CN117377675A

CN117377675A - 含有并环或螺环的布鲁顿酪氨酸激酶降解剂

含有并环或螺环的布鲁顿酪氨酸激酶降解剂 Download PDF

Info

Publication number: CN117377675A
Authority: CN; China
Prior art keywords: compound; reaction; alkyl; added; alternatively
Prior art date: 2021-06-01
Legal status : Pending

Application number

CN202280037318.XA

Other languages

English (en)

Chinese (zh)

Inventor

张寅生

任景

汪纪楠

杨晓骏

张晓平

Current Assignee

Chia Tai Tianqing Pharmaceutical Group Co Ltd

Original Assignee

Chia Tai Tianqing Pharmaceutical Group Co Ltd

Priority date

2021-06-01

Filing date

2022-06-01

Publication date

2024-01-09

2022-06-01 Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd

2024-01-09 Publication of CN117377675A publication Critical patent/CN117377675A/zh

Status Pending legal-status Critical Current

Links

230000015556 catabolic process Effects 0.000 title abstract description 15
238000006731 degradation reaction Methods 0.000 title abstract description 15
125000003003 spiro group Chemical group 0.000 title abstract description 6
108010029445 Agammaglobulinaemia Tyrosine Kinase Proteins 0.000 title abstract description 5
102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title abstract 2
150000001875 compounds Chemical class 0.000 claims abstract description 183
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
201000010099 disease Diseases 0.000 claims abstract description 26
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
239000000203 mixture Substances 0.000 claims description 168
125000000217 alkyl group Chemical group 0.000 claims description 46
150000003839 salts Chemical class 0.000 claims description 41
-1 methoxy, ethoxy Chemical group 0.000 claims description 37
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 36
229910052736 halogen Inorganic materials 0.000 claims description 35
150000002367 halogens Chemical class 0.000 claims description 35
239000000460 chlorine Substances 0.000 claims description 32
125000000753 cycloalkyl group Chemical group 0.000 claims description 26
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 25
229910052801 chlorine Inorganic materials 0.000 claims description 25
229910052757 nitrogen Inorganic materials 0.000 claims description 25
229910052731 fluorine Inorganic materials 0.000 claims description 24
239000011737 fluorine Substances 0.000 claims description 22
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 21
125000004429 atom Chemical group 0.000 claims description 19
229910052799 carbon Inorganic materials 0.000 claims description 18
125000004432 carbon atom Chemical group C* 0.000 claims description 17
229910052760 oxygen Inorganic materials 0.000 claims description 17
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
206010028980 Neoplasm Diseases 0.000 claims description 14
229910052739 hydrogen Inorganic materials 0.000 claims description 13
239000001257 hydrogen Substances 0.000 claims description 13
125000004430 oxygen atom Chemical group O* 0.000 claims description 13
125000005843 halogen group Chemical group 0.000 claims description 12
125000002393 azetidinyl group Chemical group 0.000 claims description 11
125000005842 heteroatom Chemical group 0.000 claims description 10
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
125000003386 piperidinyl group Chemical group 0.000 claims description 9
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 claims description 8
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
229910052794 bromium Inorganic materials 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 7
125000004093 cyano group Chemical group *C#N 0.000 claims description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
125000004193 piperazinyl group Chemical group 0.000 claims description 7
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
125000001153 fluoro group Chemical group F* 0.000 claims description 6
229910052740 iodine Inorganic materials 0.000 claims description 6
239000011630 iodine Substances 0.000 claims description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 5
KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
150000005405 azaspiro[5.5]undecanes Chemical class 0.000 claims description 4
DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 4
230000002265 prevention Effects 0.000 claims description 4
125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 3
125000006707 (C3-C12) heterocycloalkyl group Chemical group 0.000 claims description 3
125000006584 (C3-C10) heterocycloalkyl group Chemical group 0.000 claims description 2
UZHVXJZEHGSWQV-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole Chemical compound C1NCC2CCCC21 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 claims description 2
NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 claims description 2
QAVIPYUSPQRVKA-UHFFFAOYSA-N 1,2-diazaspiro[3.3]heptane Chemical compound C1CCC21NNC2 QAVIPYUSPQRVKA-UHFFFAOYSA-N 0.000 claims description 2
YKXOWLUZZIFXMJ-UHFFFAOYSA-N 1,2-diazaspiro[3.5]nonane Chemical compound C1NNC11CCCCC1 YKXOWLUZZIFXMJ-UHFFFAOYSA-N 0.000 claims description 2
YMANQWHUUFJQOW-UHFFFAOYSA-N 1,2-diazaspiro[4.5]decane Chemical compound N1NCCC11CCCCC1 YMANQWHUUFJQOW-UHFFFAOYSA-N 0.000 claims description 2
WJWHNTAKUNTHFX-UHFFFAOYSA-N 1-azabicyclo[3.2.0]heptane Chemical compound C1CCC2CCN21 WJWHNTAKUNTHFX-UHFFFAOYSA-N 0.000 claims description 2
YKNUXXRRPRLOBW-UHFFFAOYSA-N 1-azaspiro[3.3]heptane Chemical compound C1CCC21NCC2 YKNUXXRRPRLOBW-UHFFFAOYSA-N 0.000 claims description 2
ODSNARDHJFFSRH-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-isoindole Chemical compound C1CCCC2CNCC21 ODSNARDHJFFSRH-UHFFFAOYSA-N 0.000 claims description 2
KPXSPHQLZBMRLW-UHFFFAOYSA-N 2,3,4,4a,5,6,7,7a-octahydro-1h-cyclopenta[c]pyridine Chemical compound C1CNCC2CCCC21 KPXSPHQLZBMRLW-UHFFFAOYSA-N 0.000 claims description 2
QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 claims description 2
208000023275 Autoimmune disease Diseases 0.000 claims description 2
201000011510 cancer Diseases 0.000 claims description 2
TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
125000004434 sulfur atom Chemical group 0.000 claims description 2
208000027866 inflammatory disease Diseases 0.000 claims 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 267
102100029823 Tyrosine-protein kinase BTK Human genes 0.000 abstract description 29
239000000543 intermediate Substances 0.000 description 707
238000006243 chemical reaction Methods 0.000 description 518
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 517
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 290
239000000243 solution Substances 0.000 description 277
238000005481 NMR spectroscopy Methods 0.000 description 212
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 173
239000012074 organic phase Substances 0.000 description 172
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 161
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 144
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 129
239000011541 reaction mixture Substances 0.000 description 97
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 96
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
239000002904 solvent Substances 0.000 description 93
238000003786 synthesis reaction Methods 0.000 description 91
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 90
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 89
230000015572 biosynthetic process Effects 0.000 description 89
230000002829 reductive effect Effects 0.000 description 89
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 85
238000003756 stirring Methods 0.000 description 82
239000012071 phase Substances 0.000 description 75
239000012043 crude product Substances 0.000 description 73
239000000706 filtrate Substances 0.000 description 67
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 65
238000010898 silica gel chromatography Methods 0.000 description 65
239000012044 organic layer Substances 0.000 description 58
238000000746 purification Methods 0.000 description 56
230000002441 reversible effect Effects 0.000 description 54
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 52
229960000583 acetic acid Drugs 0.000 description 51
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 49
239000000741 silica gel Substances 0.000 description 48
229910002027 silica gel Inorganic materials 0.000 description 48
229920006395 saturated elastomer Polymers 0.000 description 47
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 46
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 46
238000004440 column chromatography Methods 0.000 description 43
238000000605 extraction Methods 0.000 description 39
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
239000000284 extract Substances 0.000 description 36
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 33
239000003480 eluent Substances 0.000 description 33
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 27
239000005695 Ammonium acetate Substances 0.000 description 27
235000019257 ammonium acetate Nutrition 0.000 description 27
229940043376 ammonium acetate Drugs 0.000 description 27
239000010410 layer Substances 0.000 description 27
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 26
229910000027 potassium carbonate Inorganic materials 0.000 description 26
238000002390 rotary evaporation Methods 0.000 description 26
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 25
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210000004027 cell Anatomy 0.000 description 25
238000000034 method Methods 0.000 description 25
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PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 20
239000012141 concentrate Substances 0.000 description 20
238000005406 washing Methods 0.000 description 19
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
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DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
239000007858 starting material Substances 0.000 description 18
PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 17
238000010438 heat treatment Methods 0.000 description 17
OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 16
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
239000012131 assay buffer Substances 0.000 description 16
FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 16
229910000024 caesium carbonate Inorganic materials 0.000 description 16
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 16
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239000008346 aqueous phase Substances 0.000 description 15
238000011534 incubation Methods 0.000 description 15
239000007787 solid Substances 0.000 description 15
WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 14
238000001914 filtration Methods 0.000 description 14
239000012634 fragment Substances 0.000 description 14
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
239000007800 oxidant agent Substances 0.000 description 14
VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 14
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239000000047 product Substances 0.000 description 13
229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
235000017557 sodium bicarbonate Nutrition 0.000 description 13
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
238000012360 testing method Methods 0.000 description 12
230000002401 inhibitory effect Effects 0.000 description 11
230000001590 oxidative effect Effects 0.000 description 11
239000012065 filter cake Substances 0.000 description 10
125000006239 protecting group Chemical group 0.000 description 10
125000001424 substituent group Chemical group 0.000 description 10
238000000967 suction filtration Methods 0.000 description 10
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 10
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239000000872 buffer Substances 0.000 description 9
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
239000000546 pharmaceutical excipient Substances 0.000 description 9
238000006646 Dess-Martin oxidation reaction Methods 0.000 description 8
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 8
241000699670 Mus sp. Species 0.000 description 8
235000019270 ammonium chloride Nutrition 0.000 description 8
238000004458 analytical method Methods 0.000 description 8
239000007864 aqueous solution Substances 0.000 description 8
238000001816 cooling Methods 0.000 description 8
NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
230000000694 effects Effects 0.000 description 8
238000004896 high resolution mass spectrometry Methods 0.000 description 8
238000010534 nucleophilic substitution reaction Methods 0.000 description 8
KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 7
101150003085 Pdcl gene Proteins 0.000 description 7
108091000080 Phosphotransferase Proteins 0.000 description 7
238000001514 detection method Methods 0.000 description 7
150000002431 hydrogen Chemical class 0.000 description 7
239000005457 ice water Substances 0.000 description 7
238000000338 in vitro Methods 0.000 description 7
102000020233 phosphotransferase Human genes 0.000 description 7
238000010791 quenching Methods 0.000 description 7
238000000926 separation method Methods 0.000 description 7
229910052717 sulfur Inorganic materials 0.000 description 7
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
239000012295 chemical reaction liquid Substances 0.000 description 6
DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 6
238000001704 evaporation Methods 0.000 description 6
230000005764 inhibitory process Effects 0.000 description 6
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GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
238000006467 substitution reaction Methods 0.000 description 6
NQHGYUZNWXIZID-UHFFFAOYSA-N tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC21CCC(O)CC2 NQHGYUZNWXIZID-UHFFFAOYSA-N 0.000 description 6
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
239000012224 working solution Substances 0.000 description 6
MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 5
JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
241000124008 Mammalia Species 0.000 description 5
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239000003153 chemical reaction reagent Substances 0.000 description 5
239000003795 chemical substances by application Substances 0.000 description 5
125000001072 heteroaryl group Chemical group 0.000 description 5
239000000463 material Substances 0.000 description 5
102000004169 proteins and genes Human genes 0.000 description 5
108090000623 proteins and genes Proteins 0.000 description 5
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