KR102487872B1 - 가용성 구아닐레이트 시클라제 자극제의 신규 제조 방법 - Google Patents
가용성 구아닐레이트 시클라제 자극제의 신규 제조 방법 Download PDFInfo
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- KR102487872B1 KR102487872B1 KR1020197003459A KR20197003459A KR102487872B1 KR 102487872 B1 KR102487872 B1 KR 102487872B1 KR 1020197003459 A KR1020197003459 A KR 1020197003459A KR 20197003459 A KR20197003459 A KR 20197003459A KR 102487872 B1 KR102487872 B1 KR 102487872B1
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- 102000007637 Soluble Guanylyl Cyclase Human genes 0.000 title abstract description 16
- 108010007205 Soluble Guanylyl Cyclase Proteins 0.000 title abstract description 16
- 238000004519 manufacturing process Methods 0.000 title description 23
- 239000000021 stimulant Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 239
- 238000006243 chemical reaction Methods 0.000 claims abstract description 118
- 238000000034 method Methods 0.000 claims abstract description 86
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 230000008569 process Effects 0.000 claims abstract description 14
- 239000003960 organic solvent Substances 0.000 claims description 83
- 239000000203 mixture Substances 0.000 claims description 62
- 150000001412 amines Chemical class 0.000 claims description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- -1 pyrazole ester Chemical class 0.000 claims description 49
- XJPZKYIHCLDXST-UHFFFAOYSA-N 4,6-dichloropyrimidine Chemical compound ClC1=CC(Cl)=NC=N1 XJPZKYIHCLDXST-UHFFFAOYSA-N 0.000 claims description 45
- 239000003153 chemical reaction reagent Substances 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 239000003054 catalyst Substances 0.000 claims description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 38
- 229910052751 metal Inorganic materials 0.000 claims description 35
- 239000002184 metal Substances 0.000 claims description 35
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 32
- 125000001072 heteroaryl group Chemical group 0.000 claims description 31
- 239000003586 protic polar solvent Substances 0.000 claims description 31
- YLZYSVYZMDJYOT-UHFFFAOYSA-N 2-methoxypyrimidine Chemical compound COC1=NC=CC=N1 YLZYSVYZMDJYOT-UHFFFAOYSA-N 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 239000007858 starting material Substances 0.000 claims description 24
- 238000009901 transfer hydrogenation reaction Methods 0.000 claims description 24
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 21
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 20
- 150000001409 amidines Chemical class 0.000 claims description 19
- 230000008878 coupling Effects 0.000 claims description 18
- 238000010168 coupling process Methods 0.000 claims description 18
- 238000005859 coupling reaction Methods 0.000 claims description 18
- 150000002009 diols Chemical class 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 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 18
- 239000000010 aprotic solvent Substances 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 16
- 150000001408 amides Chemical class 0.000 claims description 16
- 238000005660 chlorination reaction Methods 0.000 claims description 16
- 150000007522 mineralic acids Chemical class 0.000 claims description 16
- 238000006298 dechlorination reaction Methods 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 13
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims description 12
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 claims description 11
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims description 10
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 238000005576 amination reaction Methods 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- 235000019270 ammonium chloride Nutrition 0.000 claims description 8
- 239000003444 phase transfer catalyst Substances 0.000 claims description 8
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 230000029936 alkylation Effects 0.000 claims description 6
- 238000005804 alkylation reaction Methods 0.000 claims description 6
- 150000003840 hydrochlorides Chemical class 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 5
- 239000011260 aqueous acid Substances 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 238000005805 hydroxylation reaction Methods 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 238000006198 methoxylation reaction Methods 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 230000000382 dechlorinating effect Effects 0.000 claims 4
- 230000001335 demethylating effect Effects 0.000 claims 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 211
- 230000008901 benefit Effects 0.000 abstract description 13
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- BWIHJLOBZMKPKS-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)pyrimidine Chemical class N1C=CC(C=2N=CC=CN=2)=N1 BWIHJLOBZMKPKS-UHFFFAOYSA-N 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 67
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 238000004128 high performance liquid chromatography Methods 0.000 description 54
- 239000002002 slurry Substances 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 239000011541 reaction mixture Substances 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 230000015572 biosynthetic process Effects 0.000 description 37
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 239000012065 filter cake Substances 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 31
- QGLIOTYTGRWVPT-UHFFFAOYSA-N 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound NCC(O)(C(F)(F)F)C(F)(F)F QGLIOTYTGRWVPT-UHFFFAOYSA-N 0.000 description 30
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 26
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 16
- 239000010410 layer Substances 0.000 description 15
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 15
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 14
- 229940127296 soluble guanylate cyclase stimulator Drugs 0.000 description 13
- 229910052763 palladium Inorganic materials 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 235000019253 formic acid Nutrition 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000000908 ammonium hydroxide Substances 0.000 description 8
- 125000003118 aryl group Chemical group 0.000 description 8
- 229940045348 brown mixture Drugs 0.000 description 8
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000004809 Teflon Substances 0.000 description 7
- 229920006362 Teflon® Polymers 0.000 description 7
- 230000003197 catalytic effect Effects 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 7
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 5
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 5
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- OOMBRKGIWITBLL-UHFFFAOYSA-N (2-fluorophenyl)methylhydrazine Chemical compound NNCC1=CC=CC=C1F OOMBRKGIWITBLL-UHFFFAOYSA-N 0.000 description 4
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- GOWQBFVDZPZZFA-UHFFFAOYSA-N diethyl 2-fluoropropanedioate Chemical compound CCOC(=O)C(F)C(=O)OCC GOWQBFVDZPZZFA-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 125000005843 halogen group Chemical group 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 238000013341 scale-up Methods 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 4
- 235000019254 sodium formate Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical group [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 150000003278 haem Chemical class 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- ZRKSVHFXTRFQFL-UHFFFAOYSA-N isocyanomethane Chemical compound C[N+]#[C-] ZRKSVHFXTRFQFL-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- JSPCTNUQYWIIOT-UHFFFAOYSA-N piperidine-1-carboxamide Chemical compound NC(=O)N1CCCCC1 JSPCTNUQYWIIOT-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
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- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- IPILPUZVTYHGIL-UHFFFAOYSA-M tributyl(methyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](C)(CCCC)CCCC IPILPUZVTYHGIL-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Enzymes And Modification Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662359453P | 2016-07-07 | 2016-07-07 | |
| US62/359,453 | 2016-07-07 | ||
| PCT/US2017/040810 WO2018009597A1 (en) | 2016-07-07 | 2017-07-06 | Novel processes for preparation of soluble guanylate cyclase stimulators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20190025986A KR20190025986A (ko) | 2019-03-12 |
| KR102487872B1 true KR102487872B1 (ko) | 2023-01-12 |
Family
ID=59416789
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020197003459A Active KR102487872B1 (ko) | 2016-07-07 | 2017-07-06 | 가용성 구아닐레이트 시클라제 자극제의 신규 제조 방법 |
Country Status (16)
| Country | Link |
|---|---|
| US (3) | US11319308B2 (enExample) |
| EP (2) | EP3481818B1 (enExample) |
| JP (1) | JP7112384B2 (enExample) |
| KR (1) | KR102487872B1 (enExample) |
| CN (1) | CN109563077A (enExample) |
| AU (1) | AU2017291827B2 (enExample) |
| BR (1) | BR112019000291A2 (enExample) |
| CA (1) | CA3029375A1 (enExample) |
| CL (2) | CL2019000016A1 (enExample) |
| EA (1) | EA201990237A1 (enExample) |
| ES (1) | ES2963563T3 (enExample) |
| IL (1) | IL263995B (enExample) |
| MA (1) | MA45603A (enExample) |
| MX (2) | MX389920B (enExample) |
| SG (1) | SG11201900096QA (enExample) |
| WO (1) | WO2018009597A1 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3481818B1 (en) | 2016-07-07 | 2023-09-06 | Cyclerion Therapeutics, Inc. | Novel processes for preparation of soluble guanylate cyclase stimulators |
| BR112019000292A2 (pt) | 2016-07-07 | 2019-04-16 | Ironwood Pharmaceuticals, Inc. | processos inovadores para a preparação de estimuladores de guanilato ciclase solúvel |
| WO2019161534A1 (en) * | 2018-02-22 | 2019-08-29 | Ironwood Pharmaceuticals, Inc. | Novel processes and intermediates for preparation of soluble guanylate cyclase stimulators |
| JOP20200165A1 (ar) | 2018-01-10 | 2022-10-30 | Cyclerion Therapeutics Inc | عمليات ووسائط جديدة لتحضير محفزات إنزيم حلقي جوانيلات قابلة للذوبان |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013101830A1 (en) | 2011-12-27 | 2013-07-04 | Ironwood Pharmaceuticals, Inc. | 2 - benzyl, 3 - (pyrimidin- 2 -yl) substituted pyrazoles useful as sgc stimulators |
| WO2014144100A2 (en) | 2013-03-15 | 2014-09-18 | Takashi Nakai | Sgc stimulators |
| WO2015089182A1 (en) | 2013-12-11 | 2015-06-18 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
| WO2016044447A1 (en) | 2014-09-17 | 2016-03-24 | Ironwood Pharmaceuticals, Inc. | Pyrazole derivatives as sgc stimulators |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ603789A (en) | 2010-05-26 | 2015-03-27 | Sunovion Pharmaceuticals Inc | Heteroaryl compounds and methods of use thereof |
| UY33476A (es) | 2010-06-30 | 2012-02-29 | Ironwood Pharmaceuticals Inc | Estimuladores de sgc |
| CA2885645A1 (en) * | 2012-09-19 | 2014-03-27 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
| WO2016044446A2 (en) * | 2014-09-17 | 2016-03-24 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
| US20170298055A1 (en) * | 2014-09-17 | 2017-10-19 | Ironwood Pharmaceuticals, Inc. | sGC STIMULATORS |
| MX2017003517A (es) * | 2014-09-17 | 2017-07-28 | Ironwood Pharmaceuticals Inc | Estimuladores de guanilato ciclasa soluble (sgc). |
| MX389961B (es) * | 2015-11-30 | 2025-03-20 | Cyclerion Therapeutics Inc | Dispersiones sólidas que comprenden estimulador de heme guanilato ciclasa soluble (sgc). |
| EP3481818B1 (en) | 2016-07-07 | 2023-09-06 | Cyclerion Therapeutics, Inc. | Novel processes for preparation of soluble guanylate cyclase stimulators |
| BR112019000293A2 (pt) * | 2016-07-07 | 2019-04-16 | Ironwood Pharmaceuticals, Inc. | formas sólidas de um estimulador de sgc |
| BR112019000292A2 (pt) * | 2016-07-07 | 2019-04-16 | Ironwood Pharmaceuticals, Inc. | processos inovadores para a preparação de estimuladores de guanilato ciclase solúvel |
| US11897887B2 (en) * | 2017-12-19 | 2024-02-13 | Tisento Therapeutics Inc. | sGC stimulators |
| JOP20200165A1 (ar) * | 2018-01-10 | 2022-10-30 | Cyclerion Therapeutics Inc | عمليات ووسائط جديدة لتحضير محفزات إنزيم حلقي جوانيلات قابلة للذوبان |
-
2017
- 2017-07-06 EP EP17745553.2A patent/EP3481818B1/en active Active
- 2017-07-06 ES ES17745553T patent/ES2963563T3/es active Active
- 2017-07-06 WO PCT/US2017/040810 patent/WO2018009597A1/en not_active Ceased
- 2017-07-06 SG SG11201900096QA patent/SG11201900096QA/en unknown
- 2017-07-06 CA CA3029375A patent/CA3029375A1/en active Pending
- 2017-07-06 MX MX2019000105A patent/MX389920B/es unknown
- 2017-07-06 EP EP23185002.5A patent/EP4249488A3/en active Pending
- 2017-07-06 MA MA045603A patent/MA45603A/fr unknown
- 2017-07-06 AU AU2017291827A patent/AU2017291827B2/en active Active
- 2017-07-06 JP JP2019500355A patent/JP7112384B2/ja active Active
- 2017-07-06 BR BR112019000291A patent/BR112019000291A2/pt not_active Application Discontinuation
- 2017-07-06 US US16/315,218 patent/US11319308B2/en active Active
- 2017-07-06 CN CN201780047020.6A patent/CN109563077A/zh active Pending
- 2017-07-06 EA EA201990237A patent/EA201990237A1/ru unknown
- 2017-07-06 KR KR1020197003459A patent/KR102487872B1/ko active Active
-
2018
- 2018-12-27 IL IL263995A patent/IL263995B/en active IP Right Grant
-
2019
- 2019-01-04 CL CL2019000016A patent/CL2019000016A1/es unknown
- 2019-01-07 MX MX2022001495A patent/MX2022001495A/es unknown
-
2022
- 2022-03-30 US US17/708,296 patent/US11773089B2/en active Active
-
2023
- 2023-01-24 CL CL2023000228A patent/CL2023000228A1/es unknown
- 2023-08-24 US US18/237,435 patent/US20240059684A1/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013101830A1 (en) | 2011-12-27 | 2013-07-04 | Ironwood Pharmaceuticals, Inc. | 2 - benzyl, 3 - (pyrimidin- 2 -yl) substituted pyrazoles useful as sgc stimulators |
| WO2014144100A2 (en) | 2013-03-15 | 2014-09-18 | Takashi Nakai | Sgc stimulators |
| WO2015089182A1 (en) | 2013-12-11 | 2015-06-18 | Ironwood Pharmaceuticals, Inc. | Sgc stimulators |
| WO2016044447A1 (en) | 2014-09-17 | 2016-03-24 | Ironwood Pharmaceuticals, Inc. | Pyrazole derivatives as sgc stimulators |
Also Published As
| Publication number | Publication date |
|---|---|
| CL2019000016A1 (es) | 2019-05-03 |
| US11773089B2 (en) | 2023-10-03 |
| KR20190025986A (ko) | 2019-03-12 |
| AU2017291827B2 (en) | 2021-10-21 |
| WO2018009597A1 (en) | 2018-01-11 |
| MX389920B (es) | 2025-03-20 |
| CL2023000228A1 (es) | 2023-09-29 |
| EP3481818C0 (en) | 2023-09-06 |
| EP4249488A2 (en) | 2023-09-27 |
| JP2019525913A (ja) | 2019-09-12 |
| US11319308B2 (en) | 2022-05-03 |
| EP3481818A1 (en) | 2019-05-15 |
| AU2017291827A1 (en) | 2019-02-07 |
| IL263995B (en) | 2021-02-28 |
| ES2963563T3 (es) | 2024-03-27 |
| EA201990237A1 (ru) | 2019-08-30 |
| US20210323951A1 (en) | 2021-10-21 |
| MX2019000105A (es) | 2019-04-22 |
| SG11201900096QA (en) | 2019-02-27 |
| NZ750123A (en) | 2025-02-28 |
| US20240059684A1 (en) | 2024-02-22 |
| MA45603A (fr) | 2019-05-15 |
| EP3481818B1 (en) | 2023-09-06 |
| CN109563077A (zh) | 2019-04-02 |
| JP7112384B2 (ja) | 2022-08-03 |
| CA3029375A1 (en) | 2018-01-11 |
| BR112019000291A2 (pt) | 2019-04-16 |
| IL263995A (en) | 2019-02-28 |
| EP4249488A3 (en) | 2023-12-20 |
| MX2022001495A (es) | 2022-03-11 |
| US20220227748A1 (en) | 2022-07-21 |
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