HU194870B

HU194870B - Process for preparing 1-sulfo-2-oxo-azetidine derivatives and pharmaceuticals comprising such compounds

Process for preparing 1-sulfo-2-oxo-azetidine derivatives and pharmaceuticals comprising such compounds Download PDF

Info

Publication number: HU194870B
Authority: HU; Hungary
Prior art keywords: group; formula; cis; amino; oxoazetidine
Prior art date: 1980-12-05

Application number

HU813577A

Other languages

English (en)

Hungarian (hu)

Inventor

Shoji Kishimoto

Mitsumi Tomimoto

Michiyuki Sendai

Michihiko Ochiai

Taisuke Matsuo

Original Assignee

Takeda Chemical Industries Ltd

Priority date

1980-12-05

Filing date

1981-11-26

Publication date

1988-03-28

1980-12-05 Priority claimed from PCT/JP1980/000297 external-priority patent/WO1982001873A1/ja

1981-11-26 Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd

1988-03-28 Publication of HU194870B publication Critical patent/HU194870B/hu

Links

150000001875 compounds Chemical class 0.000 title claims description 84
CDFGMYLBUSYTKQ-UHFFFAOYSA-N 2-oxoazetidine-1-sulfonic acid Chemical class OS(=O)(=O)N1CCC1=O CDFGMYLBUSYTKQ-UHFFFAOYSA-N 0.000 title claims description 11
239000003814 drug Substances 0.000 title claims 2
238000004519 manufacturing process Methods 0.000 title claims 2
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 53
239000001257 hydrogen Substances 0.000 claims abstract description 35
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 33
150000003839 salts Chemical class 0.000 claims abstract description 32
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
125000003277 amino group Chemical group 0.000 claims abstract description 12
125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 5
125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims abstract description 5
-1 carboxyethylcarbonyl Chemical group 0.000 claims description 489
238000000034 method Methods 0.000 claims description 77
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 56
125000004432 carbon atom Chemical group C* 0.000 claims description 51
125000000217 alkyl group Chemical group 0.000 claims description 47
239000007858 starting material Substances 0.000 claims description 37
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 28
239000003795 chemical substances by application Substances 0.000 claims description 19
125000006239 protecting group Chemical group 0.000 claims description 18
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
125000003545 alkoxy group Chemical group 0.000 claims description 12
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
238000002360 preparation method Methods 0.000 claims description 10
125000005843 halogen group Chemical group 0.000 claims description 9
239000008194 pharmaceutical composition Substances 0.000 claims description 9
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 8
125000001544 thienyl group Chemical group 0.000 claims description 8
125000001424 substituent group Chemical group 0.000 claims description 7
125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 5
230000000845 anti-microbial effect Effects 0.000 claims description 5
125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
230000002401 inhibitory effect Effects 0.000 claims description 5
UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
108090000204 Dipeptidase 1 Proteins 0.000 claims description 4
102000006635 beta-lactamase Human genes 0.000 claims description 4
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
230000002829 reductive effect Effects 0.000 claims description 4
125000000335 thiazolyl group Chemical group 0.000 claims description 4
229910052783 alkali metal Inorganic materials 0.000 claims description 3
125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims description 3
125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 3
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
229910052736 halogen Inorganic materials 0.000 claims description 3
239000000546 pharmaceutical excipient Substances 0.000 claims description 3
125000003831 tetrazolyl group Chemical group 0.000 claims description 3
125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 2
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
125000004442 acylamino group Chemical group 0.000 claims description 2
125000005103 alkyl silyl group Chemical group 0.000 claims description 2
125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
125000004414 alkyl thio group Chemical group 0.000 claims description 2
150000001412 amines Chemical class 0.000 claims description 2
125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 2
125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 2
125000002541 furyl group Chemical group 0.000 claims description 2
125000005203 haloalkylcarbonyloxy group Chemical group 0.000 claims description 2
150000002367 halogens Chemical class 0.000 claims description 2
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 claims description 2
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 description 2
LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 2
125000004181 carboxyalkyl group Chemical group 0.000 claims 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
XVAYDLJEBGHLSX-UHFFFAOYSA-N 3-amino-2-(carbamoyloxymethyl)-4-oxoazetidine-1-sulfonic acid Chemical compound NC1C(COC(N)=O)N(S(O)(=O)=O)C1=O XVAYDLJEBGHLSX-UHFFFAOYSA-N 0.000 claims 1
CLGYPTDTSSKYIP-UHFFFAOYSA-N 3-amino-2-carbamoyl-4-oxoazetidine-1-sulfonic acid Chemical compound NC1C(C(N)=O)N(S(O)(=O)=O)C1=O CLGYPTDTSSKYIP-UHFFFAOYSA-N 0.000 claims 1
ZUILYZBSPURWPR-UHFFFAOYSA-N 3-amino-2-methoxycarbonyl-4-oxoazetidine-1-sulfonic acid Chemical compound COC(=O)C1C(N)C(=O)N1S(O)(=O)=O ZUILYZBSPURWPR-UHFFFAOYSA-N 0.000 claims 1
YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical group [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims 1
125000000676 alkoxyimino group Chemical group 0.000 claims 1
125000002393 azetidinyl group Chemical group 0.000 claims 1
125000004093 cyano group Chemical group *C#N 0.000 claims 1
125000001188 haloalkyl group Chemical group 0.000 claims 1
230000002195 synergetic effect Effects 0.000 claims 1
230000017105 transposition Effects 0.000 claims 1
239000000843 powder Substances 0.000 abstract description 31
UJTMLNARSPORHR-UHFFFAOYSA-N oc2h5 Chemical compound C=C=[O+] UJTMLNARSPORHR-UHFFFAOYSA-N 0.000 abstract 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 434
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 431
239000000203 mixture Substances 0.000 description 285
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 256
239000000243 solution Substances 0.000 description 243
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 225
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 205
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 183
238000003756 stirring Methods 0.000 description 171
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 158
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 143
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 137
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 136
238000001816 cooling Methods 0.000 description 134
239000013078 crystal Substances 0.000 description 110
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 103
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 99
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 98
238000004458 analytical method Methods 0.000 description 97
239000000706 filtrate Substances 0.000 description 88
239000011541 reaction mixture Substances 0.000 description 83
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 78
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 78
239000002244 precipitate Substances 0.000 description 75
229920001429 chelating resin Polymers 0.000 description 74
235000017557 sodium bicarbonate Nutrition 0.000 description 68
229910000030 sodium bicarbonate Inorganic materials 0.000 description 68
238000004440 column chromatography Methods 0.000 description 67
229920005989 resin Polymers 0.000 description 65
239000011347 resin Substances 0.000 description 65
238000002329 infrared spectrum Methods 0.000 description 63
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 62
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 60
239000011734 sodium Substances 0.000 description 58
159000000000 sodium salts Chemical class 0.000 description 58
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
239000002904 solvent Substances 0.000 description 55
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 53
239000000047 product Substances 0.000 description 51
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
239000011780 sodium chloride Substances 0.000 description 50
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
239000003480 eluent Substances 0.000 description 45
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 41
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 41
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
239000007864 aqueous solution Substances 0.000 description 37
FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 description 36
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
229910002027 silica gel Inorganic materials 0.000 description 36
239000000741 silica gel Substances 0.000 description 36
239000003054 catalyst Substances 0.000 description 34
229920001467 poly(styrenesulfonates) Polymers 0.000 description 34
239000000725 suspension Substances 0.000 description 34
239000002253 acid Substances 0.000 description 30
238000006243 chemical reaction Methods 0.000 description 30
125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 30
239000000284 extract Substances 0.000 description 29
229910052757 nitrogen Inorganic materials 0.000 description 29
229920006395 saturated elastomer Polymers 0.000 description 28
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
238000004108 freeze drying Methods 0.000 description 26
229910052799 carbon Inorganic materials 0.000 description 25
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 22
238000005481 NMR spectroscopy Methods 0.000 description 22
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
238000001914 filtration Methods 0.000 description 21
AFCCDDWKHLHPDF-UHFFFAOYSA-M metam-sodium Chemical compound [Na+].CNC([S-])=S AFCCDDWKHLHPDF-UHFFFAOYSA-M 0.000 description 21
239000010410 layer Substances 0.000 description 19
239000008346 aqueous phase Substances 0.000 description 18
239000000460 chlorine Substances 0.000 description 18
239000012071 phase Substances 0.000 description 18
229910052708 sodium Inorganic materials 0.000 description 18
125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 17
BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 17
235000011054 acetic acid Nutrition 0.000 description 16
239000012267 brine Substances 0.000 description 16
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 14
125000003118 aryl group Chemical group 0.000 description 14
150000002148 esters Chemical class 0.000 description 14
AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 description 14
XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 13
239000012044 organic layer Substances 0.000 description 13
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 12
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 12
239000003921 oil Substances 0.000 description 12
235000019198 oils Nutrition 0.000 description 12
VONQTDZQDYVTEV-UHFFFAOYSA-M sodium 2-oxoazetidine-1-sulfonate Chemical compound [Na+].[O-]S(=O)(=O)N1CCC1=O VONQTDZQDYVTEV-UHFFFAOYSA-M 0.000 description 12
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 12
239000007787 solid Substances 0.000 description 12
239000012298 atmosphere Substances 0.000 description 11
229910052943 magnesium sulfate Inorganic materials 0.000 description 11
235000019341 magnesium sulphate Nutrition 0.000 description 11
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
229910000027 potassium carbonate Inorganic materials 0.000 description 11
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 10
BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
239000004480 active ingredient Substances 0.000 description 10
239000012074 organic phase Substances 0.000 description 10
USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical compound [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 description 10
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 9
125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 9
239000007788 liquid Substances 0.000 description 9
150000004702 methyl esters Chemical class 0.000 description 9
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
238000010828 elution Methods 0.000 description 8
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
238000005406 washing Methods 0.000 description 8
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 7
239000002585 base Substances 0.000 description 7
229910002091 carbon monoxide Inorganic materials 0.000 description 7
238000010531 catalytic reduction reaction Methods 0.000 description 7
235000008504 concentrate Nutrition 0.000 description 7
239000012141 concentrate Substances 0.000 description 7
229910000396 dipotassium phosphate Inorganic materials 0.000 description 7
235000019797 dipotassium phosphate Nutrition 0.000 description 7
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
239000000463 material Substances 0.000 description 7
150000007524 organic acids Chemical class 0.000 description 7
LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 7
238000010898 silica gel chromatography Methods 0.000 description 7
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
WNEODWDFDXWOLU-QHCPKHFHSA-N 3-[3-(hydroxymethyl)-4-[1-methyl-5-[[5-[(2s)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl]amino]-6-oxopyridin-3-yl]pyridin-2-yl]-7,7-dimethyl-1,2,6,8-tetrahydrocyclopenta[3,4]pyrrolo[3,5-b]pyrazin-4-one Chemical compound C([C@@H](N(CC1)C=2C=NC(NC=3C(N(C)C=C(C=3)C=3C(=C(N4C(C5=CC=6CC(C)(C)CC=6N5CC4)=O)N=CC=3)CO)=O)=CC=2)C)N1C1COC1 WNEODWDFDXWOLU-QHCPKHFHSA-N 0.000 description 6
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 6
239000002198 insoluble material Substances 0.000 description 6
229910052751 metal Inorganic materials 0.000 description 6
239000002184 metal Substances 0.000 description 6
AFDQGRURHDVABZ-UHFFFAOYSA-N n,n-dimethylformamide;sulfur trioxide Chemical compound O=S(=O)=O.CN(C)C=O AFDQGRURHDVABZ-UHFFFAOYSA-N 0.000 description 6
UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 6
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