CN109867617A - 一种4-甲氧基吡咯中间体的制备方法 - Google Patents
一种4-甲氧基吡咯中间体的制备方法 Download PDFInfo
- Publication number
- CN109867617A CN109867617A CN201910265323.6A CN201910265323A CN109867617A CN 109867617 A CN109867617 A CN 109867617A CN 201910265323 A CN201910265323 A CN 201910265323A CN 109867617 A CN109867617 A CN 109867617A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- methoxypyrrole
- preparation
- iii
- 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.)
- Pending
Links
- OTODBDQJLMYYKQ-UHFFFAOYSA-N 3-methoxy-1h-pyrrole Chemical compound COC=1C=CNC=1 OTODBDQJLMYYKQ-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 230000000694 effects Effects 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 4
- WCGPCBACLBHDCI-UHFFFAOYSA-N 2,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(F)=C1 WCGPCBACLBHDCI-UHFFFAOYSA-N 0.000 claims abstract 2
- VLUWLNIMIAFOSY-UHFFFAOYSA-N 2-methylbenzenesulfinic acid Chemical compound CC1=CC=CC=C1S(O)=O VLUWLNIMIAFOSY-UHFFFAOYSA-N 0.000 claims abstract 2
- -1 compound phosphorus oxychloride Chemical class 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 238000005360 mashing Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 3
- 238000002425 crystallisation Methods 0.000 claims 3
- 230000008025 crystallization Effects 0.000 claims 3
- 230000035484 reaction time Effects 0.000 claims 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims 2
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 claims 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims 1
- 239000003377 acid catalyst Substances 0.000 claims 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 claims 1
- 150000002460 imidazoles Chemical class 0.000 claims 1
- 229910017604 nitric acid Inorganic materials 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- 239000012312 sodium hydride Substances 0.000 claims 1
- 229910000104 sodium hydride Inorganic materials 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 17
- 239000003814 drug Substances 0.000 description 15
- 230000002401 inhibitory effect Effects 0.000 description 9
- 208000025865 Ulcer Diseases 0.000 description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 201000010099 disease Diseases 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 6
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 6
- 208000007882 Gastritis Diseases 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 241000590002 Helicobacter pylori Species 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102000017927 CHRM1 Human genes 0.000 description 4
- 102000017926 CHRM2 Human genes 0.000 description 4
- 101150073075 Chrm1 gene Proteins 0.000 description 4
- 101150012960 Chrm2 gene Proteins 0.000 description 4
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 4
- 108010083204 Proton Pumps Proteins 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 4
- 230000007123 defense Effects 0.000 description 4
- 210000004211 gastric acid Anatomy 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 229940037467 helicobacter pylori Drugs 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 231100000397 ulcer Toxicity 0.000 description 4
- 230000036269 ulceration Effects 0.000 description 4
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 210000001156 gastric mucosa Anatomy 0.000 description 3
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 208000000689 peptic esophagitis Diseases 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 102100036321 5-hydroxytryptamine receptor 2A Human genes 0.000 description 2
- 101710138091 5-hydroxytryptamine receptor 2A Proteins 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 description 2
- 206010020853 Hypertonic bladder Diseases 0.000 description 2
- 241000208125 Nicotiana Species 0.000 description 2
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 2
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 208000007107 Stomach Ulcer Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 102000014384 Type C Phospholipases Human genes 0.000 description 2
- 108010079194 Type C Phospholipases Proteins 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 210000000467 autonomic pathway Anatomy 0.000 description 2
- 230000036770 blood supply Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 201000005917 gastric ulcer Diseases 0.000 description 2
- 210000001320 hippocampus Anatomy 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 208000020629 overactive bladder Diseases 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 1
- 229940116892 5 Hydroxytryptamine 2B receptor antagonist Drugs 0.000 description 1
- 102000056834 5-HT2 Serotonin Receptors Human genes 0.000 description 1
- 108091005479 5-HT2 receptors Proteins 0.000 description 1
- 102000049773 5-HT2A Serotonin Receptor Human genes 0.000 description 1
- 108010072564 5-HT2A Serotonin Receptor Proteins 0.000 description 1
- 102000006969 5-HT2B Serotonin Receptor Human genes 0.000 description 1
- 108010072584 5-HT2B Serotonin Receptor Proteins 0.000 description 1
- 102000006902 5-HT2C Serotonin Receptor Human genes 0.000 description 1
- 108010072553 5-HT2C Serotonin Receptor Proteins 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 208000020706 Autistic disease Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 206010066786 Diabetic keratopathy Diseases 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 208000004454 Hyperalgesia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- UQOFGTXDASPNLL-XHNCKOQMSA-N Muscarine Chemical compound C[C@@H]1O[C@H](C[N+](C)(C)C)C[C@H]1O UQOFGTXDASPNLL-XHNCKOQMSA-N 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 description 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002164 acetylcholinergic effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 150000007980 azole derivatives Chemical class 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 208000028683 bipolar I disease Diseases 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000009084 cardiovascular function Effects 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 description 1
- 229960002626 clarithromycin Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 208000021731 hypoalgesia Diseases 0.000 description 1
- 230000036032 hypoalgesia Effects 0.000 description 1
- 208000034783 hypoesthesia Diseases 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 230000007659 motor function Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000003551 muscarinic effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000007830 nerve conduction Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 1
- 229960004633 pirenzepine Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000037152 sensory function Effects 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 108010050939 thrombocytin Proteins 0.000 description 1
- 229940048102 triphosphoric acid Drugs 0.000 description 1
- 230000007923 virulence factor Effects 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供4‑甲氧基吡咯中间体的制备方法,包括下列步骤:(1)将式(I)化合物2,4‑二氟苯甲醛与式(II)化合物对甲苯亚磺酸在碱性溶剂及酸催化的条件下反应转化为式(III);(2)式(III)化合物在碱的存在下与化合物三氯氧磷发生反应得到式(IV)化合物;(3)式(IV)化合物在强碱作用下与式(V)化合物2‑(甲氧基亚甲基)丙二酸二甲酯反应得到式(AB03288)化合物(4‑甲氧基吡咯中间体)。该方法制备4‑甲氧基吡咯中间体原料易得,各步反应条件温和,易于纯化,操作简单,收率较高。
Description
技术领域
本发明属于化学药物合成技术领域,涉及5-(2,4-二氟苯基)-4-甲氧基-1H-吡咯-3-羧酸甲酯的制备方法。
背景技术
人体在攻击因子(例如胃酸、螺杆菌细菌胃蛋白酶、应激、酒精和烟草等)与防御因子(例如胃粘膜、碳酸氢盐、前列腺素、血液供给程度等)之间的平衡被破坏时,产生了胃肠道溃疡,胃炎和反流性食管炎,同时平衡进攻因素(例如,胃酸,胃酸杆菌,压力,酒精和烟草等)和防御因素(例如,胃粘膜,碳酸氢盐,前列腺素),血液供应的程度等)被破坏。因此,用于治疗胃肠道损伤如胃肠道溃疡,胃炎和反流性食管炎的治疗剂分为用于抑制攻击性因素的药物和用于增强防御因子的药物。作为抑制攻击因素的药物,抗酸剂,抗胆碱能药物,H;受体拮抗剂,质子泵引发剂(PPI),酸泵拮抗剂(APA)也称为可逆质子泵抑制剂,并且已知如此。例如,由于具有胃酸泵的拮抗活性。WO2006/025716公开了pyiTolo[2.3-c]吡啶衍生物,WO2007 072146公开了苯并咪唑衍生物。WO2006O36024公开了具有可逆质子泵抑制活性的吡咯衍生物。
另一方面,据报道胃肠道溃疡,胃炎和反流性食管炎甚至在没有增加胃酸分泌的情况下也会发生溃疡。因此,尽管毒性因子增加,但由于胃粘膜的病理变化导致的防御因子的减少被认为在胃溃疡的发生中起重要作用。因此,除了用于抑制攻击性因子的药物之外,用于增强防御因子的药物也用于治疗胃肠道溃疡和胃炎。作为用于增强防御因子的药物,已知附着于溃疡部位以形成物理化学膜的粘膜保护药物,以及促进药物合成和粘液分离的叮咬。另一方面,已知胃内存在的细菌幽门螺杆菌(幽门螺杆菌)会引起慢性胃炎,胃溃疡,十二指肠溃疡等,并且大量胃肠道损伤患者被感染。与幽门螺旋杆菌。
因此,这些患者必须服用抗生素,如克拉霉素,阿莫西林,甲硝唑,四环素,以及抗溃疡剂,如质子泵抑制剂或酸泵拮抗剂。因此,已经报道了各种副作用。
因此,需要开发抑制胃酸分泌的抗溃疡药物(例如,质子泵的活性)和依赖防御因子(例如,粘液分泌增加),同时具有根除活性。对幽门螺旋杆菌。
此外,还进行了可引起多种疾病的G蛋白偶联受体(GPC)的研究。
具体而言,5-羟色胺(5-HT,5-羟色胺)是胃肠道的有效因子,是血小板和中枢神经系统神经递质的调节剂,来源于色氨酸,它可以影响几乎所有的生理和行为功能,如情绪,食欲,认知,呕吐,内分泌系统功能,消化系统功能,运动功能,神经营养,感知,感觉功能,性别,睡眠和心血管功能。
像这样,5-HT参与各种功能,其原因已知是由于5-HT细胞体聚集在脑干中缝核中,5-羟色胺能系统的解剖结构具有影响所有的神经突起中枢神经系统神经系统区域,细胞膜中存在的各种5-HT受体亚型的分子多样性,以及特征性细胞学分布(Mohamrnad-Zadeh,LF;Moses,L.;Gwaltney-Brant,S。血清素:综述。J.兽医。药理学。Therap。(2008)31,187-199,Glennon,R。A。;杜卡特,M;Westkaemper,R。B.Psychopharmacology-The FourthGeneration of Progress)。根据结构,功能和药理学标准,这些5-HT受体分为7个家族(5-HT1至5-HT7),包括14个受体亚型,其中除5-HT3受体外,它是开放/关闭通道。配体,所有受体共同参与GPCR。特别是,5-HT2受体分为5-HT2A,5-HT2B和5-HT2C受体,所有这些受体通过激活磷脂酶C(PLC)增加肌醇1,4,5-三磷酸(IP3)的产生。)。
因此,最近,已知大多数用于治疗精神疾病(例如,抑郁症,躁狂抑郁症,精神分裂症,孤独症,强迫性神经症,焦虑症等)的药物通过5-羟色胺能机制起作用。。据报道,偏头痛,高血压,进食障碍和肠易激综合征(IBS)等疾病也与5-HT有关。
另一方面,乙酰胆碱是自主神经系统的神经递质,作用于中枢神经系统和周围神经系统,影响脑和肌肉系统。这种乙酰胆碱受体可分为作为离子受体的烟碱乙酰胆碱受体(nAChR)和作为代谢物受体的毒蕈碱乙酰胆碱受体(mACliR)。其中,毒蕈碱乙酰胆碱受体(mAChR)被鉴定为包括五种不同的受体亚型,每种受体亚型被称为M 1至M 5受体,并且这些也对应于GPCR。特别是。M1受体存在于海马的大脑皮层中,并且涉及自主神经,唾液腺,胃分泌等。M2受体存在于心脏,大脑皮层和海马中,并且涉及心率降低,心房收缩力降低,AV结节传导速度降低等。具体地,当暴露于乙酰胆碱达数秒时,通过与Gq型G蛋白的α亚基连接的M1毒蕈碱受体抑制皮质锥体神经元。
因此,当M1受体被激活时,存储在细胞中的钙被释放以发生由钙释放激活的钾传导,从而可以抑制锥体神经元的尖峰。通过抑制这些M1和M2受体的作用,可以预防或治疗各种疾病。具体地,作为用于抑制M1受体作用的治疗剂,用于治疗消化性溃疡如哌仑西平的治疗剂,其利用防止胃酸分泌和减少胃痉挛的作用,治疗剂用于治疗已知使用降低神经传导速度和防止触觉异常性疼痛和热痛觉减退等作用的糖尿病神经病学。作为用于抑制M2受体作用的治疗剂,已知使用抑制由M2受体引起的过敏反应的作用治疗膀胱过度活动症的治疗剂,治疗哮喘的治疗剂等。
因此,似乎毒蕈碱乙酰胆碱拮抗剂可能被开发为治疗诸如消化性溃疡,糖尿病性神经病,哮喘和膀胱过度活动症等疾病的治疗剂。因此,为了预防和治疗与5-HT和乙酰胆碱相关的疾病,有必要研究对其GPCR具有抑制作用的化合物,特别是5-HT2A,M1和M2毒蕈碱受体。
4-甲氧基吡咯衍生物或其药学上可接受的盐具有优异的抗溃疡活性(即质子泵抑制活性等)和针对幽门螺杆菌的根除活性。因此可用于预防和治疗由胃肠道溃疡,胃炎,反流性食管炎或幽门螺旋杆菌引起的胃肠道损伤。这些4-甲氧基吡咯衍生物或其药学上可接受的盐对引起疾病的GPCR具有抑制活性,例如5-HT2A,M1和M2毒蕈碱受体等,因而可以有效地发挥作用。用于预防和治疗5-HT受体或毒蕈碱乙酰胆碱受体介导的疾病。
鉴于上述情况,在制备上述4-甲氧基吡咯衍生物是,以下化合物被制备为中间体。
其中专利WO2018236153A1对该化合物采用的合成路线为:
[Reaction Scheme 1]
该路线反应步骤较长,反应总收率偏低,同时含有剧毒原料,不宜进行工业化生产。
专利WO2018221971A1对该化合物采用的的合成路线为:
该路线起始原料不易得,价格昂贵,亦无法进行规模化生产。
发明内容
鉴于现有技术的不足,本发明所要解决的技术问题是提供一种合成步骤较短,其原料易得,各步反应条件温和,易于纯化,操作简单,收率较高的4-甲氧基吡咯中间体的制备方法。
为了实现本发明的目的,本发明人通过大量试验研究,最终获得了如下技术方案:
具体实施方式
下面的实施例可以使本专业的技术人员更全面地理解本发明,但并不因此将本发明限制在所述的实施例范围之中。
1、(III)的合成:取75g(I),108g甲酰胺,3.35g樟脑磺酸,75g(II)加入到反应瓶中。氮气保护下于油浴中搅拌升温至65-70℃度搅拌16h。冷却至室温(15-30℃),加入300ml水,搅拌30min,过滤。滤饼用50ml水淋洗3次。将滤饼挖出。加入200ml甲醇,室温15-30℃搅拌30min后过滤。滤饼再加入200ml甲醇,室温15-30℃搅拌30min后过滤。滤饼干燥后,得到得117g白色粉末。收率75%。
2、(IV)的合成:取68.2g(III)、680ml无水四氢呋喃溶解、64.28g三氯氧磷加入到反应瓶中,氮气保护,冰浴降温,温度0-10℃滴加127g三乙胺,加料毕冰浴下搅拌60min。TLC检测,原料消失后处理:滴加水500ml淬灭,用MTBE萃取(200mL×3),合并有机相,用300mL饱和食盐水洗涤×2,无水硫酸钠干燥,过滤减压旋蒸除去溶剂得65g黄色半固体。加入120ml石油醚,6ml乙酸乙酯。室温15-30℃搅拌30-45min,抽滤。产品室温下吹干。得到46g淡黄色固体,收率72%。
3、AB03288的合成:取12g 60%NaH,250ml乙醚,氮气保护,冰浴降温,T=0-10℃滴加250ml乙腈溶解的46g(IV)和52.33g(V),滴加完毕升至40℃搅拌48h。反应结束后加500ml水,用100ml MTBE萃取三次,合并有机相,用300mL饱和食盐水洗涤,无水硫酸钠干燥,过滤减压旋蒸除去溶剂得油状物,加入1.5倍重量的100-200硅胶拌样制砂,4倍重量的200-300硅胶装柱,柱层析用正庚烷∶乙酸乙酯=30∶1至15∶1梯度洗脱,收集产物点,减压浓缩干后加50ml正庚烷,2ml乙酸乙酯室温15-30℃打浆1h过滤得18g黄色粉末状固体(收率45%,HPLC:99.5%)。
1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.12(td,J=9.0,6.5Hz,1H),7.31(d,J=3.8Hz,1H),6.99-6.92(m,1H),6.88(ddd,J=12.6,8.6,2.6Hz,1H),3.87(s,3H),3.85(s,3H).
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解,本发明不受上述实施例的限制,上述实施例和说明书中描述的只是说明本发明的原理,在不脱离本发明精神和范围的前提下,本发明还会有各种变化和改进,这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的的权利要求书及其等效物界定。
Claims (7)
1.一种制备4-甲氧基吡咯中间体的方法,其特征在于包括下列步骤:
(1)将式(I)化合物2,4-二氟苯甲醛与式(II)化合物对甲苯亚磺酸在碱性溶剂及酸催化的条件下反应转化为式(III):
(2)式(III)化合物在碱的存在下与化合物三氯氧磷发生反应得到式(IV)化合物:
(3)式(IV)化合物在强碱作用下与式(V)化合物2-(甲氧基亚甲基)丙二酸二甲酯反应得到式(AB03288)化合物:
所得式(AB03288)化合物为4-甲氧基吡咯中间体。
2.根据权利要求1所述4-甲氧基吡咯中间体的制备方法,其特征在于:步骤(1)的反应温度为30-80℃,反应时间为6-24小时,反应溶剂选自乙酰胺、甲酰胺、三乙胺、乙二胺中的一种;所述的酸催化剂选自樟脑磺酸、硫酸、对甲苯磺酸、硝酸、磷酸、TMSC1的一种。
3.根据权利要求1所述4-甲氧基吡咯中间体的制备方法,其特征在于:步骤(1)中化合物(III)的结晶或打浆溶剂为:正庚烷、甲醇、乙醇、异丙醇中一种或多种。温度为0-50℃。
4.根据权利要求1所述4-甲氧基吡咯中间体的制备方法,其特征在于:步骤(2)的反应温度为0-30℃,反应时间为1-4小时,反应溶剂选自二氯甲烷、甲苯、四氢呋喃中的一种;反应所用的碱选自三乙胺、乙二胺、二异丙基乙胺、咪唑中的一种。碱的用量为(III)化合物用量的2.0-6.0倍(M/M摩尔比)。三氯氧磷的用量为(III)化合物用量的1.0-4.0倍(M/M摩尔比)此处的M/M为摩尔比。
5.根据权利要求1所述4-甲氧基吡咯中间体的制备方法,其特征在于:步骤(2)中化合物(IV)的结晶或打浆溶剂为:正庚烷、乙酸乙酯、甲苯、异丙醇、甲基叔丁基醚中一种或多种。温度为0-50℃。
6.根据权利要求1所述所述4-甲氧基吡咯中间体的制备方法,其特征在于:步骤(3)的取代反应温度为0-50℃,反应时间为24-72小时,反应溶剂选自乙醚、DMF、DMSO、乙腈、DME和四氢呋喃中的一种或多种;所述的碱选自甲醇钠、氢化钠和叔丁醇钾的一种或多种,强碱的用量为(IV)化合物用量的1.5-3.0倍(M/M摩尔比)。此处的M/M为摩尔比。
7.根据权利要求1所述4-甲氧基吡咯中间体的制备方法,其特征在于:步骤(3)中化合物(III)的结晶或打浆溶剂为:正庚烷、乙酸乙酯、甲苯、甲基叔丁基醚中一种或多种。温度为0-50℃。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910265323.6A CN109867617A (zh) | 2019-04-03 | 2019-04-03 | 一种4-甲氧基吡咯中间体的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910265323.6A CN109867617A (zh) | 2019-04-03 | 2019-04-03 | 一种4-甲氧基吡咯中间体的制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN109867617A true CN109867617A (zh) | 2019-06-11 |
Family
ID=66922017
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910265323.6A Pending CN109867617A (zh) | 2019-04-03 | 2019-04-03 | 一种4-甲氧基吡咯中间体的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109867617A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022051979A1 (zh) * | 2020-09-10 | 2022-03-17 | 广东莱佛士制药技术有限公司 | 一种制备钾离子竞争性阻滞剂中间体的方法 |
CN115772110A (zh) * | 2022-12-19 | 2023-03-10 | 沈阳药科大学 | 一种制备钾离子竞争性阻滞剂非苏拉赞中间体的方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004020440A1 (en) * | 2002-08-30 | 2004-03-11 | Pfizer Products Inc. | Di and trifluoro-triazolo-pyridines anti-inflammatory compounds |
WO2009005675A1 (en) * | 2007-06-28 | 2009-01-08 | Abbott Laboratories | Novel triazolopyridazines |
WO2018236153A1 (en) * | 2017-06-21 | 2018-12-27 | Daewoong Pharmaceutical Co., Ltd. | PROCESS FOR THE PREPARATION OF INTERMEDIATE OF 4-METHOXYPYRROLE DERIVATIVE |
-
2019
- 2019-04-03 CN CN201910265323.6A patent/CN109867617A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004020440A1 (en) * | 2002-08-30 | 2004-03-11 | Pfizer Products Inc. | Di and trifluoro-triazolo-pyridines anti-inflammatory compounds |
WO2009005675A1 (en) * | 2007-06-28 | 2009-01-08 | Abbott Laboratories | Novel triazolopyridazines |
WO2018236153A1 (en) * | 2017-06-21 | 2018-12-27 | Daewoong Pharmaceutical Co., Ltd. | PROCESS FOR THE PREPARATION OF INTERMEDIATE OF 4-METHOXYPYRROLE DERIVATIVE |
Non-Patent Citations (2)
Title |
---|
FANGLI QIU等: "A Novel Synthesis of Multisubstituted Pyrroles via Trisubstituted Olefins and TosMIC Derivatives", 《LETTERS IN ORGANIC CHEMISTRY》, vol. 9, pages 305 - 308 * |
ROBERT M. BORZILLERI等: "Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo- [2, 1-f][1, 2, 4]triazine based VEGFR-2 kinase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 15, pages 1429 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022051979A1 (zh) * | 2020-09-10 | 2022-03-17 | 广东莱佛士制药技术有限公司 | 一种制备钾离子竞争性阻滞剂中间体的方法 |
CN115772110A (zh) * | 2022-12-19 | 2023-03-10 | 沈阳药科大学 | 一种制备钾离子竞争性阻滞剂非苏拉赞中间体的方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN102020651B (zh) | 6-芳基氨基吡啶酮甲酰胺mek抑制剂 | |
CN104870429B (zh) | 苯并呋喃衍生物、其制备方法及其在医药上的应用 | |
DE60315615T2 (de) | Tricyclische verbindungen basierend auf thiophen und arzneimittel, die diese umfassen | |
JP6963262B2 (ja) | 新規抗癌剤 | |
CN106573908B (zh) | 羧酸化合物及其制备方法和用途 | |
RU2683566C1 (ru) | Производное с сочлененными кольцами и способ его получения, промежуточное соединение, фармацевтическая композиция и их применение | |
AU2011274970C1 (en) | Tetrahydrocarboline derivative | |
AU2012230761A1 (en) | Opioid receptor ligands and methods of using and making same | |
CN101384593A (zh) | 用作tlr7调节剂的3-脱氮嘌呤衍生物 | |
TR201807104T4 (tr) | Sikloalkil asit türevi, bunun hazırlanış yöntemi ve farmasötik uygulaması. | |
DE3634066A1 (de) | Neue 5-alkylbenzimidazole, verfahren zu ihrer herstellung sowie arzneimittel | |
CN109867617A (zh) | 一种4-甲氧基吡咯中间体的制备方法 | |
CN105294585A (zh) | 一种治疗痛风的化合物 | |
EA031105B1 (ru) | Ингибиторы альдостеронсинтазы | |
CN101910144B (zh) | 对羟基苯丙烯酸衍生物及其应用 | |
CN104277029B (zh) | 吖啶-1,2,3-三唑类化合物及其制备方法和应用 | |
CN102307861B (zh) | 苯基咪唑化合物 | |
CN113637013A (zh) | 联芳环链接芳杂环衍生物作为免疫调节剂的制备及其应用 | |
CN111801314B (zh) | Ask1抑制剂化合物及其用途 | |
CN102260253B (zh) | 苯并[5,6]环庚基[1,2-b]吡啶衍生物、制备方法、药物组合物及其抗过敏性疾病的用途 | |
CN107162982A (zh) | 一类具有抗癌活性的咪唑类化合物及其衍生物 | |
CN115772110A (zh) | 一种制备钾离子竞争性阻滞剂非苏拉赞中间体的方法 | |
WO2019029554A1 (zh) | 磺酰胺类衍生物、其制备方法及其在医药上的用途 | |
CN107325052A (zh) | 一类具有抗癌活性的咪唑酯类化合物及其衍生物 | |
CN101265250A (zh) | 取代黄酮类化合物、其制备方法、其应用及其药物组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |