CN1382120A - 制备n－(4,5－二(甲磺酰基)－2－甲基－苯甲酰基)胍、其盐酸盐的方法 - Google Patents
制备n－(4,5－二(甲磺酰基)－2－甲基－苯甲酰基)胍、其盐酸盐的方法 Download PDFInfo
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- CN1382120A CN1382120A CN00814789A CN00814789A CN1382120A CN 1382120 A CN1382120 A CN 1382120A CN 00814789 A CN00814789 A CN 00814789A CN 00814789 A CN00814789 A CN 00814789A CN 1382120 A CN1382120 A CN 1382120A
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- methyl
- guanidine
- methylsulfonyl
- hydrochloride
- benzoyl
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- 238000000034 method Methods 0.000 title claims abstract description 24
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims abstract description 9
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 58
- -1 (methylsulfonyl)-2-methyl benzoyl Chemical group 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 23
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 22
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- XNEFVTBPCXGIRX-UHFFFAOYSA-N methanesulfinic acid Chemical class CS(O)=O XNEFVTBPCXGIRX-UHFFFAOYSA-N 0.000 claims description 6
- RHDUOFVTCTUTFX-UHFFFAOYSA-N methanesulfinic acid;sodium Chemical compound [Na].CS(O)=O RHDUOFVTCTUTFX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Chemical group 0.000 claims description 2
- 229910052801 chlorine Chemical group 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 11
- 229940121988 Antiporter inhibitor Drugs 0.000 abstract description 2
- 102100030980 Sodium/hydrogen exchanger 1 Human genes 0.000 abstract description 2
- 108010093115 growth factor-activatable Na-H exchanger NHE-1 Proteins 0.000 abstract description 2
- GROMEQPXDKRRIE-UHFFFAOYSA-N n-(diaminomethylidene)-2-methyl-4,5-bis(methylsulfonyl)benzamide Chemical compound CC1=CC(S(C)(=O)=O)=C(S(C)(=O)=O)C=C1C(=O)N=C(N)N GROMEQPXDKRRIE-UHFFFAOYSA-N 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- FZOCFRPFPKJHHP-UHFFFAOYSA-N benzyl n-(diaminomethylidene)carbamate Chemical compound NC(N)=NC(=O)OCC1=CC=CC=C1 FZOCFRPFPKJHHP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
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- XRPAJCFNQPLHGZ-UHFFFAOYSA-N 2-methyl-3-methylsulfonylbenzoyl chloride Chemical compound CS(=O)(=O)C=1C(=C(C(=O)Cl)C=CC1)C XRPAJCFNQPLHGZ-UHFFFAOYSA-N 0.000 description 1
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- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RXFQOKAZLZBMTG-UHFFFAOYSA-N CC1=CC=CC=C1ClS(C)(=O)=O Chemical compound CC1=CC=CC=C1ClS(C)(=O)=O RXFQOKAZLZBMTG-UHFFFAOYSA-N 0.000 description 1
- YDOHZTBRJORLCL-UHFFFAOYSA-N CS(=O)O.CS(=O)O Chemical compound CS(=O)O.CS(=O)O YDOHZTBRJORLCL-UHFFFAOYSA-N 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LDEZUQQQONPSBM-UHFFFAOYSA-N [Ca].CS(=O)O Chemical compound [Ca].CS(=O)O LDEZUQQQONPSBM-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
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- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
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- 230000001684 chronic effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
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- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
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- 230000004761 fibrosis Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- DASFYEIAECIAPM-UHFFFAOYSA-N magnesium;methanesulfinic acid Chemical compound [Mg].CS(O)=O DASFYEIAECIAPM-UHFFFAOYSA-N 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- REZQWZBTIUHPKX-UHFFFAOYSA-N methanesulfinic acid;potassium Chemical compound [K].CS(O)=O REZQWZBTIUHPKX-UHFFFAOYSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- AJDQRQQNNLZLPM-UHFFFAOYSA-N n-(diaminomethylidene)benzamide Chemical class NC(N)=NC(=O)C1=CC=CC=C1 AJDQRQQNNLZLPM-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Cardiology (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及NHE－1选择性的Na+/H+反向转运剂抑制剂N－(4,5－二(甲磺酰基)－2－甲基苯甲酰基)胍、盐酸盐水合物,涉及它的盐酸盐水合物,和涉及其制备方法。
Description
本发明涉及N-(4，5-二(甲磺酰基)-2-甲基-苯甲酰基)胍、盐酸盐水合物和涉及制备N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐和其盐酸盐水合物的方法。N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物是NHE-1选择性的Na+/H+反向转运剂的抑制剂(antiporter inhibitor)。
磺酰基苯甲酰胍是已知的，在例如EP0758644A1中有描述。这些物质是细胞Na+/H+反向转运剂，亦即它们是抑制细胞的Na+/H+交换机制的活性成分(Duesing等人，Med.Klin.1992 87，367-384)，因此它们适用于特别是治疗因缺氧(oxygen deficiency)而发生的心律不齐症的好的抗心律失常药。
这些物质显示出好的心脏保护作用，因而特别适用于治疗心肌梗死、预防梗塞、梗塞后治疗、慢性心肌机能不全和治疗心绞痛。此外，它们能够有效地抵制各种病理性缺氧和局部缺血造成的损害，使由此引起的主要和附属病症得到治疗。这些活性成分同样很适用于预防应用。
这些物质在病理性缺氧和局部缺血方面的保护作用使得它们在外科插入术(interventions)中保护暂时供应不足的器官、在器官移植中保护被移去的器官、在成血管细胞或心脏移入(angioplasticvascular or cardiac intervention)、在神经系统的局部缺血治疗、在休克状态治疗和预防原发性高血压方面存在其它可能的应用。
这些化合物还能被用作治疗药物，治疗由细胞增生导致的疾病，如动脉硬化、糖尿病和糖尿病晚期并发症、肿瘤、纤维变性(特别是肺、肝和肾)和器官肥大和增生。而且，这些化合物适用于确定伴随有在如血红细胞、血小板或白血球中Na+/H+反向转运剂活性上升的疾病的诊断用途。
因此，这些化合物能用作人服用的药和兽药中的药物活性成分。而且，它们能用作制备其它药物活性成分的中间体。
本发明的目的是寻找有非常好的口服吸收性能的高活性化合物。
已证明N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物为非常适合和高活性的物质，其特性在于特别好的口服吸收性能。N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物因此优选以口服的形式给药。
口服给药后消化道的吸收作用能通过比较口服和静脉给药(标准化计量AUCpo/AUCiv)[AUC＝在曲线下的面积]后测得的在血浆里的所给的活性成分的浓度计算出来。鼠表现出的吸收率为98％(基于口服的放射性标记物质)。发现在狗身上该盐酸盐水合物的生物可利用率是88％～99％，在2只猴子身上为75％～96％。因为吸收率至少等于或大于测得的生物可利用率，于是也发现在这些动物种类中有非常好的吸收作用。
本发明因而涉及N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物。本发明可以看作是EP 0758644的选择发明。
因为该物质非常有前途，它的制备是非常非常重要的。制备游离的N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍碱及其类似物在上述引用的EP0758644A1中有描述。
然而，已知的合成包括大量的独立的步骤，其中一些产率不令人满意，也有环境的污染和危险的反应条件，例如同甲基硫醇反应或氧化硫醚得到砜。
因此找到制备N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、它的盐酸盐和盐酸盐水合物的改进方法也是非常重要的。
因而找到同传统的方法相比更短也更有效的Na+/H+反向转运剂的新的合成方法变体(variant)同样是本发明的目的。
本发明涉及制备苯甲酰基胍衍生物N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、式I的盐酸盐和盐酸盐水合物的方法，其中Me是甲基，其特征在于
首先，式II的起始化合物同甲亚磺酸盐(methanesulfinate)反应，在活化的芳环上发生亲核取代，在一步反应(one-stepreaction)中引入4-甲磺酰基，
其中Me是甲基，Q是氟或氯，
然后，在第二步中，式III的化合物转化成酰氯，和胍反应得到N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍，
然后，在第三步中，通过在含水HCl中发生反应，转化成式I的盐酸盐和/或它的盐酸盐水合物。
制备分子式II的起始化合物时，例如，开始是2-溴-5-氯甲苯通过卤素-金属置换和CO2处理得到4-氯-2-甲基苯甲酸(methylbenzoicacid)，然后通过4-氯-2-甲基苯甲酸同氯磺酸、亚硫酸钠和甲基碘反应得到4-氯-2-甲基-5-甲磺酰基苯甲酸，或通过在Friedel-Crafts式反应器中在Friedel-Craft催化剂存在下2-溴-5-氯甲苯同甲磺酸和亚硫酰氯反应得到4-氯-2-甲基-4-甲磺基苯基溴，然后通过高压和高温下在高压釜里的钯催化羰基化反应用羧基置换溴，得到4-氯-2-甲基-5-甲基-磺酰基苯甲酸。选择的反应条件从已公开文献中可知(文献：Houben-Weyl，Methodender Organ.Chemie[Methods of Organic Chemistry]，Georg-Thieme-Verlag，Stuttgart)。然而，也可能使用从公开文献中可知的但这里没有详细解释的其它方法来制备分子式II的化合物。
术语甲亚磺酸盐表示甲亚磺酸的碱金属盐，特别是甲亚磺酸钠或甲亚磺酸钾，或甲亚磺酸的碱土金属盐，特别是甲亚磺酸钙或甲亚磺酸镁。特别优先的是使用甲亚磺酸钠。
分子式II的化合物同甲亚磺酸盐优选甲亚磺酸钠的反应，按照与A.Ulman等.，J.Org.Chem.1989，54，4691-4692类似的方法进行。反应优选在极性溶剂下，在10～200°的反应温度下，优选50～180°，特别优选80～140°下进行。特别优选的溶剂是二甲基亚砜(DMSO)、N，N-二甲基二甲酰胺(DMF)或1-甲基-2-吡咯烷酮(NMP)，更特别优选DMF或NMP。通常过量使用甲亚磺酸盐。在上述反应条件下，唯独形成分子式III的4，5-二(甲磺酰基)-2-甲基苯甲酸。
在第二步中，分子式III的化合物的胍化反应不限于酰基氯方法，其中，例如，分子式III的化合物同亚硫酰氯反应得到酰基氯，且进一步同胍反应。从可使胍基引入的文献中可知大量的方法(例如权威的出版物，如Houben-Weyl，Methoden der organischenChemie[Methods of Organic Chemistry]，Georg-Thieme-Verlag，Stuttgart)。
对应第二步的胍化反应，特别是，分子式III的游离酸同N-(苄氧基羰基)胍，紧接着移去苄氧基羰基保护基团(简写＝Z)释放胍基，这些是可能的，如DE199 19 349所述。对于制备苄氧基羰基胍，见M.Goodman等，PCT int.Appl.WO 9852917，1998，K，Nowak，Rocz，Chem.1969，43，231-232或R.Krug和K.Nowak，Rocz，Chem，1967，41，1087-1091)。偶合以已知的Mukaiyama方法，cf.T.Mukaiyama，Angew.Chem.，Int.Ed.Engl.1979，18，707-721进行。通过催化氢化移走Z保护基可以在为了达到该目的所采用的通常的条件下进行(文献：T.W.Greene，P.G.M Wuts，Protective Groups in OrganicChemistry，第二版.，Wiley，New York 1991或P.J.Kocienski，Protecting Groups，第一版.，Georg Thieme Verlag，Stuttgart-New York，1994)。
根据本发明的第一步和第二步制备的N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍碱也能通过从文献中得知的使用非HCl的酸的方法被转化成盐。适合该目的的酸公开在EP 0785644中。
以EP0785644中描述的方法制备磺酰基苯甲酰基胍时，通过亲核卤素-硫烷基置换且氧化得到的苯硫酚醚引入在羧基对位位置上的磺酰基。
本发明的方法以单级反应步骤引入在对位位置上的磺酰基。减少了合成步骤和与之相关联的制备成本。而且，没有同甲基硫醇的反应和氧化反应，因为可能形成过酸，在大的工业规模上这些反应需要特殊的工艺安全措施。
于是有了有效的方法来制备N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐和它的盐酸盐水合物，同迄今已知的方法相比，该方法在合成步骤的数量和总产出方面有显著的提高。
即使没有更多的解释，可以设想本领域技术人员能在最宽的范围内利用上述描述。优选实施方案因此应当只看作客观描述，它绝对不以任何方式限制发明。
上述和下述所提到的所有的申请和出版物的全部公开内容通过引用的方式结合到本申请中。
上述和下述的温度数据都为℃。
实施例：
1.合成4，5-二(甲磺酰基)-2-甲基苯甲酸
6kg 4-氯-2-甲基-5-(甲基磺酰基)苯甲酸在室温下(25°)溶解到15升N，N-二甲基甲酰胺(DMF)中，紧接着温热到50°。3.6kg甲亚磺酸钠加入到溶液中。然后内部的温度被升高到120°，在该温度下搅拌2天，24小时后再加入3kg甲亚磺酸钠。冷却到25℃后，反应混合物被引入到40升水中，且加入300g活性炭和1kg硅藻土。5升冰加到滤出液中，且逐滴加入(pH＝1)3.5升浓盐酸。用2-丙醇重结晶得到3.8kg 4，5-二(甲磺酰基)-2-甲基苯甲酸；m.p.234-235℃。
2.合成N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍
2.1.合成酰氯
15升亚硫酰氯最初在40°被引入，加入50ml DMF。3.8kg4，5-二(甲磺酰基)-2-甲基苯甲酸在搅拌下缓慢地被加入，然后该混合物在沸点搅拌1小时。冷却后，去掉多余的SOCl2，剩余物同5升甲苯共馏数次，得到4，5-二(甲磺酰基)-2-甲基苯甲酰氯，它作为粗产物进一步发生反应。
2.2胍的合成
在保护气下，1.4kg钠溶解在15升沸腾的甲醇中，并用另外的10升甲醇稀释。5.9kg胍盐酸盐加到溶液中，冷却到20-22°，然后混合物被搅拌1小时。得到的氯化钠然后被过滤出，溶液被蒸发。剩余物同甲苯共馏，然后被溶解到10升DMF中。
2.3 合成N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍
如2.1所述制备的4，5-二(甲磺酰基)-2-甲基苯甲酰氯溶液，在5升DMF中，在12°下逐滴加入到如2.2所述制备的胍溶液中。反应混合物在20°搅拌5小时，然后缓慢加入45升冷水(0-5°)。沉淀晶体被过滤出，用冰水、乙腈和二乙基醚洗净。粗晶体溶解在315升热乙腈/水(20∶1)中。溶液用200g活性炭处理，过滤且冷却到0°，得到作为乙腈加合物的N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍，产率为64.8％，m.p.233-234°。
3.1 合成N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物
2.7kg N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍在60°悬浮在25升水中，加入10.6升1N的HCl溶液。加热到80°，得到透明的溶液。使该溶液缓慢冷却，结晶在50°开始，得到N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物，产率为97％，，m.p.181-188 °。
3.2 合成N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐
从3.1得到的N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物在120°、减压下被干燥到恒重，得到N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐.
3.3 合成N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐
2.7kg N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍在60°下悬浮在25升乙醇中，加入10.6升1N的HCl溶液。加热到80°，得到透明的溶液。使该溶液缓慢冷却，结晶在50°开始。得到的N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐在60°、减压下被干燥到恒重，得到N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐。
Claims (5)
1.N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、盐酸盐水合物。
2.制备N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍、式I的盐酸盐和盐酸盐水合物的方法，其中Me是甲基，其特征在于
首先，式II的起始化合物同甲亚磺酸盐发生亲核取代反应，，在一步反应中引入4-甲磺酰基，
其中Me是甲基，Q是氟或氯，
然后，在第二步中，式III的化合物转化成酰氯，并和胍反应得到N-(4，5-二(甲磺酰基)-2-甲基苯甲酰基)胍，
然后，在第三步中，通过在含水HCl中发生反应，转化成式I的盐酸盐和/或它的盐酸盐水合物。
3.根据权利要求2的方法，其特征在于在第一步中使用甲亚磺酸钠。
4.根据权利要求2或3的方法，其特征在于在第一步中使用极性溶剂。
5.根据权利要求2或3的方法，其特征在于在第一步中反应温度为80～140°。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19951418A DE19951418A1 (de) | 1999-10-26 | 1999-10-26 | Verfahren zur Herstellung von N-(4,5-Bismethansulfonyl-2-methyl-benzoyl) -guanidin, Hydrochlorid |
| DE19951418.6 | 1999-10-26 |
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| CN108602767A (zh) * | 2016-02-08 | 2018-09-28 | 默克专利股份有限公司 | N-(4,5-双甲磺酰基-2-甲基苯甲酰基)胍盐酸盐和n-(4,5-双甲磺酰基-2-甲基苯甲酰基)胍盐的结晶变体 |
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| DE10023405A1 (de) * | 2000-05-12 | 2001-11-15 | Merck Patent Gmbh | Verfahren zur Herstellung von Sulfonyl-benzoylguanidinum-Salzen |
| US7629493B2 (en) * | 2003-05-06 | 2009-12-08 | Merck Patent Gmbh | Process for the crystallisation of guandinium salts |
| AU2009243749B2 (en) | 2008-05-09 | 2013-11-21 | Merck Patent Gmbh | Pharmaceutical composition comprising rimeporide for treating diseases associated with insulin resistance and beta-cell dysfunction |
| JOP20200296A1 (ar) * | 2013-06-10 | 2017-06-16 | Amgen Inc | عمليات صنع وأشكال بلورية من mdm2 مثبط |
| JP6562221B2 (ja) * | 2014-06-23 | 2019-08-21 | 日産化学株式会社 | スルホニル結合を有するシラン化合物の製造方法 |
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| JPS59216865A (ja) * | 1983-05-26 | 1984-12-06 | Mitsui Toatsu Chem Inc | システイン塩酸塩水和物の乾燥方法 |
| DE3929582A1 (de) * | 1989-09-06 | 1991-03-07 | Hoechst Ag | Benzoylguanidine, verfahren zu ihrer herstellung, ihre verwendung als medikament sowie sie enthaltendes medikament |
| EP0589336B1 (de) * | 1992-09-22 | 1997-01-08 | Hoechst Aktiengesellschaft | Benzoylguanidine, Verfahren zu ihrer Herstellung, sowie ihre Verwendung als Antiarrhythmika |
| EP0604852A1 (de) * | 1992-12-28 | 1994-07-06 | Hoechst Aktiengesellschaft | 2,4-Substituierte 5-(N-substituierte-Sulfamoyl)-Benzoylguanidine, als Antiarrythmika, Inhibitoren der Proliferationen von Zellen, und Inhibitoren des Natrium-Protonen-Antiporters |
| JPH07206857A (ja) * | 1993-12-28 | 1995-08-08 | Synthelabo Sa | アルフゾシン塩酸塩の二水和物 |
| JP3755908B2 (ja) * | 1994-08-17 | 2006-03-15 | 塩野義製薬株式会社 | セファロスポリン化合物の晶析法 |
| ATE185557T1 (de) * | 1995-01-30 | 1999-10-15 | Hoechst Ag | Basisch-substituierte benzoylguanidine, verfahren zu ihrer herstellung, ihre verwendung als medikament oder diagnostikum sowie sie enthaltendes medikament |
| DE19502895A1 (de) * | 1995-01-31 | 1996-08-01 | Merck Patent Gmbh | 4-Mercapto-benzoylguanidin-Derivate |
| DE19529612A1 (de) * | 1995-08-11 | 1997-02-13 | Merck Patent Gmbh | Sulfonyl- oder Sulfinyl-benzoylguanidin-Derivate |
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| CN108602767A (zh) * | 2016-02-08 | 2018-09-28 | 默克专利股份有限公司 | N-(4,5-双甲磺酰基-2-甲基苯甲酰基)胍盐酸盐和n-(4,5-双甲磺酰基-2-甲基苯甲酰基)胍盐的结晶变体 |
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