CN115385845A - 一种吡咯磺酸类化合物盐型制备 - Google Patents
一种吡咯磺酸类化合物盐型制备 Download PDFInfo
- Publication number
- CN115385845A CN115385845A CN202211060475.0A CN202211060475A CN115385845A CN 115385845 A CN115385845 A CN 115385845A CN 202211060475 A CN202211060475 A CN 202211060475A CN 115385845 A CN115385845 A CN 115385845A
- Authority
- CN
- China
- Prior art keywords
- acid
- fluorophenyl
- methylamine
- organic
- benzenesulfonyl chloride
- 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
- -1 pyrrole sulfonic acid compound salt Chemical class 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims description 6
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims abstract description 28
- 150000007524 organic acids Chemical class 0.000 claims abstract description 10
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 206010063655 Erosive oesophagitis Diseases 0.000 claims abstract 2
- 241000590002 Helicobacter pylori Species 0.000 claims abstract 2
- 208000007107 Stomach Ulcer Diseases 0.000 claims abstract 2
- 208000000718 duodenal ulcer Diseases 0.000 claims abstract 2
- 230000008029 eradication Effects 0.000 claims abstract 2
- 201000005917 gastric ulcer Diseases 0.000 claims abstract 2
- 229940037467 helicobacter pylori Drugs 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 11
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-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
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 229940116298 l- malic acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 206010020601 Hyperchlorhydria Diseases 0.000 claims 1
- 239000012065 filter cake Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000967 suction filtration Methods 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 210000004211 gastric acid Anatomy 0.000 abstract description 4
- 235000005985 organic acids Nutrition 0.000 abstract description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 abstract 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 25
- 239000002253 acid Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 7
- 229940126409 proton pump inhibitor Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 108091006112 ATPases Proteins 0.000 description 3
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000612 proton pump inhibitor Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000002860 competitive effect Effects 0.000 description 2
- 208000010643 digestive system disease Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 201000000052 gastrinoma Diseases 0.000 description 2
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 208000011906 peptic ulcer disease Diseases 0.000 description 2
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 2
- LECZXZOBEZITCL-UHFFFAOYSA-N revaprazan Chemical compound C1CC2=CC=CC=C2C(C)N1C(C(=C(C)N=1)C)=NC=1NC1=CC=C(F)C=C1 LECZXZOBEZITCL-UHFFFAOYSA-N 0.000 description 2
- 229950000859 revaprazan Drugs 0.000 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 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 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
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 230000009858 acid secretion Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960004157 rabeprazole Drugs 0.000 description 1
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 229950003825 vonoprazan Drugs 0.000 description 1
- 238000005406 washing Methods 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
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
- C07C55/07—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/10—Succinic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
- C07C59/08—Lactic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Abstract
本发明提供了一种1‑(5‑(2‑氟苯基)‑1‑3‑(3‑甲氧丙氧基)苯磺酰氯)‑1H‑吡咯‑3‑基)‑N‑甲基胺盐型,包括有机酸盐或无机酸盐。本发明主要对各种有机酸和无机酸进行筛选,得到纯度更高、稳定性更好的1‑(5‑(2‑氟苯基)‑1‑3‑(3‑甲氧丙氧基)苯磺酰氯)‑1H‑吡咯‑3‑基)‑N‑甲基胺盐酸盐和1‑(5‑(2‑氟苯基)‑1‑3‑(3‑甲氧丙氧基)苯磺酰氯)‑1H‑吡咯‑3‑基)‑N‑甲基胺富马酸盐,可用于治疗糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺杆菌根除适应症,并治疗由于胃酸过多而引起的相关疾病。
Description
技术领域
本发明属于化合物领域,具体的涉及1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺盐型及其制备方法。
背景技术
胃酸相关性疾病是消化系统疾病中最为常见的一类疾病,是指一类由于胃酸分泌过多,或对胃酸特别敏感而引起的一类消化道疾病的总称,常见的有胃食管反流病,消化性溃疡、卓-艾综合征及非甾体类抗炎药物引起的消化系统疾病。
自1988年以来,以奥美拉唑为代表的质子泵抑制剂通过抑制胃酸分泌以治疗消化性溃疡、反流性食管炎和卓-艾综合症等在临床上得到广泛应用。长期的临床应用发现,现有质子泵抑制剂在药代动力学、药效学方面还有局限性。如:给药时间对药效的影响;夜间酸突破起效慢;酸性条件下不稳定(需要配制成肠制剂);对CYP450酶的依赖性(导致个体差异显著)等。
PPI是目前抑酸作用最强的一类药物,如奥美拉唑、兰索拉唑、泮托拉唑、雷贝拉唑等。由于PPI存在着夜间酸反跳现象,从而影响治疗效果。钾离子竞争型酸阻滞剂(P-CAB)类药物的出现很好地解决了这一问题,通过竞争型抑制剂质子泵(H+,ATPase)中的K+而起作用,临床上可明显减少夜间酸反跳的发生,此类药物包括:TAK438、瑞伐拉赞(Revaprazan)等。
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers,P-CABs)通过直接、可逆性的过程竞争性地抑制H+/K+-ATP酶中的K+而产生作用。与传统质子泵抑制剂相比,P-CABs具有亲脂性、弱碱性、解离常数高和在低pH条件下稳定的特点。在酸性环境下,P-CABs以离子化形式与H+/K+-ATP酶结合,阻止H+运送及酸分泌到胃腔中,迅速升高胃中pH值。动物实验和临床研究表明:P-CABs具备起效迅速,在1小时内就能达到最大治疗效果;血药浓度与口服给药剂量线性相关,比较容易达到最佳抑酸效果的优势。
尽管目前已公开了一系列钾竞争性酸阻滞剂,但仍需要开发结构类型更丰富,新的可能具有更好的成药性质的化合物,经过不断努力,本发明设计具有通式所示的结构的化合物,并发现具有此类结构的化合物表现出优异的效果和作用。
发明内容
本发明目的在于,在现有的基础上,提供了一种新的胃酸分泌抑制剂,该化合物具有更好的稳定性以及生物活性。本文主要研究了该化合物的盐型,对各种有机酸和无机酸进行筛选,得到了纯度更高,稳定性更好的一种盐型。1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺盐酸盐在这一系列化合物中有着更高的纯度和稳定性,为以后的剂型研究提供了支持,从而更有效的治疗胃酸相关性疾病,满足不同的临床用药需求。
本发明的技术方案为:公布了具有下列通式的1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺有机酸盐或无机酸盐。
式中n为1或1/2,HA为有机酸或无机酸
其所述的有机酸为:草酸、丁二酸、乳酸、甲磺酸、L-苹果酸、枸橼酸。
其所述的无机酸为:硝酸、氢溴酸、磷酸、硫酸。
本发明提供上述有机酸盐或无机酸盐的制备方法,该方法包括以下步骤:
方法一(酸为液体):将1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺与有机溶剂搅拌下溶解(一般每克游离胺用4-8mL),在室温下,将相应的酸(游离胺与相应的酸的摩尔比为1:1.05)滴加到反应体系中,搅拌2小时,后将所得固体过滤,固体用有机溶剂洗2次(一般每克游离胺用5-6mL),并将得到的固体在真空烘箱中干燥(35℃)4小时,即制得相关的盐。
方法二(酸为固体):将1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺与有机溶剂混合,并在搅拌下溶解(一般每克游离胺用4-8mL),在室温下,将相应的酸(一般每克游离胺用3-5mL,游离胺与相应的酸的摩尔比为1:1.05),加到反应体系中,加热搅拌搅拌1小时,后将所得固体过滤,固体用有机溶剂洗2次(一般每克游离胺用5-6mL),并将得到的固体在真空烘箱中干燥(35℃)4小时,即制得相关盐。
具体实施方式
以下实施例用以说明本发明,但不作为对本发明的限制。
以下参考实施例中,所用仪器:
核磁共振仪:德国BRUKER 500MHZ
高效液相色谱仪:安捷伦1260
电子天平:Mettler XS105
真空烘箱:上海索谱仪器公司真空干燥箱DZF6021
恒温恒湿试验箱:
实施例1
1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺甲磺酸盐
在100mL单口瓶中,加入1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺(5.0g,11.6mmol)和乙酸乙酯(25mL),并在室温下(25℃)搅拌溶解,向反应体系中滴加甲磺酸(1.3g,13.9mml),在该温度下搅拌2h,有固体析出,将固体过滤出,并用乙酸乙酯洗(8mL*2次),将所得到固体在真空烘箱中干燥(35℃)4小时,得类白色固体2.8g,收率为45.9%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)7.60(s,1H),7.43(m,2H),7.24(m,1H),7.21(m,2H),7.05(m,2H),6.81(s,1H),6.35(s,1H),3.86(m,2H),3.70(s,2H),3.45(m,2H),3.23(s,3H),2.82(s,3H),2.38(s,3H),1.91(m,2H)。
实施例2
1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺硝酸盐在100mL单口瓶中,加入1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺(5.0g,11.6mmol)和乙酸乙酯(25mL),并在室温下(25℃)搅拌溶解,向反应体系中滴加硝酸(0.8g,13.9mmol),在该温度下搅拌2h,有固体析出,将固体过滤出,并用乙酸乙酯洗(8mL*2次),将所得到固体在真空烘箱中干燥(35℃)4小时,得类白色固体4.8g,收率为84.2%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)7.59(s,1H),7.44(m,2H),7.34(m,1H),7.28(m,2H),7.15(m,2H),6.81(s,1H),6.55(s,1H),3.84(m,2H),3.72(s,2H),3.41(m,2H),3.22(s,3H),2.38(s,3H),1.93(m,2H)。
实施例3
1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺氢溴酸盐在100mL三口瓶中,加入1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺(5.0g,11.6mmol)和甲醇(25mL),并在室温下(25℃)搅拌溶解,加入氢溴酸(3.7g,13.9mmol,30%),在该温度下搅拌2h,有固体析出,将固体过滤出,并用乙酸乙酯洗(6mL*2次),将所得到固体在真空烘箱中干燥(35℃)4小时,得到当黄色固体1.3g,收率为22%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)7.62(s,1H),7.56(m,2H),7.38(m,1H),7.35(m,2H),7.19(m,2H),6.93(s,1H),6.49(s,1H),3.96(m,2H),3.83(s,2H),3.55(m,2H),3.36(s,3H),2.30(s,3H),1.98(m,2H)。
实施例4
1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺丁二酸盐
在100mL三口瓶中,加入1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺(5.0g,11.6mmol)和甲醇(25mL),并在室温下(25℃)搅拌溶解,向反应体系加热至50℃,加入丁二酸(1.6g,13.9mmol),在该温度下搅拌2h,后将温度降至室温下(25℃),并搅拌10分钟,有固体析出,将固体过滤出,并用甲醇洗(6mL*2次),将所得到固体在真空烘箱中干燥(35℃)4小时,得到当白色固体4.1g,收率为65%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)7.68(s,1H),7.58(m,2H),7.35(m,1H),7.31(m,2H),7.16(m,2H),6.98(s,1H),6.49(s,1H),3.96(m,2H),3.80(s,2H),3.57(m,2H),3.36(s,3H),2.58(m,4H),2.30(s,3H),1.93(m,2H)。
实施例5
1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺草酸盐
在100mL三口瓶中,加入1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺(5.0g,11.6mmol)和甲醇(30mL),并在室温下(25℃)搅拌溶解,后将温度升至50℃,加入草酸(1.2g,13.9mmol),并搅拌2h,有固体析出,将固体过滤出,并用甲醇洗(10mL*2次),将所得到固体在真空烘箱中干燥(35℃)4小时,得类白色固体5.0g,产率为:83%。
1HNMR(DMSO-d6;500MHZ)δ(ppm)7.56(s,1H),7.41(m,2H),7.34(m,1H),7.28(m,2H),7.16(m,2H),6.81(s,1H),6.65(s,1H),3.84(m,2H),3.72(s,2H),3.41(m,2H),3.22(s,3H),2.38(s,3H),1.92(m,2H)。
本发明化合物的稳定性考察实验
1.影响因素实验:将其中1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺甲磺酸盐、1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺氢溴酸盐、1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺硝酸盐、1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺丁二酸盐、1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺草酸盐分别进行影响因素实验:高温(60℃)分别在第5天和第10天取样,对化合物性状进行研究(颜色、溶解度),用高效液相色谱仪检测有关物质与含量。
高湿(92.5%RH)分别在第5天和第10天取样,对化合物性状进行研究(颜色、溶解度),用高效液相色谱仪检测关物质与含量。
光照(4500lx)分别在第5天和第10天取样,对化合物性状进行研究(颜色、溶解度),用高效液相色谱仪检测关物质与含量。
表1盐型稳定性实验表
Claims (5)
2.根据权利要求1所述的1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺有机或无机酸盐,其制备方法如下:
(1)将5-(2-氟苯基)-N-甲基-1-(3-吡啶基磺酰基)-1H-吡咯-3-甲氨溶于有机溶剂中,
(2)向反应瓶中加入有机酸或无机酸,
(3)在相应的反应温度下搅拌2h,
(4)抽滤,滤饼真空干燥。
3.根据权利要求2所述的1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺有机或无机酸盐,其特征在于,制备方法中所用的有机溶剂选自乙酸乙酯、甲醇、丙酮、乙腈、四氢呋喃。
4.根据权利要求3所述的1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺有机或无机酸盐,其特征在于,制备方法中反应温度为0℃-50℃。
5.权利要求1-4任一所述的1-(5-(2-氟苯基)-1-3-(3-甲氧丙氧基)苯磺酰氯)-1H-吡咯-3-基)-N-甲基胺有机酸盐或无机酸盐在制备治疗糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺杆菌根除适应症、并治疗由于胃酸过多而引起的相关疾病的药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211060475.0A CN115385845A (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202211060475.0A CN115385845A (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
CN201610815046.8A CN107814758B (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610815046.8A Division CN107814758B (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115385845A true CN115385845A (zh) | 2022-11-25 |
Family
ID=61600995
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202211060475.0A Pending CN115385845A (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
CN201610815046.8A Active CN107814758B (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610815046.8A Active CN107814758B (zh) | 2016-09-12 | 2016-09-12 | 一种吡咯磺酸类化合物盐型制备 |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN115385845A (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116239606A (zh) * | 2021-07-09 | 2023-06-09 | 天地恒一制药股份有限公司 | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
WO2023280293A1 (zh) * | 2021-07-09 | 2023-01-12 | 天地恒一制药股份有限公司 | 一种吡咯磺酰类衍生物、及其制备方法与应用 |
WO2024027549A1 (zh) * | 2022-08-04 | 2024-02-08 | 江苏柯菲平医药股份有限公司 | 一种含有吡咯类胃酸分泌抑制剂的药物组合物及其制备方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101300229A (zh) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 作为胃酸分泌抑制剂的1-杂环基磺酰基、2-氨基甲基、5-(杂)芳基取代的1-h-吡咯衍生物 |
CN104718189A (zh) * | 2012-11-19 | 2015-06-17 | 江苏豪森药业股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN105693693A (zh) * | 2014-11-27 | 2016-06-22 | 江苏柯菲平医药股份有限公司 | 一种吡咯类胃酸分泌和抑制剂化合物盐的制备 |
WO2016119505A1 (zh) * | 2015-01-27 | 2016-08-04 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
-
2016
- 2016-09-12 CN CN202211060475.0A patent/CN115385845A/zh active Pending
- 2016-09-12 CN CN201610815046.8A patent/CN107814758B/zh active Active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101300229A (zh) * | 2005-08-30 | 2008-11-05 | 武田药品工业株式会社 | 作为胃酸分泌抑制剂的1-杂环基磺酰基、2-氨基甲基、5-(杂)芳基取代的1-h-吡咯衍生物 |
CN104718189A (zh) * | 2012-11-19 | 2015-06-17 | 江苏豪森药业股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
CN105693693A (zh) * | 2014-11-27 | 2016-06-22 | 江苏柯菲平医药股份有限公司 | 一种吡咯类胃酸分泌和抑制剂化合物盐的制备 |
WO2016119505A1 (zh) * | 2015-01-27 | 2016-08-04 | 江苏柯菲平医药股份有限公司 | 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN107814758A (zh) | 2018-03-20 |
CN107814758B (zh) | 2022-10-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6027662B2 (ja) | 前立腺癌およびアンドロゲン受容体関連病態の治療のためのアンドロゲン受容体の調節剤 | |
JP5064024B2 (ja) | イマチニブの製造方法、及び該方法により製造されたイマチニブ | |
CN108602771B (zh) | 化合物的酸加成盐 | |
JP7404561B2 (ja) | 新規な酸分泌抑制剤及びその用途 | |
CN105693693A (zh) | 一种吡咯类胃酸分泌和抑制剂化合物盐的制备 | |
CN107814758B (zh) | 一种吡咯磺酸类化合物盐型制备 | |
EP1861391B1 (en) | Methods for preparing substituted sulfoxide compounds | |
CN105130955A (zh) | 富马酸沃诺拉赞的制备方法 | |
AU2015303724A1 (en) | Quinazoline derivative | |
WO2021238007A1 (zh) | 可诱导prc2蛋白复合物核心亚基降解的双功能化合物和药物组合物及应用 | |
JPH0348680A (ja) | 抗菌剤 | |
JP2007504223A (ja) | オメプラゾール及びエソメプラゾールiiの新規な塩 | |
CN103509001B (zh) | 一种埃索美拉唑镁三水合物及其制备方法 | |
CN115322158A (zh) | 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物 | |
EP4063361A1 (en) | Crystal forms of fused ring compound, and composition thereof, preparation method therefor and application thereof | |
CN108069891B (zh) | 一类甲基甲胺盐酸盐的a晶型、制备及其应用 | |
US7326724B2 (en) | Salts of omeprazole and esomeprazole I | |
WO2010083649A1 (zh) | 双芳基脲类衍生物及用途 | |
CN107778289B (zh) | 5-(2-氟苯基)-n-甲基-1-(3-吡啶基磺酰基)-1h-吡咯-3-甲氨醋酸盐的多晶型物 | |
CN108947961B (zh) | 吲唑类衍生物及其制备方法和用途 | |
CN105440016B (zh) | 吲哚、氮杂吲哚类衍生物、其制备方法及其在医药上的应用 | |
CN107849018A (zh) | 哌嗪衍生物 | |
CN114957252B (zh) | 一种化合物及其制备方法以及药物组合物和在制备eed抑制剂中的应用 | |
CN112384506B (zh) | 吲哚啉-1-甲酰胺类化合物、其制备方法及其在医药学上的应用 | |
KR20230091056A (ko) | 1-설포닐 피롤 유도체의 신규 염, 이의 제조 방법 및 이를 포함하는 약학 조성물 |
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 | ||
CB03 | Change of inventor or designer information | ||
CB03 | Change of inventor or designer information |
Inventor after: Su Mei Inventor after: Xiong Jie Inventor before: Su Mei |