CN111527067A - Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt - Google Patents
Process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic acid salt Download PDFInfo
- Publication number
- CN111527067A CN111527067A CN201880082979.8A CN201880082979A CN111527067A CN 111527067 A CN111527067 A CN 111527067A CN 201880082979 A CN201880082979 A CN 201880082979A CN 111527067 A CN111527067 A CN 111527067A
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- CN
- China
- Prior art keywords
- pyrrole
- fluorophenyl
- compound
- protecting group
- represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 pyridin-3-ylsulfonyl Chemical group 0.000 title claims description 46
- 238000000034 method Methods 0.000 title claims description 23
- 230000008569 process Effects 0.000 title claims description 12
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 title claims description 6
- 150000003839 salts Chemical class 0.000 title claims description 4
- 239000002253 acid Substances 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 38
- MQULPEUCGKEHEG-UHFFFAOYSA-N 5-(2-fluorophenyl)-1h-pyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1 MQULPEUCGKEHEG-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 53
- 125000006239 protecting group Chemical group 0.000 claims description 31
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 19
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 15
- 229910052751 metal Inorganic materials 0.000 claims description 11
- 239000002184 metal Substances 0.000 claims description 11
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 9
- 150000003233 pyrroles Chemical class 0.000 claims description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 8
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 claims description 7
- CHNYVNOFAWYUEG-UHFFFAOYSA-N 1h-pyrrole-3-carbaldehyde Chemical class O=CC=1C=CNC=1 CHNYVNOFAWYUEG-UHFFFAOYSA-N 0.000 claims description 6
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical class FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 abstract description 11
- 238000010511 deprotection reaction Methods 0.000 abstract description 8
- 238000006170 formylation reaction Methods 0.000 abstract description 4
- 230000022244 formylation Effects 0.000 abstract description 2
- 230000006103 sulfonylation Effects 0.000 abstract 1
- 238000005694 sulfonylation reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- 238000001816 cooling Methods 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000012312 sodium hydride Substances 0.000 description 13
- 229910000104 sodium hydride Inorganic materials 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 10
- ZFKKLKZBDLEYLE-UHFFFAOYSA-N 2-(2-fluorophenyl)-1h-pyrrole Chemical compound FC1=CC=CC=C1C1=CC=CN1 ZFKKLKZBDLEYLE-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 229950003825 vonoprazan Drugs 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 229940057995 liquid paraffin Drugs 0.000 description 8
- OVRKATYHWPCGPZ-UHFFFAOYSA-N 4-methyloxane Chemical compound CC1CCOCC1 OVRKATYHWPCGPZ-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- KUSUUKJGWNAOJI-UHFFFAOYSA-N [2-(2-fluorophenyl)pyrrol-1-yl]-tri(propan-2-yl)silane Chemical compound FC1=C(C=CC=C1)C=1N(C=CC1)[Si](C(C)C)(C(C)C)C(C)C KUSUUKJGWNAOJI-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 5
- CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical group CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- 239000011592 zinc chloride Substances 0.000 description 5
- 235000005074 zinc chloride Nutrition 0.000 description 5
- TYHUGKGZNOULKD-UHFFFAOYSA-N 1-fluoro-2-iodobenzene Chemical compound FC1=CC=CC=C1I TYHUGKGZNOULKD-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- 239000002798 polar solvent Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 3
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 2
- QDNWNJSLWKHNTM-UHFFFAOYSA-N 2-bromo-1-(2-fluorophenyl)ethanone Chemical compound FC1=CC=CC=C1C(=O)CBr QDNWNJSLWKHNTM-UHFFFAOYSA-N 0.000 description 2
- YBDQLHBVNXARAU-UHFFFAOYSA-N 2-methyloxane Chemical compound CC1CCCCO1 YBDQLHBVNXARAU-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IXCSYEVJOAWXRH-UHFFFAOYSA-N 5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1S(=O)(=O)C1=CC=CN=C1 IXCSYEVJOAWXRH-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000005874 Vilsmeier-Haack formylation reaction Methods 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 150000003983 crown ethers Chemical class 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- ZUVAACFIEPYYOP-UHFFFAOYSA-N methoxycyclopropane Chemical compound COC1CC1 ZUVAACFIEPYYOP-UHFFFAOYSA-N 0.000 description 2
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 2
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 1
- NOUFLZSMHQHSHA-UHFFFAOYSA-N 2-[2-(2-fluorophenyl)-2-oxoethyl]propanedinitrile Chemical compound FC1=CC=CC=C1C(=O)CC(C#N)C#N NOUFLZSMHQHSHA-UHFFFAOYSA-N 0.000 description 1
- XJAINPOVVPZLBI-UHFFFAOYSA-N 2-methylbutan-2-yl carbonochloridate Chemical compound CCC(C)(C)OC(Cl)=O XJAINPOVVPZLBI-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- SNNVSEONCOCCRZ-UHFFFAOYSA-N C1CC=CCCC=C1[Ni]C1=CCCC=CCC1 Chemical compound C1CC=CCCC=C1[Ni]C1=CCCC=CCC1 SNNVSEONCOCCRZ-UHFFFAOYSA-N 0.000 description 1
- FLAKGKCBSLMHQU-UHFFFAOYSA-N CC[Mg] Chemical compound CC[Mg] FLAKGKCBSLMHQU-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 101000813777 Homo sapiens Splicing factor ESS-2 homolog Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 238000007013 Reimer-Tiemann formylation reaction Methods 0.000 description 1
- 238000006958 Rieche formylation reaction Methods 0.000 description 1
- 102100039575 Splicing factor ESS-2 homolog Human genes 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- VYPKVJUNYSEWKB-UHFFFAOYSA-N benzyl n-diazocarbamate Chemical compound [N-]=[N+]=NC(=O)OCC1=CC=CC=C1 VYPKVJUNYSEWKB-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- UBIJTWDKTYCPMQ-UHFFFAOYSA-N hexachlorophosphazene Chemical compound ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1 UBIJTWDKTYCPMQ-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- ZBRJXVVKPBZPAN-UHFFFAOYSA-L nickel(2+);triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].[Ni+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 ZBRJXVVKPBZPAN-UHFFFAOYSA-L 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 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
- ISHLCKAQWKBMAU-UHFFFAOYSA-N tert-butyl n-diazocarbamate Chemical compound CC(C)(C)OC(=O)N=[N+]=[N-] ISHLCKAQWKBMAU-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B61/00—Other general methods
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
The present invention relates to a method for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde by formylation and deprotection reactions, and a method for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine monofumarate by sulfonylation or the like.
Description
Technical Field
The present invention relates to a process for the manufacture of 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which is an acid secretion inhibitor, and intermediates thereof.
Background
1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine monofumarate (hereinafter vonoprazan fumarate) represented by the following formula is a potassium ion competitive acid blocker, inhibits the binding of potassium ions to H +, K + -ATPase, and inhibits gastric acid secretion, and therefore, is used for the treatment and prevention of gastric/duodenal ulcer and the like, and for the intragastric pH adjustment at the time of the sterilization of helicobacter pylori. Vonoprazan fumarate is known to be stable to acids, reach an effective concentration quickly, show an action quickly after administration, and strongly inhibit gastric acid for a long period of time, as compared with conventional proton pump inhibitors.
Regarding the method for producing vonoprazan fumarate, for example, patent document 1 discloses a method for synthesizing a pyrrole-3-carbaldehyde derivative as a synthesis intermediate from a cyano compound represented by the following formula via an azole.
In this method, [ 2- (2-fluorophenyl) -2-oxoethyl ] malononitrile (a) is used as a starting material. It is described that this raw material can be produced by the method described in patent document 2, and the synthesis by the reaction of α -bromo o-fluoroacetophenone and malononitrile is disclosed. Further, it is described that α -bromo-o-fluoroacetophenone can be produced by a generally known method. Although not specifically described, for example, a method of reacting bromine in acetic acid (non-patent document 1) and a method of reacting bromine in the presence of aluminum chloride (non-patent document 2) are known. Since the synthesis of the raw material requires 2 steps, the production of the target compound requires a plurality of steps. In addition, in these reactions, propionitrile and bromine which are highly corrosive and irritant and are concerned about toxicity and influence on the environment are used, and therefore a production method which is further considered safe to the human body and the environment is desired. Further, 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde was synthesized from the starting material in a yield of 53% to 60%, and improvement of the yield was also desired.
Therefore, a production method which has less influence on the human body and the environment, has a shorter process, and has a good yield has been desired.
Documents of the prior art
Patent document
Patent document 1: japanese patent No. 5819494
Patent document 2: japanese patent No. 3140818
Non-patent document
Non-patent document 1: organic Synthesis, Coll, Vol.1, 127(1941)
Non-patent document 2: organic Synthesis, Coll, Vol.2, 480(1943)
Non-patent document 3: synthesis,49(16), 3692-3699; 2017
Non-patent document 4: journal of Organic Chemistry,75(9), 3109-; 2010
Disclosure of Invention
The purpose of the present invention is to provide a method for producing a pyrrole-3-carbaldehyde derivative, which is an intermediate for synthesizing vonoprazan fumarate, and a novel industrial production method for vonoprazan fumarate, which uses the derivative.
The present inventors have conducted intensive studies and, as a result, have found a method for producing a pyrrole-3-carbaldehyde derivative efficiently and easily by using a coupling reaction between readily available fluoroiodobenzene and pyrrole and a regioselective formylation reaction based on appropriate protection of the nitrogen atom on the pyrrole ring, and have completed the present invention.
That is to say that the first and second electrodes,
[1] the invention relates to a method for preparing 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde,
a protecting group is introduced into a nitrogen atom of a pyrrole ring in a pyrrole derivative represented by the following general formula (I) to obtain an N-protected pyrrole derivative represented by the following formula (II) (wherein P represents a protecting group), a pyrrole-3-carbaldehyde derivative represented by the following formula (III) is obtained by formylation, and a 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the following formula (IV) is obtained by deprotection reaction.
[2] The present invention also relates to the production method according to [1], wherein the protecting group represented by P is a silyl protecting group.
[3] The present invention also relates to the production method according to [1] or [2], wherein the protecting group represented by P is triisopropylsilyl.
[4] The present invention also relates to a process for producing the compound (I) according to the above [1] to [3], wherein the pyrrole derivative of the general formula (I) is obtained by reacting an o-fluorobenzene derivative represented by the following formula (V) (wherein L represents a leaving group) with pyrrole in the presence of a metal catalyst.
[5] The present invention also relates to the production method according to item 4 above, wherein the metal catalyst is a palladium catalyst.
[6] The present invention also relates to a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine, which comprises reacting 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the general formula (IV) obtained by the above production process with pyridine-3-sulfonyl chloride or a salt thereof in the presence of an inorganic or organic base to obtain a pyrrole derivative represented by the following formula (VI), further condensing the pyrrole derivative with methylamine, and then subjecting the condensation reaction to a reduction reaction to obtain 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine represented by the following formula (VII).
[7] The present invention also relates to a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which comprises using the compound of the general formula (VII) obtained by the above production process and fumaric acid.
The present invention can obtain 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde using easily available raw materials such as pyrrole and 2-fluoroiodobenzene at low cost in a short time and in a short process and in a good yield (70% or more), and is more economical and productive than conventional methods, and suitable for industrial production. Further, the use of the transition metal catalyst is suppressed to a very small amount and is used in an upstream process, whereby the possibility of residual metal impurities in the final product can be further reduced.
Detailed Description
The present invention will be described in further detail below.
In the general formula (V), examples of the leaving group represented by L include a halogen atom such as chlorine, bromine or iodine, a lower alkanesulfonyloxy group such as a methanesulfonyloxy group or a trifluoromethanesulfonyloxy group, an arylsulfonyloxy group such as a benzenesulfonyloxy group or a p-toluenesulfonyloxy group, and the like.
In the above general formulae (II) and (III), examples of the pyrrole ring nitrogen-protecting group represented by P include a silyl-based protecting group, an alkyl-based protecting group, a heteroaryl-based protecting group, an acyl-based protecting group, a carbamate-based protecting group, and the like, and examples of the silyl-based protecting group include a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a triisopropylsilyl group, a t-butyldiphenylsilyl group, and the like, and preferably a t-butyldimethylsilyl group, a triisopropylsilyl group, and the like.
Examples of the alkyl-based protecting group include allyl, dimethoxymethyl, diethoxymethyl, tert-butyl, triphenylmethyl, benzyl, and 4-methoxybenzyl.
Examples of the heteroaryl-based protecting group include a 2-pyridyl group, a 4-pyridyl group, a 2-pyrazinyl group, a 2-pyrimidinyl group and a 2-triazinyl group.
Examples of the carbamate-based protecting group include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-phenylazobenzyloxycarbonyl, p-methoxyphenyl-azobenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 3,4, 5-trimethoxybenzyloxycarbonyl, p-biphenylisopropoxycarbonyl, diisopropylmethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, and 9-fluorenylmethoxycarbonyl.
As other protecting groups, there may be used alkylsulfonyl such as methylsulfonyl, arylsulfonyl such as p-toluenesulfonyl, alkanoyl such as acetyl, and aroyl such as benzoyl.
Among these protecting groups, the protecting group is preferably a silyl-based protecting group, particularly preferably a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group or a triisopropylsilyl group, and more preferably a triisopropylsilyl group, from the viewpoint of yield and the like.
In the present invention, as the metal catalyst used in the reaction for obtaining the compound (I) from the compound (V), a nickel catalyst, a palladium catalyst, or the like can be used.
Examples of the nickel catalyst used in the present invention include 0-valent nickel catalysts such as bis (1, 5-cyclooctadienyl) nickel and the like, and 2-valent nickel catalysts such as nickel chloride and bis (triphenylphosphine) nickel chloride and the like, and phosphine ligands such as triphenylphosphine, 2- (di-t-butylphosphino) biphenyl, Xantphos, bis [ 2- (diphenylphosphino) phenyl ] ether (hereinafter, DPEPhos), and (±) -2, 2 ' -bis (diphenylphosphino) -1, 1 ' -binaphthyl (hereinafter, (+ -) -BINAP), and the like, and N, N ' -tetramethylethylenediamine and the like may be added as necessary.
The palladium catalyst used in the present invention includes 0-valent palladium catalysts such as palladium carbon and tetrakis (triphenylphosphine) palladium, 2-valent palladium catalysts such as palladium chloride, palladium acetate and (dichlorobis (tri-o-tolylphosphine)) palladium, and phosphine ligands such as triphenylphosphine, 2- (di-t-butylphosphino) biphenyl, xanthphos, DPEPhos and (±) -BINAP may be added as necessary.
As the base used in the present invention, a tertiary amine such as triethylamine or diisopropylethylamine, a metal base such as lithium hydride, sodium hydride, potassium hydride, sodium amide, lithium diisopropylamide (hereinafter, LDA), lithium hexamethyldisilazide (hereinafter, LiHMDS), ethylmagnesium, sodium carbonate, or calcium carbonate, or the like can be added.
A method for producing a pyrrole-3-carbaldehyde derivative, which is a synthetic intermediate in producing vonoprazan fumarate according to the present invention, and a method for producing vonoprazan fumarate using the same are shown below.
(production of Compound (I))
Compound (I) can be produced by a cross-coupling reaction or the like described in non-patent document 3 and non-patent document 4. For example, the non-halogenated unsubstituted pyrrole can be used by radical coupling reaction under an inert gas atmosphere of nitrogen or argon to 1 to 3 equivalents of the above base, preferably a metal base, more preferably diethyl ether, cyclopropyl methyl ether, sodium hydride,Tetrahydrofuran, 4-methyltetrahydropyran, bis1 to 3 equivalents of a solution of pyrrole/the above solvent is added dropwise to a solvent suspension of ethers such as alkane, monoglyme, diglyme, etc., or aromatic hydrocarbons such as benzene, toluene, xylene, etc., at-10 ℃ to room temperature, followed by stirring for 10 minutes to 1 hour, and then 1 to 3 equivalents of inorganic zinc such as zinc halide (zinc chloride, zinc bromide), etc., or organic zinc (preferably zinc halide, particularly preferably zinc chloride), such as zinc dipentanoyl, etc., are added thereto, followed by stirring for 10 minutes to 1 hour at room temperature. Then, compound (I) can be produced by adding 1 to 3 equivalents of compound (V), 0.0001 to 1.0 equivalent (preferably 0.001 to 0.003 equivalent) of the catalyst such as palladium and 0.0001 to 1.0 equivalent (preferably 0.001 to 0.003 equivalent) of the phosphine ligand, and reacting at room temperature to 150 ℃ (preferably 90 to 130 ℃) for 5 minutes to 24 hours.
(production of Compound (II))
The compound (II) can be produced by introducing a protecting group into the compound (I), and the method for producing the protecting group varies depending on the protecting group selected, but a generally known method can be employed. For example, when a silyl protecting group is introduced, 1 to 1.5 equivalents of the above base, preferably a metal base, more preferably diethyl ether of sodium hydride, cyclopropylmethyl ether, tetrahydrofuran, 4-methyltetrahydropyran, or bisCompound (I) is added dropwise to a solvent suspension of an ether such as an alkane, monoglyme, diglyme, or the like, an aprotic polar solvent such as N, N-dimethylformamide, or a mixed solvent thereof, preferably an ether, at-10 ℃ to room temperature, then a metal chelating agent such as a crown ether, tetraethylene diamine, or dimethylimidazolidinone, preferably dimethylimidazolidinone, is added dropwise, and then a protecting group-introducing reagent in an amount of 1 to 1.5 equivalents is added dropwise to the mixture to react the mixture for 5 minutes to 3 hours, whereby compound (II) can be produced.
When introducing a urethane-based protecting group, the urethane-based protecting group is usedThe reaction conditions vary depending on the kind, and for example, when a t-butoxycarbonyl (Boc group), a t-pentyloxycarbonyl (Aoc group), a benzyloxycarbonyl (Z group), a 9-fluorenylmethoxycarbonyl (Fmoc) group, a 2,2, 2-trichloroethoxycarbonyl group, a 2- (trimethylsilyl) ethoxycarbonyl group or the like is introduced into the compound (I), a di-n-ethyloxycarbonyl group or the like can be usedAlkane, diIn a solvent such as an alkane/water, methylene chloride or tetrahydrofuran, di-tert-butyl dicarbonate ((Boc) is reacted in the presence of an organic base such as triethylamine or pyridine, and an inorganic base such as sodium hydride, potassium hydroxide, sodium hydroxide, potassium hydrogen carbonate or sodium hydrogen carbonate2O), tert-butoxycarbonyl chloride, benzyloxycarbonyl chloride, tert-pentyloxycarbonyl chloride, 9-fluorenylmethoxycarbonyl chloride, 2,2, 2-trichloroethyl chloroformate, 2- (trimethylsilyl) ethoxymethyl chloride, tert-butoxycarbonyl azide, benzyloxycarbonyl azide and the like, and 1 to 1.5 equivalents of a commonly known introducing reagent such as a Boc group and the like are reacted at 0 to 100 ℃ for 5 minutes to 10 hours.
(production of Compound (III))
The compound (III) can be produced by a generally known formylation reaction such as Vilsmeier reaction, Rieche reaction, Daff reaction, Reimer-Tiemann reaction, etc., for example, in the Vilsmeier reaction, Vilsmeier reagent ((chloromethylene) dimethylammonium chloride) is prepared from N, N-disubstituted formamide such as N, N-Dimethylformamide (DMF), N-Methylformanilide (MFA), N-formylmorpholine, N-diisopropylformamide, etc., and acid chlorides such as phosphorus oxychloride, oxalyl chloride, thionyl chloride, triphenylphosphine-bromide, hexachlorocyclotriphosphazene, etc., or a commercially available product is purchased, and the compound (II) is reacted with a solvent such as phosphorus oxychloride; or halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, etc.; aromatic hydrocarbons such as benzene, toluene, and nitrobenzene; tetrahydrofuran, methyltetrahydropyran, bisThe compound (III) can be produced by stirring ethers such as alkanes, aprotic polar solvents such as ethyl acetate, acetonitrile, N-dimethylformamide, or a mixed solvent thereof, preferably ether solvents, aromatic hydrocarbons, aprotic polar solvents, or a mixed solvent thereof, more preferably methyl tetrahydropyran at 0 to 100 ℃ (preferably 40 to 80 ℃) for 0.5 to 12 hours, and then reacting the mixture.
(production of Compound (IV))
The compound (IV) can be produced by deprotection reaction of the compound (III). The deprotection reaction differs depending on the protecting group, and a generally known method can be used, and for example, when the protecting group is a silyl protecting group, it can be produced by reacting a fluorine source such as tetrabutylammonium fluoride, HF pyridine complex, HF triethylamine complex or the like in a solution such as tetrahydrofuran at-10 ℃ to room temperature. The deprotection reaction of the silyl protecting group can be carried out in the same manner even under acidic conditions such as hydrochloric acid and trifluoroacetic acid or under basic conditions such as aqueous sodium hydroxide, whereby compound (IV) can be produced. The deprotecting reagent may be 3 to 10 equivalents (preferably 5 equivalents) of an aqueous sodium hydroxide solution with respect to the compound (III).
In the case of the carbamate-based protecting group, the reaction conditions may vary depending on the type of the carbamate-based protecting group, and the reaction may be carried out by a generally known method, for example, by catalytic reduction under a hydrogen atmosphere in the presence of palladium black, palladium on carbon, or the like, or by appropriately selecting acetic acid/hydrogen bromide, trifluoroacetic acid, hydrochloric acid/an organic solvent, or the like according to the protecting group.
In addition, compound (IV) can be produced by one-pot operation without isolating compound (III) from compound (II). In this case, the deprotection can be carried out by adding a reagent for the deprotection to the reaction system after the reaction of the compounds (II) to (III) is completed.
The compound (IV) may be produced by one pot operation without separating the compound (II) and the compound (III) from the compound (I), and for example, after the reaction in the production of the compound (III) is completed, a reaction reagent in the production of the compound (IV) is added to the reaction system, and after the reaction is completed, a reagent for the deprotection reaction is further added to the reaction system, and the reaction is similarly performed, whereby the compound (IV) can be produced. The same amounts as described above can be used in relation to the amounts of the reagents in any production.
(production of Compound (VI))
Adding dropwise a solution of a compound (IV) such as tetrahydrofuran to a 1 to 1.5 equivalent of a sodium hydride/tetrahydrofuran suspension at-10 ℃ to room temperature, stirring the mixture for 0.5 to 1 hour, further stirring the mixture for 0.5 to 1 hour at-10 ℃ to room temperature in the presence of a metal chelating agent such as crown ether, tetramethylethylenediamine or dimethylimidazolidinone, subsequently adding pyridine-3-sulfonyl chloride, and stirring the mixture for 0.5 hour at 0 ℃. Further, pyridine-3-sulfonyl chloride is added thereto, and the mixture is stirred at-10 ℃ to room temperature for 0.5 to 1 hour, whereby the compound (VI) can be produced.
The compound (VI) can be produced by adding a base such as triethylamine or N, N-diisopropylamine, a catalytic amount of 4-dimethylaminopyridine or pyridine-3-sulfonyl chloride to a solution of the compound (IV) in dichloromethane or acetonitrile at 0 to room temperature, and stirring the mixture at room temperature to 100 ℃ for 0.5 to 12 hours.
(production of Compound (VII))
The compound (VII) can be obtained by adding a solution of methylamine in methanol or the like dropwise to a solution of the compound (VI) in methanol or the like at 0 ℃ to room temperature, stirring the mixture for 0.5 to 1 hour, and adding 1 to 3 equivalents of a reducing agent such as sodium borohydride or the like to the mixture at 0 ℃ to room temperature to react the mixture for 0.5 to 1 hour.
(Vonoprazan fumarate production)
Vonoprazan fumarate can be produced by adding a solution of fumaric acid in methanol or the like to a solution of compound (VII) in ethyl acetate, methanol or the like at 0 ℃ to room temperature, stirring for 0.5 to 1 hour, filtering the precipitated crystal, and, if necessary, recrystallizing with methanol/water.
Examples
The present invention will be described in more detail below with reference to examples, comparative examples and test examples, but the present invention is not limited to these examples.
Example 1
Production of 2- (2-fluorophenyl) -1H-pyrrole
After pyrrole (2.1mL, 30.0mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2g, 30.0mmol) and tetrahydrofuran (10mL) under ice-cooling and stirred for 0.5 hour, zinc chloride (4.1g, 30.0mmol) was added and stirred at room temperature for 0.5 hour. Next, palladium acetate (11mg, 0.05mmol), 2- (di-t-butylphosphino) biphenyl (15mg, 0.05mmol) and 1-fluoro-2-iodobenzene (1.1mL, 10.0mmol) were added and degassed, followed by stirring at 60 ℃ for 6 hours. The reaction mixture was cooled at 0 ℃ and water was added dropwise thereto, and after insoluble matter was filtered, the mixture was separated with ethyl acetate. After adding ethyl acetate to the aqueous layer and re-extracting, the organic layers were combined and washed with saturated brine. The solvent was distilled off under reduced pressure, and the product was purified by silica gel column chromatography and dried under reduced pressure to obtain the title compound (1.18g, yield 74%).
Mass spectrum (ESI): m/z calcd for C10H7FN [ M-H ] -: 160.06, respectively; found: 160.18, respectively; 1H-NMR (400MHz, CDCl3) (ppm): 6.30-6.33 (m, 1H), 6.64-6.67 (m, 1H), 6.90-6.93 (m, 1H), 7.07-7.16 (m, 1H), 7.13-7.17 (m, 2H), 7.60-7.65 (m, 1H), 9.05(brs, 1H).
Example 2
Production of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole
After a solution of 2- (2-fluorophenyl) -1H-pyrrole (172mg, 1.07mmol) in tetrahydrofuran (2mL) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 64mg, 1.61mmol) and tetrahydrofuran (2mL) under ice-cooling and stirred for 0.5 hour, 15-crown-5-ether (0.32mL, 1.61mmol) was added and stirred at 0 ℃ for 0.5 hour. Triisopropylsilyl chloride (0.35mL, 1.61mmol) was then added dropwise and stirred at room temperature for 4 hours. Cooled to 0 ℃, water was added dropwise, and the mixture was separated with ethyl acetate. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column and dried under reduced pressure, whereby the title compound (272mg, yield 80%) was obtained.
Mass spectrum (ESI): m/z calcd for C19H28FNNaSi [ M + Na ] +: 340.19, respectively; found: 340.16, respectively; 1H-NMR (400MHz, CDCl3) (ppm): 1.01(d, J ═ 6.9Hz, 18H), 1.13-1.21 (m, 3H), 6.25(dd, J ═ 3.2, 1.2Hz, 1H), 6.37(t, J ═ 3.2Hz, 1H), 6.93(dd, J ═ 2.8, 2.0Hz, 1H), 7.03-7.12 (m, 2H), 7.29-7.37 (m, 2H).
Example 3
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
To a solution of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole (100mg, 0.32mmol) in dichloromethane (3.0mL) was added Vilsmeier reagent (123mg, 0.96mmol) under ice-cooling and stirred at 40 ℃ for 0.5 hour. After the solvent was distilled off under reduced pressure, an aqueous sodium hydroxide solution (1.0M, 3mL) was added thereto, and the mixture was stirred at room temperature for 6 hours, followed by addition of ethyl acetate for liquid separation. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. Purification by silica gel column and drying under reduced pressure were carried out, whereby the title compound (48mg, yield 80%) was obtained.
Mass spectrum (ESI): m/z calcd for C11H8FNNaO [ M + Na ] +: 212.05, respectively; found: 212.03, respectively; 1H-NMR (400MHz, CDCl3) (ppm): 7.07(dd, J ═ 2.0, 1.2Hz, 1H), 7.12-7.26 (m, 3H), 7.53(dd, J ═ 2.8, 1.2Hz, 1H), 7.64(dt, J ═ 7.6, 1.6Hz, 1H), 9.45(brs, 1H), 9.86(s, 1H).
Example 4
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
After pyrrole (2.1mL, 30.0mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 1.2g, 30.0mmol) and 4-methyltetrahydropyran (10mL) under ice-cooling and stirred for 0.5 hour, zinc chloride (4.1g, 30.0mmol) was added and stirred at room temperature for 0.5 hour. Palladium acetate (11mg, 0.05mmol), 2- (di-t-butylphosphino) biphenyl (15mg, 0.05mmol) and 1-fluoro-2-iodobenzene (1.1mL, 10.0mmol) were then added, and the mixture was stirred at 100 ℃ for 0.5 hour. The reaction mixture was cooled at 0 ℃ and 28% aqueous ammonia was added dropwise thereto, and after insoluble matter was filtered, the mixture was separated with ethyl acetate. After the solvent was distilled off under reduced pressure, 2- (2-fluorophenyl) -1H-pyrrole was obtained as a crude product.
To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 600mg, 15mmol) in tetrahydrofuran (10mL) and dimethylimidazolidinone (2mL) was added dropwise a solution of the resulting crude product of 2- (2-fluorophenyl) -1H-pyrrole in tetrahydrofuran (2mL) under ice-cooling, and stirred for 0.5 hour. Triisopropylsilyl chloride (3.2mL, 15mmol) was then added dropwise and stirred at room temperature for 2 hours. While cooling to 0 ℃, water was added dropwise and the solution was separated with ethyl acetate. After the solvent was distilled off under reduced pressure, liquid separation was again performed using heptane and water, and the solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was obtained as a crude product.
To a dichloromethane (50mL) solution of the resulting crude product of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was added Vilsmeier reagent (3.8g, 30mmol) under ice-cooling and stirred at 40 ℃ for 0.5 hour. After the solvent was distilled off under reduced pressure, an aqueous solution of sodium hydroxide (1.0M, 100mL) was added thereto, and the mixture was stirred at room temperature for 6 hours, followed by addition of ethyl acetate for liquid separation. The organic layer was washed with saturated brine, and the solvent was distilled off under reduced pressure. Recrystallization from heptane and ethyl acetate and drying under reduced pressure were carried out, whereby the title compound (1.34g, yield 70%) was obtained.
Example 5
Preparation of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde
After a solution of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (100mg, 0.53mmol) in tetrahydrofuran (2mL) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 32mg, 0.79mmol) and tetrahydrofuran (2mL) under ice-cooling and stirred for 0.5 hour, 15-crown-5-ether (0.16mL, 0.79mmol) was added and stirred for 0.5 hour at 0 ℃. Next, pyridine-3-sulfonyl chloride (95. mu.L, 0.79mmol) was added, and the mixture was stirred at 0 ℃ for 0.5 hour. Pyridine-3-sulfonyl chloride (95. mu.L, 0.79mmol) was further added and stirred at 0 ℃ for 0.5 hour. Water was added dropwise and the solution was separated with ethyl acetate. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. After the solvent was distilled off under reduced pressure, the residue was purified by a silica gel column and dried under reduced pressure, whereby the title compound (167mg, yield 95%) was obtained.
Mass spectrum (ESI): m/z calcd for C16H11FN2NaO3S "M + Na" +: 353.04, respectively; found: 353.00; 1H-NMR (400MHz, CDCl3) (ppm): 6.68(d, J ═ 1.7Hz, 1H), 7.01-7.05 (m, 1H), 7.16-7.18 (m, 2H), 7.37-7.40 (m, 1H), 7.45-7.51 (m, 1H), 7.69-7.72 (m, 1H), 8.15(d, J ═ 1.8Hz, 1H), 8.58(d, J ═ 1.7Hz, 1H), 8.82(dd, J ═ 4.8, 1.5Hz, 1H), 9.90(s, 1H).
Example 6
Preparation of 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanemetic fumarate
To a solution of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde (100mg, 0.30mmol) in methanol (3mL) was added dropwise a solution of methylamine in methanol (2.0M, 1.06mL, 2.12mmol) at room temperature, and the mixture was stirred for 0.5 hour. Cooled to 0 deg.C, sodium borohydride (34mg, 0.91mmol) was added and stirred for 0.5 h. 1N hydrochloric acid (3mL) was added dropwise at 0 ℃ and stirred at room temperature for 0.5 hour. Saturated sodium bicarbonate solution and ethyl acetate were added to separate the solution. After re-extraction by adding ethyl acetate to the aqueous layer, the organic layers were combined and washed with saturated brine. After the organic layer was concentrated, ethyl acetate (3mL) was added, and a solution of fumaric acid (39mg, 0.30mmol) in methanol (0.3mL) was added. After stirring at room temperature for 30 minutes, the precipitated crystals were filtered and washed with ethyl acetate and methanol to give a crude product. The obtained crude crystals were recrystallized from methanol and water, and the precipitated crystals were filtered and dried under reduced pressure to obtain the title compound (90mg, yield 64%).
Mass spectrum (ESI): m/z calcd for C17H17FN3NaO2S "M + H" +: 346.09, respectively; found: 346.11, respectively; 1H-NMR (400MHz, DMSO-d 6) (ppm): 2.39(s, 3H), 3.76(s, 2H), 6.44(d, J ═ 2.0Hz, 1H), 6.47(s, 2H), 7.10 to 7.13(m, 1H), 7.20 to 7.26(m, 2H), 7.50 to 7.56(m, 1H), 7.60 to 7.67(m, 2H), 7.85 to 7.89(m, 1H), 8.56(d, J ═ 2.8Hz, 1H), 8.87 to 8.89(m, 1H), 3H were not detected.
Example 7
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde
After pyrrole (15.7mL, 220.0mmol) was added dropwise to a suspension of sodium hydride (dispersed in 60% liquid paraffin, 8.8g, 220.0mmol) and 4-methyltetrahydropyran (100mL) under ice-cooling and stirred for 0.5 hour, zinc chloride (30.3g, 220.0mmol) was added and stirred at room temperature for 0.5 hour. Next, palladium acetate (56.1mg, 0.25mmol), 2- (di-t-butylphosphino) biphenyl (74.6mg, 0.25mmol) and 1-fluoro-2-iodobenzene (11.5mL, 100.0mmol) were added, and the mixture was stirred at about 100 ℃ for 1 hour. An aqueous solution of sodium hydroxide (5.0N, 220.0mmol) was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 0.5 hour. Insoluble matter was filtered, washed with toluene (100mL), and the organic layer was separated and the aqueous layer was extracted with toluene (100 mL). The organic layers were combined and washed with distilled water (167mL) and saturated brine (167 mL). After the solvent was distilled off under reduced pressure, toluene (167mL) was added to the residue. The solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1H-pyrrole was obtained as a crude product (20.9 g).
To a suspension of sodium hydride (dispersed in 60% liquid paraffin, 4.4g, 110.0mmol) in tetrahydrofuran (100mL) and dimethylimidazolidinone (32.6mL, 300.0mmol), a solution of the resulting crude product of 2- (2-fluorophenyl) -1H-pyrrole in tetrahydrofuran (10mL) was added dropwise under ice-cooling, washed with tetrahydrofuran (10mL) and stirred for 0.5 hour. Triisopropylsilyl chloride (23.5mL, 110.0mmol) was then added dropwise and stirred at room temperature for 1 hour. Distilled water (17mL) was added dropwise under an ice bath, and further distilled water (167mL) was added. Ethyl acetate (84mL) was used for 2 extractions, which were washed with distilled water (167mL) and saturated brine (167 mL). After the solvent was distilled off under reduced pressure, toluene (167mL) was added to the residue. After the solvent was distilled off under reduced pressure, whereby 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole was obtained as a crude product (45.2 g).
Oxalyl chloride (17.2mL, 200.0mmol) was added to dichloromethane (100mL), and DMF (15.5mL, 200.0mmol) was added dropwise under ice-cooling, followed by stirring for 0.5 hour. A solution of the resulting crude product of 2- (2-fluorophenyl) -1- (triisopropylsilyl) -1H-pyrrole in 4-methyltetrahydropyran (100mL) was added in one portion and stirred at about 50 ℃ for 3 hours. Aqueous sodium hydroxide (5.0M, 100mL) was added under ice-cooling and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was separated with ethyl acetate (200 mL). The organic layers were combined, washed with saturated brine (200mL), and the solvent was distilled off under reduced pressure. To the resulting solid residue was added ethyl acetate (47mL), which was dissolved at about 70 ℃ and heptane (300mL) was added. After cooling at room temperature, the mixture was stirred for 1 hour in an ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate/heptane (1:6, 70 mL). Dried under reduced pressure at 50 ℃ for 1.5 hours, whereby the title compound (13.6g, yield 72%) was obtained.
Example 8
Production of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (one-pot synthesis from 2- (2-fluorophenyl) -1H-pyrrole)
After dimethyl imidazolidinone (20.0mL, 186mmol) was added to a solution of 2- (2-fluorophenyl) -1H-pyrrole (10.0g, 62.0mmol) in 4-methyltetrahydropyran (62mL), sodium hydride (dispersed in 60% liquid paraffin, 2.7g, 68.2mmol) was slowly added under ice-cooling, and stirred for 10 minutes. Next, triisopropylsilyl chloride (14.6mL, 68.2mmol) was added dropwise and stirred under ice-cooling for 2 hours. To a solution of Vilsmeier reagent prepared from oxalyl chloride (10.6mL, 124mmol) and DMF (9.65mL, 124mmol) in dichloromethane (90mL) was added the reaction solution of 2- (2-fluorophenyl) -1H-pyrrole in one portion under ice-cooling, washed with 4-methyltetrahydropyran (20mL) and stirred at about 60 ℃ for 2 hours. Aqueous sodium hydroxide (2.0M, 310mL) was added under ice-cooling and stirred at room temperature overnight. The organic layer was separated, and the aqueous layer was separated with ethyl acetate (120 mL). The organic layers were combined, washed with saturated brine (120mL), and the solvent was distilled off under reduced pressure. To the resulting solid residue was added ethyl acetate (29mL), which was dissolved at about 70 ℃ and heptane (180mL) was added. After cooling at room temperature, the mixture was stirred for 1 hour in an ice bath, and the precipitated crystals were collected by filtration and washed with cooled ethyl acetate/heptane (1:6, 42 mL). Dried at 50 ℃ for 1.5 hours under reduced pressure, whereby the title compound (8.30g, yield 71%) was obtained.
Claims (7)
1. A process for producing 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde, which comprises introducing a protecting group to the nitrogen atom of the pyrrole ring in a pyrrole derivative represented by the following formula (I) to obtain an N-protected pyrrole derivative represented by the following formula (II), formylating the N-protected pyrrole derivative to obtain a pyrrole-3-carbaldehyde derivative represented by the following formula (III), and deprotecting the N-protected pyrrole derivative to obtain 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the following formula (IV) wherein P represents a protecting group,
2. the production method according to claim 1, wherein the protecting group represented by P is a silyl protecting group.
3. The production process according to claim 1 or 2, wherein the protecting group represented by P is triisopropylsilyl.
4. A process for producing a compound (I) according to any one of claims 1 to 3, wherein the pyrrole derivative of the general formula (I) is obtained by reacting an o-fluorobenzene derivative represented by the following formula (V) with pyrrole in the presence of a metal catalyst,
in the formula (V), L represents a leaving group.
5. The production method according to claim 4, wherein the metal catalyst is a palladium catalyst.
6. A process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine, which comprises reacting 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde represented by the general formula (IV) obtained by the above production process with pyridine-3-sulfonyl chloride or a salt thereof in the presence of an inorganic or organic base to obtain a pyrrole derivative represented by the following formula (VI), further condensing the pyrrole derivative with methylamine, and then subjecting the condensation reaction to a reduction reaction to obtain 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanamine represented by the following formula (VII),
7. a process for producing 1- [ 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethanemethanamine monofumarate, which comprises using a compound of the general formula (VII) obtained by the above production process and fumaric acid.
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