CN115448907A - Compound for treating peptic ulcer, intermediate and preparation method - Google Patents
Compound for treating peptic ulcer, intermediate and preparation method Download PDFInfo
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- CN115448907A CN115448907A CN202211243523.XA CN202211243523A CN115448907A CN 115448907 A CN115448907 A CN 115448907A CN 202211243523 A CN202211243523 A CN 202211243523A CN 115448907 A CN115448907 A CN 115448907A
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- room temperature
- fluorophenyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 208000008469 Peptic Ulcer Diseases 0.000 title abstract description 4
- 208000011906 peptic ulcer disease Diseases 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 81
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 33
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 16
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 pyridine-3-sulfonyl Chemical group 0.000 claims abstract description 10
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 8
- BZWNGOCDFFQIEN-UHFFFAOYSA-N [5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]methanamine Chemical compound FC1=C(C=CC=C1)C1=CC(=CN1S(=O)(=O)C=1C=NC=CC=1)CN BZWNGOCDFFQIEN-UHFFFAOYSA-N 0.000 claims abstract description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 7
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 6
- KXQMTNMMOMBDLC-UHFFFAOYSA-N ethyl 5-(2-fluorophenyl)-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C1=CNC(C=2C(=CC=CC=2)F)=C1 KXQMTNMMOMBDLC-UHFFFAOYSA-N 0.000 claims abstract description 6
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 claims abstract description 5
- WFJUOMSCRJFQFT-UHFFFAOYSA-N ethyl 5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrole-3-carboxylate Chemical compound FC1=C(C=CC=C1)C1=CC(=CN1S(=O)(=O)C=1C=NC=CC=1)C(=O)OCC WFJUOMSCRJFQFT-UHFFFAOYSA-N 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 19
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- 230000002829 reductive effect Effects 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- SSZWWUDQMAHNAQ-UHFFFAOYSA-N 3-chloropropane-1,2-diol Chemical compound OCC(O)CCl SSZWWUDQMAHNAQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002841 Lewis acid Substances 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- 150000007517 lewis acids Chemical class 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- 230000001105 regulatory effect Effects 0.000 claims description 5
- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- OXRSCXFOUBLJAR-TYYBGVCCSA-N (e)-but-2-enedioic acid;methanamine Chemical compound NC.OC(=O)\C=C\C(O)=O OXRSCXFOUBLJAR-TYYBGVCCSA-N 0.000 claims description 3
- 230000001276 controlling effect Effects 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 230000001502 supplementing effect Effects 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- OCNNQEMNJDZIME-UHFFFAOYSA-N 5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrole-3-carboxamide Chemical compound NC(C(C=C1C(C=CC=C2)=C2F)=CN1S(C1=CC=CN=C1)(=O)=O)=O OCNNQEMNJDZIME-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 2
- 239000005695 Ammonium acetate Substances 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- 229940043376 ammonium acetate Drugs 0.000 claims description 2
- 235000019257 ammonium acetate Nutrition 0.000 claims description 2
- 235000019270 ammonium chloride Nutrition 0.000 claims description 2
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 3
- XOOFLVNFEPIPIW-KQQUZDAGSA-N (1e,4e)-1,5-bis(furan-2-yl)penta-1,4-dien-3-one Chemical group C=1C=COC=1\C=C\C(=O)\C=C\C1=CC=CO1 XOOFLVNFEPIPIW-KQQUZDAGSA-N 0.000 claims 2
- GLJRUXJFSCIQFV-UHFFFAOYSA-N 3-iodopropane-1,2-diol Chemical compound OCC(O)CI GLJRUXJFSCIQFV-UHFFFAOYSA-N 0.000 claims 2
- 230000000171 quenching effect Effects 0.000 claims 2
- SIBFQOUHOCRXDL-UHFFFAOYSA-N 3-bromopropane-1,2-diol Chemical compound OCC(O)CBr SIBFQOUHOCRXDL-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 229960004063 propylene glycol Drugs 0.000 description 5
- 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 description 4
- 229950003825 vonoprazan Drugs 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- 229940126409 proton pump inhibitor Drugs 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 206010061459 Gastrointestinal ulcer Diseases 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 206010013864 duodenitis Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 1
- 229910001414 potassium ion Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a compound for treating peptic ulcer, an intermediate and a preparation method thereof. The present invention provides the following reaction scheme, wherein the chemical name of the compound I is 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-yl]-N-propyleneglycolmethylamine monofumaric acid, compound II ethyl 5- (2-fluorophenyl) -1H-pyrrole-3-carboxylate, compound III pyridine-3-sulfonyl chloride, compound IV ethyl 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-carboxylate, compound V5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-carboxamide, compound VI 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-methylamine, compound VII 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -1H-pyrrol-3-yl]The N-propylene glycol methylamine adopts a new synthetic route, has low price and easily-available raw materials in the marketObtaining; compared with the prior synthetic route, the reagent used in the reaction is green and environment-friendly, the reaction condition is mild, the selectivity is good, and the post-treatment is simpler.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a compound for treating peptic ulcer, an intermediate and a preparation method thereof.
Background
Gastric Acid Related Diseases (ARDs) are upper gastrointestinal diseases in which gastric acid is closely related to pathogenesis, and comprise gastroesophageal reflux disease, dyspepsia, gastrointestinal ulcer, gastritis, duodenitis and gastrointestinal diseases caused by some anti-inflammatory drugs. The incidence of ARDs is on the rise year by year worldwide. In China, ARDS has become one of the major diseases, and seriously affects the quality of life of patients. Proton Pump Inhibitors (PPIs) have been widely used clinically in the treatment of ARDs, and are the main therapeutic drugs for such diseases.
As a potassium ion competitive acid blocker (P-CAB), vonoprazan fumarate has the following advantages compared with conventional irreversible proton pump inhibitors (such as omeprazole, pantoprazole, and the like): (1) conventional proton pump inhibitors form covalent bonds with the cysteine residues of H +/K + -atpase, irreversibly inhibiting enzymatic activity; whereas TAK438 is reversible, is a potassium competitive acid blocker, and has a faster onset of action since it does not require strong acid-dependent activation transformation. (2) Has good stability under acidic condition, and can be highly enriched in gastric acid tubule wall cells to take effect. (3) The occurrence of acid breakthrough at night can be obviously reduced in clinical application.
However, since vonoprazan fumarate is poor in water solubility, it cannot be formulated into an injection, and it can be formulated into only an oral solid preparation, which generally takes several hours to exhibit therapeutic effects, and is disadvantageous for emergency administration.
At present, aiming at the problem of poor water solubility of vonoprazan fumarate, the known technology reports a novel compound with good water solubility, and the structural formula is shown as I:
the compound has obvious effect of inhibiting gastric mucosa injury on the basis of water solubility. Patent CN112812099B discloses a synthesis method of compound I, which route is as follows:
the starting material (compound 1) used in the method is expensive, and the world patent WO2007026916 discloses a synthetic method of the compound 1, and the route is as follows:
according to the route reported in patent WO2007026916, compound 1 needs to be reduced into alcohol through ester group, the alcohol is oxidized into aldehyde group, expensive and air-sensitive reagent diisobutylaluminum hydride (DIBAL-H) is used in the process of reducing the ester group, and the reaction needs to be carried out under the condition of-78 ℃, and the conditions are harsh. Diisobutylaluminum hydride reagent is highly flammable and requires ultra low temperature for reaction, thus not suitable for industrial production operation.
Disclosure of Invention
In order to overcome the technical defects of the existing synthesis process of the compound I, a new synthesis process is urgently needed to be developed, and a compound which is low in price and easy to obtain in the market is used as a raw material; the reagent used in the reaction is green and environment-friendly, the reaction condition is milder, the selectivity is good, and the post-treatment is simpler.
In order to achieve the above object, the present invention provides a novel preparation method of compound I, which comprises four steps of reaction and one step of salt formation, for a total of five steps. The method comprises the following specific steps:
the solvent used in the first step is one or more of acetonitrile, acetone, butanone, tetrahydrofuran, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the alkaline reagent selected in the first step is one or more of diisopropylethylamine, triethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium methoxide;
the solvent selected in the second step reaction is one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the second step reaction selects one or more of diisopropylethylamine, triethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium methoxide as alkaline reagents;
the reaction reagents selected in the second step of reaction comprise: one or more of ammonia water, ammonia gas, ammonium chloride and ammonium acetate;
the solvent selected in the third step is one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, isopropyl ether, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the reducing agent selected in the third step is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride and lithium aluminum hydride;
the Lewis acid selected for the reaction in the third step is one or more of aluminum trichloride, zinc chloride, boron trifluoride and sulfuric acid;
the solvent selected in the fourth step is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, toluene, methyl tert-butyl ether, isopropyl ether, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the reaction reagent selected in the fourth step is one or more of 3-chlorine-1, 2-propylene glycol, 3-bromine-1, 2-propylene glycol and 3-iodine-1, 2-propylene glycol;
the alkaline reagents selected in the fourth step of reaction comprise: one or more of diisopropylethylamine, triethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium methoxide.
The method comprises the following steps:
(1) Putting a compound II and a compound III into a solvent, adding an alkaline reagent, and adding a catalyst DMAP (dimethyl formamide) to perform a catalytic reaction to obtain a compound IV; preferably, the selected solvent is acetonitrile and the selected basic agent is DIEA; preferably, the catalytic reaction temperature is usually 0 to 100 ℃, further preferably 10 ℃ to 50 ℃. (Compound II,5- (2-fluorophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester, commercially available as raw material, available from Saiboda chemical Co., ltd., lot No. SBD 220301.)
(2) Putting the compound IV into a solvent, adding an alkaline reagent, and carrying out urethane exchange reaction with a reaction reagent to obtain a compound V; preferably, the solvent is methanol, the alkaline reagent is sodium methoxide, and the reaction reagent is ammonia water; preferably, the urethane exchange reaction temperature is usually 0 to 100 ℃ and more preferably 10 to 50 ℃.
(3) The compound V is subjected to reduction reaction in a non-aqueous solvent under the action of a metal reducing agent and Lewis acid to prepare a compound VI; preferably, the reduction reaction temperature is usually 0 to 150 ℃, and more preferably 10 ℃ to 80 ℃; the reducing agent molar equivalent is: 0.25 to 10 molar equivalents, preferably 1 to 2 molar equivalents; lewis acid molar equivalents are: 0.25 to 10 molar equivalents, preferably 1 to 2 molar equivalents.
(4) Putting a compound VI and a reaction reagent into a solvent, adding an alkaline reagent, and carrying out condensation reaction to obtain a compound VII, wherein preferably, the solvent is methanol, the reaction reagent is 3-chloro-1, 2-propanediol, and the alkaline reagent is sodium hydroxide; preferably, the condensation reaction temperature is usually 0 to 100 ℃ and more preferably 10 to 50 ℃. Adding N, N-dimethylacetamide into the compound VII, stirring for dissolving, adding fumaric acid, stirring for dissolving, adding ethyl acetate, stirring for crystallizing at room temperature, filtering, and drying under reduced pressure to obtain the compound I.
The invention has the advantages that a new synthetic route is adopted, 5- (2-fluorophenyl) -1H-pyrrole-3-ethyl formate is selected, diisobutyl aluminum hydride (DIBAL-H) is not needed, the price is low, and raw materials are easily available in the market; compared with the prior synthetic route, the reagents used in the reaction are more environment-friendly, the reaction conditions are milder, the selectivity is good, and the post-treatment is simpler.
Detailed Description
EXAMPLE 1 Synthesis of ethyl 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-carboxylate (Compound IV)
To the reaction flask were added 30g of ethyl 5- (2-fluorophenyl) -1H-pyrrole-3-carboxylate (Compound II), 100ml of acetonitrile (CH) 3 CN), 29g of N, N-Diisopropylethylamine (DIEA) and 4g of 4-Dimethylaminopyridine (DMAP), adding 35g of pyridine-3-sulfonyl chloride (compound III) at room temperature, stirring at room temperature for reaction for 30min, adding water to quench the reaction after the reaction is finished, regulating the pH to 5 by using hydrochloric acid, cooling to room temperature, stirring for crystallization, filtering, and drying under reduced pressure to obtain a compound IV, wherein the compound IV is 44g of off-white crystalline powder, and the yield is 84%.
1H-NMR(CDCl 3 )δ：1.35(3H，t，J＝7.2Hz)，4.30(2H，q，J＝7.2Hz)，6.69(1H，d，J＝1.8Hz)，7.05(1H，m)，7.20(2H，m)，7.40(1H，m)，7.50(1H，m)，7.7(1H，m)，8.]5(1H，d，J＝1.8Hz)，8.59(1H，d，J＝2.2Hz)，8.81(1H，m)。
EXAMPLE 2 Synthesis of 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-carboxamide (Compound V)
Adding 40g of compound IV, 200ml of methanol and 16ml of 25% ammonia water into a reaction bottle, cooling to below 20 ℃, dropwise adding 20ml of 30% sodium methoxide methanol solution, controlling the temperature to be below 30 ℃ in the dropwise adding process, stirring at room temperature for reaction for 5 hours after the dropwise adding is finished.
After the reaction is finished, regulating the pH value to 6-7 by using hydrochloric acid, supplementing 200ml of purified water, cooling to 0-10 ℃, stirring and crystallizing for 6h, separating out a white-like solid, filtering, and drying under reduced pressure to obtain 34.3g of a compound V, wherein the yield is 93 percent, and the purity is 95 percent.
Example 3 Synthesis of 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-methanamine (Compound VI)
Under the protection of nitrogen, 30g of compound V and 300ml of tetrahydrofuran are added into a reaction flask, then 3.6g of sodium borohydride and 12.6g of boron trifluoride diethyl etherate are added in portions, the temperature is increased to reflux, and the reaction is stirred for 6 hours.
After the reaction is finished, cooling to room temperature, regulating the pH value to 2-3 by hydrochloric acid, cooling to 0-10 ℃, stirring for crystallization overnight, filtering, stirring and pulping a filter cake by 100ml of ethyl acetate at room temperature for 1h, filtering, and drying the filter cake under reduced pressure to obtain a compound VI which is a white-like solid 28.4g, the yield is 89%, and the purity is 98%.
1H-NMR(MeOD)δ：8.76(1H，dd，J＝4.9，1.6Hz)，8.51(1H，dd，J＝2.4，0.8Hz)，7.87(1H，m)，7.57-7.39(3H，m)，7.23-7.02(3H，m)，6.32(1H，d，J＝1.8Hz)，3.90(2H，d，J＝1.0Hz).
EXAMPLE 4 Synthesis of 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -N-propyleneglycolmethanaminemethanemethanesulfonic acid (Compound I)
(1) At room temperature, 25g of compound VI, 34ml of 2N sodium hydroxide solution and 200ml of methanol are added into a reaction bottle, 9g of 3-chloro-1, 2-propanediol is added, the temperature is raised to 40-50 ℃, and the reaction is stirred for 5 hours. After the reaction is finished, regulating the pH value to 10 by hydrochloric acid, decompressing and concentrating to remove methanol, adding 200ml of ethyl acetate and 200ml of purified water for extraction, washing an organic phase by water, decompressing and concentrating to obtain an oily substance, namely 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-yl ] -N-propylene glycol methylamine (a compound VII); compound VII is free state of 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-yl ] -N-propylene glycol methylamine monofumaric acid (compound I)
(2) To compound VII was added 100ml of N, N-dimethylacetamide, and dissolved with stirring, 7.5g of fumaric acid was added and dissolved with stirring, and 100ml of ethyl acetate was added, followed by crystallization with stirring at room temperature for 1H, filtration and drying under reduced pressure to give 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -N-propanediol methylamine monofumaric acid (compound I) as a white solid (32 g), yield 91% and purity 99%.
LC-MS：[M+1] + It was 405.8.
1H-NMR(DMSO)δ：δ8.90(1H，dd，J＝1.2，4.8Hz)、δ8.57(1H，d，J＝2.1Hz)、7.88(1H，m)、7.78(1H，s)、7.61(1H，dd，J＝4.9，8.1Hz)、7.51(1H，m)、7.22(2H，m)、7.10(1H，m)、6.56(1H，d，J＝1.6Hz)、6.54(2H，s)、4.04(2H，s)、3.88(1H，m)、4.45(1H，m)、4.35(1H，m)、3.00(1H，m)、2.79(1H，m)。
Although the invention has been described in detail hereinabove by way of general description, specific embodiments and experiments, it will be apparent to those skilled in the art that modifications and improvements can be made thereto without departing from the scope of the invention. Accordingly, it is intended that all such modifications and alterations be included within the scope of this invention as defined in the appended claims.
Claims (10)
1. Process for the preparation of compound I, characterized in that said compound I is prepared according to the following reaction scheme:
wherein compound I is chemically known as 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -N-propanediol methylamine monofumaric acid, compound II is chemically known as ethyl 5- (2-fluorophenyl) -1H-pyrrole-3-carboxylate, compound III is chemically known as pyridine-3-sulfonyl chloride, compound IV is chemically known as ethyl 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-carboxylate, compound V is chemically known as 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-carboxamide, compound VI is chemically known as 5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-methylamine, compound VII is chemically known as 1- [5- (2-fluorophenyl) -1- (pyridine-3-sulfonyl) -1H-pyrrol-3-yl ] -N-propanediol methylamine;
the solvent selected in the first step reaction is one or more of acetonitrile, acetone, butanone, tetrahydrofuran, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the alkaline reagent selected in the first step is one or more of diisopropylethylamine, triethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium methoxide;
the solvent selected in the second step reaction is one or more of methanol, ethanol, isopropanol, acetonitrile, tetrahydrofuran, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the alkaline reagent selected in the second step is one or more of diisopropylethylamine, triethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium methoxide;
the reaction reagents selected in the second step of reaction comprise: one or more of ammonia water, ammonia gas, ammonium chloride and ammonium acetate;
the solvent selected in the third step is one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, isopropyl ether, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the reducing agent selected in the third step is one or more of sodium borohydride, potassium borohydride, sodium cyanoborohydride and lithium aluminum hydride;
the Lewis acid selected for the reaction in the third step is one or more of aluminum trichloride, zinc chloride, boron trifluoride and sulfuric acid;
the solvent used in the fourth step is one or more of methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, toluene, methyl tert-butyl ether, isopropyl ether, dioxane, N-dimethylformamide and N, N-dimethylacetamide;
the reaction reagent selected in the fourth step is one or more of 3-chloro-1, 2-propanediol, 3-bromo-1, 2-propanediol and 3-iodo-1, 2-propanediol;
the alkaline reagent selected in the fourth step of reaction comprises: one or more of diisopropylethylamine, triethylamine, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and sodium methoxide.
2. The preparation method of the compound I according to claim 1, wherein in the first step of the reaction for preparing the compound IV, the compound II and the compound III are put into a solvent, an alkaline reagent is added, and a catalyst DMAP is added for catalytic reaction to obtain the compound IV; preferably, the selected solvent is acetonitrile and the selected basic agent is DIFA; preferably, the catalytic reaction temperature is usually 0 to 100 ℃, further preferably 10 ℃ to 50 ℃.
3. The method for preparing the compound I according to claim 1, wherein the second step of the reaction for preparing the compound V is prepared by putting the compound IV into a solvent, adding a basic reagent, and performing urethane exchange reaction with the reaction reagent; preferably, the solvent is methanol, the alkaline reagent is sodium methoxide, and the reaction reagent is ammonia water; preferably, the urethane exchange reaction temperature is usually 0 to 100 ℃ and more preferably 10 to 50 ℃.
4. The process for preparing compound I according to claim 1, wherein compound VI is prepared by the reduction of compound V in a non-aqueous solvent with a metal reducing agent in combination with a Lewis acid. Preferably, the reduction reaction temperature is usually 0 to 150 ℃, and more preferably 10 ℃ to 80 ℃.
5. The process for preparing the compound I according to claim 1, wherein in the fourth reaction step for preparing the compound VII, the compound VI and a reaction reagent are put into a solvent, a basic reagent is added, and the condensation reaction is carried out to generate the compound VII, preferably, the solvent is methanol, the reaction reagent is 3-chloro-1, 2-propanediol, and the basic reagent is sodium hydroxide; preferably, the condensation reaction temperature is usually 0 to 100 ℃ and more preferably 10 ℃ to 50 ℃.
In the fifth step of reaction for preparing the compound I, N-dimethylacetamide is added into a compound VII, stirred and dissolved, fumaric acid is added, stirred and dissolved, ethyl acetate is added, stirred and crystallized at room temperature, filtered, and dried under reduced pressure to obtain the compound I.
6. The process for preparing compound I according to claim 1, wherein the first reaction step is: to the reaction flask were added ethyl 5- (2-fluorophenyl) -1H-pyrrole-3-carboxylate (Compound II), acetonitrile (CH) 3 CN), N-Diisopropylethylamine (DIFA) and 4-Dimethylaminopyridine (DMAP), adding pyridine-3-sulfonyl chloride (compound III) at room temperature, stirring for reaction at room temperature, adding water for quenching reaction after the reaction is finished, adjusting pH with hydrochloric acid, cooling to room temperature, stirring for crystallization, filtering, and drying under reduced pressure to obtain a compound IV;
the second step of reaction is as follows: adding a compound IV, methanol and 25% ammonia water into a reaction bottle, cooling to below 20 ℃, dropwise adding a methanol solution of 30% sodium methoxide, controlling the temperature to be below 30 ℃ in the dropwise adding process, stirring and reacting at room temperature after dropwise adding, adjusting the pH value to 6-7 by using hydrochloric acid after reaction, supplementing purified water, cooling to 0-10 ℃, stirring and crystallizing, separating out a white-like solid, filtering, and drying under reduced pressure to obtain a compound V;
the third step of reaction is as follows: adding a compound V and tetrahydrofuran into a reaction bottle under the protection of nitrogen, then adding sodium borohydride and boron trifluoride diethyl etherate in batches, heating to reflux, stirring for reaction, cooling to room temperature after the reaction is finished, adjusting the pH to 2-3 with hydrochloric acid, cooling to 0-10 ℃, stirring for crystallization overnight, filtering, stirring and pulping a filter cake with ethyl acetate at room temperature, filtering, and drying the filter cake under reduced pressure to obtain a compound VI;
the fourth reaction step is as follows: adding the compound VI, 2N sodium hydroxide solution and methanol into a reaction bottle at room temperature, adding 3-chloro-1, 2-propanediol, heating to 40-50 ℃, and stirring for reaction. After the reaction is finished, regulating the pH value by using hydrochloric acid, decompressing and concentrating to remove methanol, adding ethyl acetate and purified water for extraction, washing an organic phase by using water, decompressing and concentrating to obtain a compound VII;
the fifth step reaction is: adding N, N-dimethylacetamide into the compound VII, stirring for dissolving, adding fumaric acid, stirring for dissolving, adding ethyl acetate, stirring at room temperature for crystallizing, filtering, and drying under reduced pressure to obtain the compound I.
7. An intermediate useful in the preparation of compound I according to any one of claims 1 to 6, which is compound IV, as synthesized by the following method:
to the reaction flask were added ethyl 5- (2-fluorophenyl) -1H-pyrrole-3-carboxylate (Compound II), acetonitrile (CH) 3 CN), N-Diisopropylethylamine (DIEA) and 4-Dimethylaminopyridine (DMAP), adding pyridine-3-sulfonyl chloride (compound III) at room temperature, stirring for reaction at room temperature, adding water for quenching reaction after the reaction is finished, adjusting pH value by hydrochloric acid, cooling to room temperature, stirring for crystallization, filtering, and drying under reduced pressure to obtain a compound IV.
8. A synthetic method for preparing an intermediate as claimed in any one of claims 1 to 6, compound V, is as follows:
adding the compound IV, methanol and 25% ammonia water into a reaction bottle, cooling to below 20 ℃, dropwise adding 30% sodium methoxide methanol solution, controlling the temperature to be below 30 ℃ in the dropwise adding process, stirring at room temperature for reaction after the dropwise adding is finished, adjusting the pH value to 6-7 by hydrochloric acid after the reaction is finished, supplementing purified water, cooling to 0-10 ℃, stirring for crystallization, separating out off a white-like solid, filtering, and drying under reduced pressure to obtain the compound V.
9. A synthetic method for preparing an intermediate according to any one of claims 1 to 6, compound VI, is as follows:
adding a compound V and tetrahydrofuran into a reaction bottle under the protection of nitrogen, then adding sodium borohydride and boron trifluoride diethyl etherate in batches, heating to reflux, stirring for reaction, cooling to room temperature after the reaction is finished, adjusting the pH to 2-3 with hydrochloric acid, cooling to 0-10 ℃, stirring for crystallization overnight, filtering, stirring and pulping a filter cake with ethyl acetate at room temperature, filtering, and drying the filter cake under reduced pressure to obtain a compound VI.
10. Compound I, prepared by the process of any one of claims 1 to 6.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115772110A (en) * | 2022-12-19 | 2023-03-10 | 沈阳药科大学 | Method for preparing potassium ion competitive retarder non-surazan intermediate |
| CN116003383A (en) * | 2022-12-30 | 2023-04-25 | 山东铂源药业股份有限公司 | Preparation method of voronoi |
| CN116514774A (en) * | 2023-04-28 | 2023-08-01 | 湖南赛隆药业(长沙)有限公司 | Crystal form of minoprazan fumarate and preparation method thereof |
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| CN102212040A (en) * | 2010-04-07 | 2011-10-12 | 上海奥博生物医药技术有限公司 | Novel preparation method for chiral 2-hydroxymethyl morpholine compounds |
| CN107915720A (en) * | 2016-10-08 | 2018-04-17 | 常州市第四制药厂有限公司 | The new preparation process of Wo Nuolazan |
| CN112812099A (en) * | 2021-01-19 | 2021-05-18 | 珠海赛隆药业股份有限公司 | Compound for treating peptic ulcer and preparation method and application thereof |
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| CN102212040A (en) * | 2010-04-07 | 2011-10-12 | 上海奥博生物医药技术有限公司 | Novel preparation method for chiral 2-hydroxymethyl morpholine compounds |
| CN107915720A (en) * | 2016-10-08 | 2018-04-17 | 常州市第四制药厂有限公司 | The new preparation process of Wo Nuolazan |
| CN112812099A (en) * | 2021-01-19 | 2021-05-18 | 珠海赛隆药业股份有限公司 | Compound for treating peptic ulcer and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115772110A (en) * | 2022-12-19 | 2023-03-10 | 沈阳药科大学 | Method for preparing potassium ion competitive retarder non-surazan intermediate |
| CN116003383A (en) * | 2022-12-30 | 2023-04-25 | 山东铂源药业股份有限公司 | Preparation method of voronoi |
| CN116514774A (en) * | 2023-04-28 | 2023-08-01 | 湖南赛隆药业(长沙)有限公司 | Crystal form of minoprazan fumarate and preparation method thereof |
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