Methods 0.000 description 19
239000000047 product Substances 0.000 description 19
239000007787 solid Substances 0.000 description 19
JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 18
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 16
CVDLBKMNONQOHJ-OLQVQODUSA-N (1r,5s)-8-azabicyclo[3.2.1]octan-3-one Chemical group C1C(=O)C[C@@]2([H])CC[C@]1([H])N2 CVDLBKMNONQOHJ-OLQVQODUSA-N 0.000 description 15
AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 15
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
229940125904 compound 1 Drugs 0.000 description 15
238000000746 purification Methods 0.000 description 15
239000000725 suspension Substances 0.000 description 15
239000000546 pharmaceutical excipient Substances 0.000 description 14
UOXJNGFFPMOZDM-UHFFFAOYSA-N 2-[di(propan-2-yl)amino]ethylsulfanyl-methylphosphinic acid Chemical compound CC(C)N(C(C)C)CCSP(C)(O)=O UOXJNGFFPMOZDM-UHFFFAOYSA-N 0.000 description 13
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
238000009472 formulation Methods 0.000 description 13
MENILFUADYEXNU-DTORHVGOSA-N tert-butyl (1r,5s)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1C(=O)C[C@H]2CC[C@@H]1N2C(=O)OC(C)(C)C MENILFUADYEXNU-DTORHVGOSA-N 0.000 description 13
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
239000000460 chlorine Substances 0.000 description 12
150000002170 ethers Chemical class 0.000 description 12
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 12
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
150000004795 grignard reagents Chemical class 0.000 description 11
239000008194 pharmaceutical composition Substances 0.000 description 11
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
239000006227 byproduct Substances 0.000 description 10
239000000463 material Substances 0.000 description 10
238000001953 recrystallisation Methods 0.000 description 10
238000012216 screening Methods 0.000 description 10
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
239000003054 catalyst Substances 0.000 description 9
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
239000012043 crude product Substances 0.000 description 9
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 8
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
239000007818 Grignard reagent Substances 0.000 description 8
229940011051 isopropyl acetate Drugs 0.000 description 8
GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 8
239000007788 liquid Substances 0.000 description 8
239000007858 starting material Substances 0.000 description 8
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
229910052794 bromium Inorganic materials 0.000 description 7
229910052801 chlorine Inorganic materials 0.000 description 7
239000004615 ingredient Substances 0.000 description 7
239000012074 organic phase Substances 0.000 description 7
238000003756 stirring Methods 0.000 description 7
SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 6
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 6
230000002378 acidificating effect Effects 0.000 description 6
239000003085 diluting agent Substances 0.000 description 6
238000006460 hydrolysis reaction Methods 0.000 description 6
KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
239000000314 lubricant Substances 0.000 description 6
150000002825 nitriles Chemical class 0.000 description 6
238000010966 qNMR Methods 0.000 description 6
239000003826 tablet Substances 0.000 description 6
150000003527 tetrahydropyrans Chemical group 0.000 description 6
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
238000005481 NMR spectroscopy Methods 0.000 description 5
238000003776 cleavage reaction Methods 0.000 description 5
150000004820 halides Chemical class 0.000 description 5
125000005842 heteroatom Chemical group 0.000 description 5
150000002500 ions Chemical class 0.000 description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
239000003880 polar aprotic solvent Substances 0.000 description 5
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 5
238000010992 reflux Methods 0.000 description 5
238000013341 scale-up Methods 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
239000012453 solvate Substances 0.000 description 5
239000000126 substance Substances 0.000 description 5
238000012360 testing method Methods 0.000 description 5
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
125000006847 BOC protecting group Chemical group 0.000 description 4
BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
239000002202 Polyethylene glycol Substances 0.000 description 4
238000006069 Suzuki reaction reaction Methods 0.000 description 4
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
150000001298 alcohols Chemical class 0.000 description 4
RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
125000004429 atom Chemical group 0.000 description 4
239000011230 binding agent Substances 0.000 description 4
239000012455 biphasic mixture Substances 0.000 description 4
125000004432 carbon atom Chemical group C* 0.000 description 4
125000001309 chloro group Chemical group Cl* 0.000 description 4
238000004440 column chromatography Methods 0.000 description 4
238000010511 deprotection reaction Methods 0.000 description 4
239000004210 ether based solvent Substances 0.000 description 4
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
239000012634 fragment Substances 0.000 description 4
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
239000003960 organic solvent Substances 0.000 description 4
238000007911 parenteral administration Methods 0.000 description 4
239000012071 phase Substances 0.000 description 4
229920001223 polyethylene glycol Polymers 0.000 description 4
230000035484 reaction time Effects 0.000 description 4
230000007017 scission Effects 0.000 description 4
150000003460 sulfonic acids Chemical class 0.000 description 4
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
239000007821 HATU Substances 0.000 description 3
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
239000004480 active ingredient Substances 0.000 description 3
150000001412 amines Chemical class 0.000 description 3
SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 3
229910052796 boron Inorganic materials 0.000 description 3
239000012267 brine Substances 0.000 description 3
BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 3
239000001768 carboxy methyl cellulose Substances 0.000 description 3
150000001768 cations Chemical class 0.000 description 3
229920002678 cellulose Polymers 0.000 description 3
239000001913 cellulose Substances 0.000 description 3
235000010980 cellulose Nutrition 0.000 description 3
239000013058 crude material Substances 0.000 description 3
239000007884 disintegrant Substances 0.000 description 3
239000002552 dosage form Substances 0.000 description 3
CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 3
PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
235000003599 food sweetener Nutrition 0.000 description 3
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